|
1
|
Lyu Y, Zhang T, Zhong W, Yi S, Zhu L. Exposure to Sodium p-Perfluorous Nonenoxybenzenesulfonate Induces Renal Fibrosis in Mice by Disrupting Lysine Metabolism. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2025; 59:7461-7473. [PMID: 40116701 DOI: 10.1021/acs.est.4c10724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/23/2025]
Abstract
Environmental exposure is one driving factor of chronic kidney disease (CKD), yet the intrinsic molecular mechanisms are largely unexplored. As a persistent chemical, perfluorooctanesulfonate (PFOS) is regulated due to a great potential to induce multiple diseases, including renal fibrosis, a major pathological characteristic of CKD. It is hypothesized that sodium p-perfluorous nonenoxybenzenesulfonate (OBS), a typical alternative to PFOS, may also induce renal fibrosis. We observed distinct renal fibrosis in mice exposed to OBS. Metabolomics analysis showed that Nα-acetyllysine was the primary metabolite biomarker, whose level decreased greatly due to its excessive consumption by lysyloxidase (LOX). This suppressed the miR-140-5p expression, promoting upregulation of fibroblast growth factor 9 (FGF9), which activated the PI3K/Akt signaling pathway through fibroblast growth factor receptor 3 (FGFR3), thereby enhancing proliferation and activation of fibroblasts. Supplement of Nα-acetyllysine upregulated miR-140-5p expression, reduced expressions of FGF9 and FGFR3, and eventually ameliorated OBS-induced renal fibrosis. Similarly, treatment with miR-140-5p agomir and PI3K/Akt signaling pathway inhibitor LY294002 attenuated OBS-induced renal fibrosis. Taken together, OBS caused renal fibrosis through the LOX-Nα-acetyllysine-miR-140-5p-FGF9-FGFR3-PI3K/Akt-Bad-Bcl-2-fibroblast axis. The results of this study reveal a specific molecular axis for OBS to induce renal fibrosis and call for concerns in supervising the application of OBS.
Collapse
Affiliation(s)
- Yang Lyu
- Key Laboratory of Pollution Processes and Environmental Criteria of Ministry of Education, Tianjin Key Laboratory of Environmental Remediation and Pollution Control, College of Environmental Science and Engineering of Nankai University, Tianjin 300350, China
| | - Tianxu Zhang
- Key Laboratory of Pollution Processes and Environmental Criteria of Ministry of Education, Tianjin Key Laboratory of Environmental Remediation and Pollution Control, College of Environmental Science and Engineering of Nankai University, Tianjin 300350, China
| | - Wenjue Zhong
- Key Laboratory of Pollution Processes and Environmental Criteria of Ministry of Education, Tianjin Key Laboratory of Environmental Remediation and Pollution Control, College of Environmental Science and Engineering of Nankai University, Tianjin 300350, China
| | - Shujun Yi
- Key Laboratory of Pollution Processes and Environmental Criteria of Ministry of Education, Tianjin Key Laboratory of Environmental Remediation and Pollution Control, College of Environmental Science and Engineering of Nankai University, Tianjin 300350, China
| | - Lingyan Zhu
- Key Laboratory of Pollution Processes and Environmental Criteria of Ministry of Education, Tianjin Key Laboratory of Environmental Remediation and Pollution Control, College of Environmental Science and Engineering of Nankai University, Tianjin 300350, China
| |
Collapse
|
|
2
|
Hassan FU, Safdar M, Younus M, Arain MA. Regulation of energy metabolism by non-coding RNAs in livestock species: a review. J Comp Physiol B 2025; 195:1-12. [PMID: 39638953 DOI: 10.1007/s00360-024-01596-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 10/17/2024] [Accepted: 10/29/2024] [Indexed: 12/07/2024]
Abstract
The optimisation of livestock production relies on efficient energy metabolism. This review focused on elaborate regulatory processes governed by non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs). It explores the complex energy metabolism processes in livestock, elucidating the functions of ncRNAs in the expression of genes and pathways. miRNAs have been identified as significant regulators of glycolysis and glucose metabolism, whereas lncRNAs are known to affect adipogenesis and mitochondrial activity. Moreover, circRNAs have a substantial influence on the regulation of energy. In addition, this is not only enriching non-coding RNA-mediated energy control but also sheds light on possible applications. It is derived from its ability to condense complex molecular systems, thereby offering crucial insights to researchers. Through a comprehensive analysis of the intricate relationship between ncRNAs and energy metabolism, the information of this review provides a valuable framework for the implementation of focused interventions that hold the potential to significantly enhance the efficiency of livestock production.
Collapse
Affiliation(s)
- Faiz-Ul Hassan
- Department of Breeding and Genetics, Cholistan University of Veterinary and Animal Sciences, Bahawalpur, 63000, Pakistan.
| | - Muhammad Safdar
- Department of Breeding and Genetics, Cholistan University of Veterinary and Animal Sciences, Bahawalpur, 63000, Pakistan
| | - Muhammad Younus
- Department of Zoology, Cholistan University of Veterinary and Animal Sciences, Bahawalpur, 63000, Pakistan
| | - Muhammad Asif Arain
- Faculty of Veterinary and Animal Sciences, Water and Marine Sciences, Lasbela University of Agriculture, Uthal, 90150, Balochistan, Pakistan
| |
Collapse
|
|
3
|
Li JN, Wang MY, Ruan JW, Lyu YJ, Weng YH, Brindangnanam P, Coumar MS, Chen PS. A transcription-independent role for HIF-1α in modulating microprocessor assembly. Nucleic Acids Res 2024; 52:11806-11821. [PMID: 39319577 PMCID: PMC11514450 DOI: 10.1093/nar/gkae792] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 08/22/2024] [Accepted: 08/31/2024] [Indexed: 09/26/2024] Open
Abstract
Microprocessor is an essential nuclear complex responsible for the initial RNase-mediated cleavage of primary miRNA, which is a tightly controlled maturation process that requires the proper assembly of Drosha and DGCR8. Unlike previously identified mechanisms directly targeting the enzymatic subunit Drosha, current knowledge about the biological ways of controlling miRNA nuclear maturation through DGCR8 is less addressed. In this study, we unveiled that the microprocessor assembly is governed by a master gene regulator HIF-1α irrespective of its canonical transcriptional activity. First, a widespread protein binding of HIF-1α with DGCR8 instead of Drosha was observed in response to biological stimulations. Similar protein interactions between their corresponding orthologues in model organisms were also observed. After dissecting the essential protein domains, we noticed that HIF-1α suppresses microprocessor assembly via binding to DGCR8. Furthermore, our results showed that HIF-1α hijacks monomeric DGCR8 thus reducing its dimer formation prior to microprocessor assembly, and consequently, the suppressed microprocessor formation and nuclear processing of primary miRNA were demonstrated. In conclusion, here we unveiled the mechanism of how microprocessor assembly is regulated by HIF-1α, which not only demonstrates a non-transcriptional function of nuclear HIF-1α but also provides new molecular insights into the regulation of microprocessor assembly through DGCR8.
Collapse
Affiliation(s)
- Jie-Ning Li
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Breast Medical Center, National Cheng Kung University Hospital, Tainan, Taiwan
- Research Center for Medical Laboratory Biotechnology, National Cheng Kung University, Tainan, Taiwan
| | - Ming-Yang Wang
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
- Department of Surgical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan
| | - Jhen-Wei Ruan
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Research Center for Medical Laboratory Biotechnology, National Cheng Kung University, Tainan, Taiwan
| | - Yu-Jhen Lyu
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
| | - Yi-Hsiu Weng
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Research Center for Medical Laboratory Biotechnology, National Cheng Kung University, Tainan, Taiwan
| | - Pownraj Brindangnanam
- Department of Bioinformatics, School of Life Sciences, Pondicherry University, Kalapet, Pondicherry 605014, India
| | - Mohane Selvaraj Coumar
- Department of Bioinformatics, School of Life Sciences, Pondicherry University, Kalapet, Pondicherry 605014, India
| | - Pai-Sheng Chen
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Breast Medical Center, National Cheng Kung University Hospital, Tainan, Taiwan
- Research Center for Medical Laboratory Biotechnology, National Cheng Kung University, Tainan, Taiwan
| |
Collapse
|
|
4
|
Yuan M, Cao Z, Li Q, Liu R, Wang J, Xue W, Lyu Q. Fasting-induced miR-7a-5p in AgRP neurons regulates food intake. Metabolism 2024; 158:155959. [PMID: 38942170 DOI: 10.1016/j.metabol.2024.155959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Revised: 06/21/2024] [Accepted: 06/23/2024] [Indexed: 06/30/2024]
Abstract
OBJECTIVE The molecular control of feeding after fasting is essential for maintaining energy homeostasis, while overfeeding usually leads to obesity. Identifying non-coding microRNAs (miRNAs) that control food intake could reveal new oligonucleotide-based therapeutic targets for treating obesity and its associated diseases. This study aims to identify a miRNA modulating food intake and its mechanism in neuronal regulation of food intake and energy homeostasis. METHODS A comprehensive genome-wide miRNA screening in the arcuate nucleus of the hypothalamus (ARC) of fasted mice and ad libitum mice was performed. Through stereotactic virus injections, intracerebroventricular injections, and miRNA sponge technology, miR-7a-5p was inhibited specifically in AgRP neurons and the central nervous system, and metabolic phenotypes were monitored. Quantitative real-time PCR, Western blotting, immunofluorescence, whole-cell patch-clamp recording, and luciferase reporter assay were used to investigate the mechanisms underlying miR-7a-5p's regulation of food intake. RESULTS We found a significant increase in miR-7a-5p levels after fasting. miR-7a-5p was highly expressed in the ARC, and inhibition of miR-7a-5p specifically in AgRP neurons reduced food intake and body weight gain. miR-7a-5p inhibited S6K1 gene expression by binding to its 3'-UTR. Furthermore, the knockdown of ribosomal S6 kinase 1 (S6K1) in AgRP neurons can partially reverse the effects caused by miR-7a-5p inhibition. Importantly, intracerebroventricular administration of the miR-7a-5p inhibitor could also reduce food intake and body weight gain. CONCLUSION Our findings suggest that miR-7a-5p responds to energy deficit and regulates food intake by fine-tuning mTOR1/S6K1 signaling in the AgRP neurons, which could be a promising oligonucleotide-based therapeutic target for treating obesity and its associated diseases.
Collapse
Affiliation(s)
- Mingyang Yuan
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China; Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, SJTUSM, Shanghai, China
| | - Zhiwen Cao
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China; Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, SJTUSM, Shanghai, China
| | - Qian Li
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China; Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, SJTUSM, Shanghai, China
| | - Ruixin Liu
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China; Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, SJTUSM, Shanghai, China
| | - Jiqiu Wang
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China; Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, SJTUSM, Shanghai, China.
| | - Wenzhi Xue
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China; Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, SJTUSM, Shanghai, China; Clinical Neuroscience Center, Ruijin Hospital Luwan Branch, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China.
| | - Qianqian Lyu
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China; Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, SJTUSM, Shanghai, China.
| |
Collapse
|
|
5
|
Hou A, Xu X, Zhang Y, He H, Feng Y, Fan W, Tan R, Gong L, Chen J. Excessive fatty acids activate PRMT5/MDM2/Drosha pathway to regulate miRNA biogenesis and lipid metabolism. Liver Int 2024; 44:1634-1650. [PMID: 38517158 DOI: 10.1111/liv.15906] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 02/26/2024] [Accepted: 03/07/2024] [Indexed: 03/23/2024]
Abstract
BACKGROUND Excessive fatty acids in the liver lead to the accumulation of lipotoxic lipids and then cellular stress to further evoke the related disease, like non-alcoholic fatty liver disease (NAFLD). As reported, fatty acid stimulation can cause some specific miRNA dysregulation, which caused us to investigate the relationship between miRNA biogenesis and fatty acid overload. METHODS Gene expression omnibus (GEO) dataset analysis, miRNA-seq, miRNA cleavage assay, RT-qPCR, western blotting, immunofluorescence and co-immunoprecipitation (co-IP) were used to reveal the change of miRNAs under pathological status and explore the relevant mechanism. High fat, high fructose, high cholesterol (HFHFrHC) diet-fed mice transfected with AAV2/8-shDrosha or AAV2/8-shPRMT5 were established to investigate the in vivo effects of Drosha or PRMT5 on NAFLD phenotype. RESULTS We discovered that the cleavage of miRNAs was inhibited by analysing miRNA contents and detecting some representative pri-miRNAs in multiple mouse and cell models, which was further verified by the reduction of the Microprocessor activity in the presence of palmitic acid (PA). In vitro, PA could induce Drosha, the core RNase III in the Microprocessor complex, degrading through the proteasome-mediated pathway, while in vivo, knockdown of Drosha significantly promoted NAFLD to develop to a more serious stage. Mechanistically, our results demonstrated that PA can increase the methyltransferase activity of PRMT5 to degrade Drosha through MDM2, a ubiquitin E3 ligase for Drosha. The above results indicated that PRMT5 may be a critical regulator in lipid metabolism during NAFLD, which was confirmed by the knocking down of PRMT5 improved aberrant lipid metabolism in vitro and in vivo. CONCLUSIONS We first demonstrated the relationship between miRNA dosage and NAFLD and proved that PA can activate the PRMT5-MDM2-Drosha signalling pathway to regulate miRNA biogenesis.
Collapse
Affiliation(s)
- Aijun Hou
- Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
- School of Pharmacy, University of Chinese Academy of Sciences, Beijing, China
| | - Xiaoding Xu
- Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yu Zhang
- Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
- School of Pharmacy, University of Chinese Academy of Sciences, Beijing, China
| | - Hongxiu He
- Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yihan Feng
- Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, China
| | - Wenhui Fan
- Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
| | - Rongrong Tan
- Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Likun Gong
- Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
- School of Pharmacy, University of Chinese Academy of Sciences, Beijing, China
| | - Jing Chen
- Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
- School of Pharmacy, University of Chinese Academy of Sciences, Beijing, China
| |
Collapse
|
|
6
|
Sanz-Ros J, Mas-Bargues C, Romero-García N, Huete-Acevedo J, Dromant M, Borrás C. MicroRNA biogenesis pathway alterations in aging. EXTRACELLULAR VESICLES AND CIRCULATING NUCLEIC ACIDS 2023; 4:486-501. [PMID: 39698023 PMCID: PMC11648461 DOI: 10.20517/evcna.2023.29] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 08/01/2023] [Accepted: 08/15/2023] [Indexed: 12/20/2024]
Abstract
Aging is characterized by genomic instability and dysregulation of gene expression. MicroRNAs (miRNAs) are small non-coding RNAs that play a crucial role in post-transcriptional gene regulation. This work explores the impact of dysregulated miRNA biogenesis on the aging process. During aging, alterations in the transcription of primary miRNAs (pri-miRNAs) occur due to genomic changes, DNA damage, and epigenetic modifications. The microprocessor complex, comprising DGCR8 and Drosha proteins, is vital for pri-miRNA processing. Age-related changes in this complex affect miRNA biogenesis and miRNA expression profiles, linking these alterations with age-related conditions. Conversely, interventions like caloric restriction and mTOR inhibition enhance microprocessor activity, suggesting a connection between microprocessor function, aging-related pathways, and lifespan extension. Exportin-5 mediates the transport of pre-miRNAs from the nucleus to the cytoplasm. Although the role of miRNA export in aging is not well understood, accelerated export of pre-miRNAs is observed in response to DNA damage, and nucleocytoplasmic transport has been linked to cellular senescence. Dicer is responsible for processing pre-miRNAs into mature miRNAs. Reduced Dicer expression during aging is reported in various organisms and tissues and is associated with premature aging phenotypes. Conversely, the upregulation of Dicer improves stress resistance and metabolic adaptations induced by caloric restriction and exercise training. Understanding the role of miRNA biogenesis disruption in aging provides insights into the molecular mechanisms of aging and age-related diseases. Targeting this pathway may hold promise for therapeutic strategies and contribute to healthy aging.
Collapse
Affiliation(s)
- Jorge Sanz-Ros
- Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia, Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable-Instituto de Salud Carlos III (CIBERFES-ISCIII), INCLIVA, Valencia 46010, Spain
- Department of Cardiology, Hospital Universitari i Politècnic La Fe, Valencia 46026, Spain
| | - Cristina Mas-Bargues
- Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia, Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable-Instituto de Salud Carlos III (CIBERFES-ISCIII), INCLIVA, Valencia 46010, Spain
| | - Nekane Romero-García
- Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia, Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable-Instituto de Salud Carlos III (CIBERFES-ISCIII), INCLIVA, Valencia 46010, Spain
- Department of Anesthesiology and Surgical Trauma Intensive Care, Hospital Clinic Universitari de Valencia, University of Valencia, Valencia 46010, Spain
| | - Javier Huete-Acevedo
- Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia, Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable-Instituto de Salud Carlos III (CIBERFES-ISCIII), INCLIVA, Valencia 46010, Spain
| | - Mar Dromant
- Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia, Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable-Instituto de Salud Carlos III (CIBERFES-ISCIII), INCLIVA, Valencia 46010, Spain
| | - Consuelo Borrás
- Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia, Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable-Instituto de Salud Carlos III (CIBERFES-ISCIII), INCLIVA, Valencia 46010, Spain
| |
Collapse
|
|
7
|
Metaxakis A, Pavlidis M, Tavernarakis N. Neuronal atg1 Coordinates Autophagy Induction and Physiological Adaptations to Balance mTORC1 Signalling. Cells 2023; 12:2024. [PMID: 37626835 PMCID: PMC10453232 DOI: 10.3390/cells12162024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 08/04/2023] [Accepted: 08/05/2023] [Indexed: 08/27/2023] Open
Abstract
The mTORC1 nutrient-sensing pathway integrates metabolic and endocrine signals into the brain to evoke physiological responses to food deprivation, such as autophagy. Nevertheless, the impact of neuronal mTORC1 activity on neuronal circuits and organismal metabolism remains obscure. Here, we show that mTORC1 inhibition acutely perturbs serotonergic neurotransmission via proteostatic alterations evoked by the autophagy inducer atg1. Neuronal ATG1 alters the intracellular localization of the serotonin transporter, which increases the extracellular serotonin and stimulates the 5HTR7 postsynaptic receptor. 5HTR7 enhances food-searching behaviour and ecdysone-induced catabolism in Drosophila. Along similar lines, the pharmacological inhibition of mTORC1 in zebrafish also stimulates food-searching behaviour via serotonergic activity. These effects occur in parallel with neuronal autophagy induction, irrespective of the autophagic activity and the protein synthesis reduction. In addition, ectopic neuronal atg1 expression enhances catabolism via insulin pathway downregulation, impedes peptidergic secretion, and activates non-cell autonomous cAMP/PKA. The above exert diverse systemic effects on organismal metabolism, development, melanisation, and longevity. We conclude that neuronal atg1 aligns neuronal autophagy induction with distinct physiological modulations, to orchestrate a coordinated physiological response against reduced mTORC1 activity.
Collapse
Affiliation(s)
- Athanasios Metaxakis
- Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology Hellas, Nikolaou Plastira 100, 70013 Heraklion, Crete, Greece
| | - Michail Pavlidis
- Department of Biology, University of Crete, 71409 Heraklion, Crete, Greece;
| | - Nektarios Tavernarakis
- Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology Hellas, Nikolaou Plastira 100, 70013 Heraklion, Crete, Greece
- Department of Basic Sciences, Faculty of Medicine, University of Crete, 71110 Heraklion, Crete, Greece
| |
Collapse
|
|
8
|
Li Y, Carey TS, Feng CH, Zhu HM, Sun XX, Dai MS. The Ubiquitin-specific Protease USP36 Associates with the Microprocessor Complex and Regulates miRNA Biogenesis by SUMOylating DGCR8. CANCER RESEARCH COMMUNICATIONS 2023; 3:459-470. [PMID: 36950067 PMCID: PMC10026737 DOI: 10.1158/2767-9764.crc-22-0344] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 01/19/2023] [Accepted: 02/13/2023] [Indexed: 02/18/2023]
Abstract
miRNA biogenesis is a cellular process that produces mature miRNAs from their primary transcripts, pri-miRNAs, via two RNAse III enzyme complexes: the Drosha-DGCR8 microprocessor complex in the nucleus and the Dicer-TRBP complex in the cytoplasm. Emerging evidence suggests that miRNA biogenesis is tightly regulated by posttranscriptional and posttranslational modifications and aberrant miRNA biogenesis is associated with various human diseases including cancer. DGCR8 has been shown to be modified by SUMOylation. Yet, the SUMO ligase mediating DGCR8 SUMOylation is currently unknown. Here, we report that USP36, a nucleolar ubiquitin-specific protease essential for ribosome biogenesis, is a novel regulator of DGCR8. USP36 interacts with the microprocessor complex and promotes DGCR8 SUMOylation, specifically modified by SUMO2. USP36-mediated SUMOylation does not affect the levels of DGCR8 and the formation of the Drosha-DGCR8 complex, but promotes the binding of DGCR8 to pri-miRNAs. Consistently, abolishing DGCR8 SUMOylation significantly attenuates its binding to pri-miRNAs and knockdown of USP36 attenuates pri-miRNA processing, resulting in marked reduction of tested mature miRNAs. Induced expression of a SUMOylation-defective mutant of DGCR8 inhibits cell proliferation. Together, these results suggest that USP36 plays an important role in regulating miRNA biogenesis by SUMOylating DGCR8. Significance This study identifies that USP36 mediates DGCR8 SUMOylation by SUMO2 and is critical for miRNA biogenesis. As USP36 is frequently overexpressed in various human cancers, our study suggests that deregulated USP36-miRNA biogenesis pathway may contribute to tumorigenesis.
Collapse
Affiliation(s)
- Yanping Li
- Department of Molecular and Medical Genetics, School of Medicine, Oregon Health & Science University, Portland, Oregon
| | - Timothy S. Carey
- Department of Molecular and Medical Genetics, School of Medicine, Oregon Health & Science University, Portland, Oregon
| | - Catherine H. Feng
- Department of Molecular and Medical Genetics, School of Medicine, Oregon Health & Science University, Portland, Oregon
| | - Hong-Ming Zhu
- Department of Molecular and Medical Genetics, School of Medicine, Oregon Health & Science University, Portland, Oregon
| | - Xiao-Xin Sun
- Department of Molecular and Medical Genetics, School of Medicine, Oregon Health & Science University, Portland, Oregon
| | - Mu-Shui Dai
- Department of Molecular and Medical Genetics, School of Medicine, Oregon Health & Science University, Portland, Oregon
| |
Collapse
|
|
9
|
Li X, Jin DS, Eadara S, Caterina MJ, Meffert MK. Regulation by noncoding RNAs of local translation, injury responses, and pain in the peripheral nervous system. NEUROBIOLOGY OF PAIN (CAMBRIDGE, MASS.) 2023; 13:100119. [PMID: 36798094 PMCID: PMC9926024 DOI: 10.1016/j.ynpai.2023.100119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 01/17/2023] [Accepted: 01/21/2023] [Indexed: 06/18/2023]
Abstract
Neuropathic pain is a chronic condition arising from damage to somatosensory pathways that results in pathological hypersensitivity. Persistent pain can be viewed as a consequence of maladaptive plasticity which, like most enduring forms of cellular plasticity, requires altered expression of specific gene programs. Control of gene expression at the level of protein synthesis is broadly utilized to directly modulate changes in activity and responsiveness in nociceptive pathways and provides an effective mechanism for compartmentalized regulation of the proteome in peripheral nerves through local translation. Levels of noncoding RNAs (ncRNAs) are commonly impacted by peripheral nerve injury leading to persistent pain. NcRNAs exert spatiotemporal regulation of local proteomes and affect signaling cascades supporting altered sensory responses that contribute to hyperalgesia. This review discusses ncRNAs found in the peripheral nervous system (PNS) that are dysregulated following nerve injury and the current understanding of their roles in pathophysiological pain-related responses including neuroimmune interactions, neuronal survival and axon regeneration, Schwann cell dedifferentiation and proliferation, intercellular communication, and the generation of ectopic action potentials in primary afferents. We review progress in the field beyond cataloging, with a focus on the relevant target transcripts and mechanisms underlying pain modulation by ncRNAs.
Collapse
Affiliation(s)
- Xinbei Li
- Department of Biological Chemistry, Johns Hopkins University School of Medicine, United States
| | - Daniel S. Jin
- Department of Biological Chemistry, Johns Hopkins University School of Medicine, United States
| | - Sreenivas Eadara
- Department of Biological Chemistry, Johns Hopkins University School of Medicine, United States
| | - Michael J. Caterina
- Department of Biological Chemistry, Johns Hopkins University School of Medicine, United States
- Department of Neurosurgery and Neurosurgery Pain Research Institute, Johns Hopkins University School of Medicine, United States
- Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, United States
| | - Mollie K. Meffert
- Department of Biological Chemistry, Johns Hopkins University School of Medicine, United States
- Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, United States
| |
Collapse
|
|
10
|
Yamamura J, Ma S, Jia H, Kato H. Activating transcription factor 4-dependent hsa-miR-663a transcription mediates mTORC1/p70S6K1 signaling underleucine deprivation. Front Nutr 2022; 9:965771. [PMID: 35990342 PMCID: PMC9389164 DOI: 10.3389/fnut.2022.965771] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Accepted: 07/15/2022] [Indexed: 11/15/2022] Open
Abstract
The mechanistic target of rapamycin complex 1 (mTORC1) is involved in nutrient-induced signaling and is a master regulator of cell growth and metabolism. Amino acid-deficient conditions affect mTORC1 activity; however, its upstream regulators warrant further investigation. MicroRNAs are key regulators of nutrient-related responses; therefore, the present study aimed to assess the leucine starvation-induced microRNA profile and its impact on mTORC1 activity. Transcriptome analysis of human hepatocellular carcinoma cells (HepG2) under leucine deprivation revealed that hsa-miR-663a and hsa-miR-1469 were altered in a transcription factor 4-dependent manner. Overexpression of these microRNAs induced phosphorylation of the ribosomal protein S6 kinase beta-1, a mTORC1 downstream target. Furthermore, hsa-miR-663a downregulated proline-rich Akt1 substrate of 40 kDa (PRAS40), one of the mTORC1 components. In summary, this study provides new insights into the regulatory role of microRNAs in amino acid metabolism and demonstrates alterations in microRNA profile under leucine deprivation in human hepatocytes.
Collapse
Affiliation(s)
- Junki Yamamura
- Health Nutrition, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Sihui Ma
- Health Nutrition, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Huijuan Jia
- Health Nutrition, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Hisanori Kato
- Health Nutrition, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| |
Collapse
|
|
11
|
Li HL, Deng NH, He XS, Li YH. Small biomarkers with massive impacts: PI3K/AKT/mTOR signalling and microRNA crosstalk regulate nasopharyngeal carcinoma. Biomark Res 2022; 10:52. [PMID: 35883139 PMCID: PMC9327212 DOI: 10.1186/s40364-022-00397-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Accepted: 07/06/2022] [Indexed: 12/15/2022] Open
Abstract
Nasopharyngeal carcinoma (NPC) is one of the most common malignant tumours of the head and neck in Southeast Asia and southern China. The Phosphatidylinositol 3-kinase/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signalling pathway is involved in processes related to tumour initiation/progression, such as proliferation, apoptosis, metastasis, and drug resistance, and is closely related to the clinicopathological features of NPC. In addition, key genes involved in the PI3K/AKT/mTOR signalling pathway undergo many changes in NPC. More interestingly, a growing body of evidence suggests an interaction between this signalling pathway and microRNAs (miRNAs), a class of small noncoding RNAs. Therefore, in this review, we discuss the interactions between key components of the PI3K/AKT/mTOR signalling pathway and various miRNAs and their importance in NPC pathology and explore potential diagnostic biomarkers and therapeutic targets.
Collapse
Affiliation(s)
- Hai-Long Li
- Key Laboratory of Cancer Cellular and Molecular Pathology in Hunan Province, Cancer Research Institute of Medical College, Hengyang Medical School, University of South China, 421001, Hengyang, Hunan, P.R. China
| | - Nian-Hua Deng
- Key Lab for Arteriosclerology of Hunan Province, International Joint Laboratory for Arteriosclerotic Disease Research of Hunan Province, Institute of Cardiovascular Disease, Hengyang Medical School, University of South China, 421001, Hengyang, Hunan, P.R. China
| | - Xiu-Sheng He
- Key Laboratory of Cancer Cellular and Molecular Pathology in Hunan Province, Cancer Research Institute of Medical College, Hengyang Medical School, University of South China, 421001, Hengyang, Hunan, P.R. China.
| | - Yue-Hua Li
- Department of Medical Oncology, The First Affiliated Hospital, Hengyang Medical School, University of South China, 421001, Hengyang, P.R. China.
| |
Collapse
|
|
12
|
Lv Y, Lv Y, Wang Z, Yuan K, Zeng Y. Noncoding RNAs as sensors of tumor microenvironmental stress. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2022; 41:224. [PMID: 35842651 PMCID: PMC9288030 DOI: 10.1186/s13046-022-02433-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Accepted: 07/06/2022] [Indexed: 12/19/2022]
Abstract
The tumor microenvironment (TME) has been demonstrated to modulate the biological behavior of tumors intensively. Multiple stress conditions are widely observed in the TME of many cancer types, such as hypoxia, inflammation, and nutrient deprivation. Recently, accumulating evidence demonstrates that the expression levels of noncoding RNAs (ncRNAs) are dramatically altered by TME stress, and the dysregulated ncRNAs can in turn regulate tumor cell proliferation, metastasis, and drug resistance. In this review, we elaborate on the signal transduction pathways or epigenetic pathways by which hypoxia-inducible factors (HIFs), inflammatory factors, and nutrient deprivation in TME regulate ncRNAs, and highlight the pivotal roles of TME stress-related ncRNAs in tumors. This helps to clarify the molecular regulatory networks between TME and ncRNAs, which may provide potential targets for cancer therapy.
Collapse
Affiliation(s)
- Yue Lv
- Department of Liver Surgery & Liver Transplantation, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
| | - Yinghao Lv
- Department of Liver Surgery & Liver Transplantation, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
| | - Zhen Wang
- Department of Liver Surgery & Liver Transplantation, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China.,Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Kefei Yuan
- Department of Liver Surgery & Liver Transplantation, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China. .,Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China.
| | - Yong Zeng
- Department of Liver Surgery & Liver Transplantation, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China. .,Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China.
| |
Collapse
|
|
13
|
Zeng C, Hu J, Chen F, Huang T, Zhang L. The Coordination of mTOR Signaling and Non-Coding RNA in Regulating Epileptic Neuroinflammation. Front Immunol 2022; 13:924642. [PMID: 35898503 PMCID: PMC9310657 DOI: 10.3389/fimmu.2022.924642] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 06/16/2022] [Indexed: 11/13/2022] Open
Abstract
Epilepsy accounts for a significant proportion of the burden of neurological disorders. Neuroinflammation acting as the inflammatory response to epileptic seizures is characterized by aberrant regulation of inflammatory cells and molecules, and has been regarded as a key process in epilepsy where mTOR signaling serves as a pivotal modulator. Meanwhile, accumulating evidence has revealed that non-coding RNAs (ncRNAs) interfering with mTOR signaling are involved in neuroinflammation and therefore articipate in the development and progression of epilepsy. In this review, we highlight recent advances in the regulation of mTOR on neuroinflammatory cells and mediators, and feature the progresses of the interaction between ncRNAs and mTOR in epileptic neuroinflammation.
Collapse
Affiliation(s)
- Chudai Zeng
- Departments of Neurosurgery, and National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Jason Hu
- Department of Neonatology, Yale School of Medicine, New Haven, CT, United States
| | - Fenghua Chen
- Departments of Neurosurgery, and National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Fenghua Chen, ; Tianxiang Huang, ; Longbo Zhang,
| | - Tianxiang Huang
- Departments of Neurosurgery, and National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Fenghua Chen, ; Tianxiang Huang, ; Longbo Zhang,
| | - Longbo Zhang
- Departments of Neurosurgery, and National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- Department of Neurosurgery, Yale School of Medicine, New Haven, CT, United States
- *Correspondence: Fenghua Chen, ; Tianxiang Huang, ; Longbo Zhang,
| |
Collapse
|
|
14
|
Hebbar S, Panzade G, Vashisht AA, Wohlschlegel JA, Veksler-Lublinsky I, Zinovyeva AY. Functional identification of microRNA-centered complexes in C. elegans. Sci Rep 2022; 12:7133. [PMID: 35504914 PMCID: PMC9065084 DOI: 10.1038/s41598-022-10771-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 04/08/2022] [Indexed: 02/02/2023] Open
Abstract
microRNAs (miRNAs) are crucial for normal development and physiology. To identify factors that might coordinate with miRNAs to regulate gene expression, we used 2'O-methylated oligonucleotides to precipitate Caenorhabditis elegans let-7, miR-58, and miR-2 miRNAs and the associated proteins. A total of 211 proteins were identified through mass-spectrometry analysis of miRNA co-precipitates, which included previously identified interactors of key miRNA pathway components. Gene ontology analysis of the identified interactors revealed an enrichment for RNA binding proteins, suggesting that we captured proteins that may be involved in mRNA lifecycle. To determine which miRNA interactors are important for miRNA activity, we used RNAi to deplete putative miRNA co-factors in animals with compromised miRNA activity and looked for alterations of the miRNA mutant phenotypes. Depletion of 25 of 39 tested genes modified the miRNA mutant phenotypes in three sensitized backgrounds. Modulators of miRNA phenotypes ranged from RNA binding proteins RBD-1 and CEY-1 to metabolic factors such as DLST-1 and ECH-5, among others. The observed functional interactions suggest widespread coordination of these proteins with miRNAs to ultimately regulate gene expression. This study provides a foundation for future investigations aimed at deciphering the molecular mechanisms of miRNA-mediated gene regulation.
Collapse
Affiliation(s)
- Shilpa Hebbar
- Division of Biology, Kansas State University, Manhattan, 66506, USA
| | - Ganesh Panzade
- Division of Biology, Kansas State University, Manhattan, 66506, USA
| | - Ajay A Vashisht
- Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, 90095, USA
- Genomics Institute of the Novartis Research Foundation, San Diego, 92121, USA
| | - James A Wohlschlegel
- Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, 90095, USA
| | - Isana Veksler-Lublinsky
- Department of Software and Information Systems Engineering, Ben-Gurion University of the Negev, 8410501, Beer-Sheva, Israel
| | - Anna Y Zinovyeva
- Division of Biology, Kansas State University, Manhattan, 66506, USA.
| |
Collapse
|
|
15
|
Mekala JR, Kurappalli RK, Ramalingam P, Moparthi NR. N-acetyl l-aspartate and Triacetin modulate tumor suppressor MicroRNA and class I and II HDAC gene expression induce apoptosis in Glioblastoma cancer cells in vitro. Life Sci 2021; 286:120024. [PMID: 34626605 DOI: 10.1016/j.lfs.2021.120024] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 09/27/2021] [Accepted: 09/30/2021] [Indexed: 02/07/2023]
Abstract
Glioblastoma multiforme (GBM), grade IV glioma and is aggressive, malignant primary brain cancer. Altered expression and activity of epigenetic proteins such as histone deacetylases (HDACs) are involved in GBM metastasis. Also, acetates are important to brain metabolites that regulate cell proliferation and apoptosis. Here, we have examined the effect of the acetates on the cell-cycle. U87MG cancer cells treated with N-acetyl l-aspartate (NAA) and sodium acetate have exhibited G1 phase cell-cycle arrest whereas U87MG cells treated with Triacetin (TA), and potassium acetate has induced G2/M cell cycle arrest. We have observed inhibition of histone deacetylase (HDAC) mRNA levels in acetate treated U87MG cells. Interestingly, acetates-treated U87MG cells have shown a significant reduction in the mRNA level of class II HDACs than class I HDACs. Acetate treated cells have exhibited an enhanced expression of various microRNAs such as miR-15b, miR-92, miR-101, miR-155, miR-199, miR-200, miR-223, miR-16, and miR-17 that are involved in the inhibition of cancer cell proliferation, invasion, migration, and angiogenesis. Further, these acetate molecules regulate genes involved in mammalian target of rapamycin complex 2 (mTORC2) such as mammalian stress-activated protein kinase-interacting protein (mSIN1), protein observed with Rictor 2 (Protor 2), and protein kinase C α (PKCα). The present study reveals the possible involvement of the mTORC2 complex during acetate-mediated HDAC inhibition, as well as microRNA modulation. Furthermore, molecular modeling studies were employed to understand the binding mode of these acetate molecules to mTOR, Rapamycin-insensitive companion of mammalian target of rapamycin (Rictor), and HDAC-8 proteins. Thus in this study, we have identified the pivotal role of acetates in the modulation of mTOR complex, epigenetic genes and provide structural as well as functional insights that will help in future drug discovery against GBM cancer therapy.
Collapse
Affiliation(s)
- Janaki Ramaiah Mekala
- Functional Genomics and Disease Biology Laboratory, School of Chemical and Biotechnology, SASTRA Deemed University, Thanjavur 613401, Tamil Nadu, India; Department of Biotechnology, Koneru Lakshmaiah Education Foundation, Green Fields, Vaddeswaram, Guntur, Andhra Pradesh, India.
| | - Rohil Kumar Kurappalli
- Functional Genomics and Disease Biology Laboratory, School of Chemical and Biotechnology, SASTRA Deemed University, Thanjavur 613401, Tamil Nadu, India
| | - PrasannaSrinivasan Ramalingam
- Functional Genomics and Disease Biology Laboratory, School of Chemical and Biotechnology, SASTRA Deemed University, Thanjavur 613401, Tamil Nadu, India
| | - Nageswara Rao Moparthi
- Department of Computer Science and Engineering, Koneru Lakshmaiah Education Foundation, Green Fields, Vaddeswaram, Guntur, Andhra Pradesh, India
| |
Collapse
|
|
16
|
Akbarzadeh M, Mihanfar A, Akbarzadeh S, Yousefi B, Majidinia M. Crosstalk between miRNA and PI3K/AKT/mTOR signaling pathway in cancer. Life Sci 2021; 285:119984. [PMID: 34592229 DOI: 10.1016/j.lfs.2021.119984] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 09/09/2021] [Accepted: 09/19/2021] [Indexed: 01/07/2023]
Abstract
Phosphoinositide-3 kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway is one of the most important proliferative signaling pathways with critical undeniable function in various aspects of cancer initiation/progression, including proliferation, apoptosis, metastasis, angiogenesis, and drug resistance. On the other hand, numerous genetic alterations in the key genes involved in the PI3K/AKT/mTOR signaling pathway have been identified in multiple solid and hematological tumors. In addition, accumulating recent evidences have demonstrated a reciprocal interaction between this signaling pathway and microRNAs, a large group of small non-coding RNAs. Therefore, in this review, it was attempted to discuss about the interaction between key components of PI3K/AKT/mTOR signaling pathway with various miRNAs and their importance in cancer biology.
Collapse
Affiliation(s)
- Maryam Akbarzadeh
- Department of biochemistry, Urmia University of Medical Sciences, Urmia, Iran
| | - Ainaz Mihanfar
- Department of biochemistry, Urmia University of Medical Sciences, Urmia, Iran
| | - Shabnam Akbarzadeh
- Department of Physical Education and Sport Medicine, University of Tabriz, Tabriz, Iran
| | - Bahman Yousefi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Majidinia
- Solid Tumor Research Center, Urmia University of Medical Sciences, Urmia, Iran.
| |
Collapse
|
|
17
|
Mahmoud MM, Sanad EF, Hamdy NM. MicroRNAs' role in the environment-related non-communicable diseases and link to multidrug resistance, regulation, or alteration. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2021; 28:36984-37000. [PMID: 34046834 DOI: 10.1007/s11356-021-14550-w] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 05/19/2021] [Indexed: 05/28/2023]
Abstract
The discovery of microRNAs (miRNAs) 20 years ago has advocated a new era of "small molecular genetics." About 2000 miRNAs are present that regulate one third of the genome. MiRNA dysregulated expression arising as a response to our environment insult or stress or changes may contribute to several diseases, namely non-communicable diseases, including tumor growth. Their presence in body fluids, reflecting level alteration in various cancers, merit circulating miRNAs as the "next-generation biomarkers" for early-stage tumor diagnosis and/or prognosis. Herein, we performed a comprehensive literature search focusing on the origin, biosynthesis, and role of miRNAs and summarized the foremost studies centering on miR value as non-invasive biomarkers in different environment-related non-communicable diseases, including various cancer types. Moreover, during chemotherapy, many miRNAs were linked to multidrug resistance, via modulating numerous, environment triggered or not, biological processes and/or pathways that will be highlighted as well.
Collapse
Affiliation(s)
- Marwa M Mahmoud
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, 11566, Abassia, Cairo, Egypt
| | - Eman F Sanad
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, 11566, Abassia, Cairo, Egypt
| | - Nadia M Hamdy
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, 11566, Abassia, Cairo, Egypt.
| |
Collapse
|
|
18
|
Monaghan TM, Seekatz AM, Markham NO, Yau TO, Hatziapostolou M, Jilani T, Christodoulou N, Roach B, Birli E, Pomenya O, Louie T, Lacy DB, Kim P, Lee C, Kao D, Polytarchou C. Fecal Microbiota Transplantation for Recurrent Clostridioides difficile Infection Associates With Functional Alterations in Circulating microRNAs. Gastroenterology 2021; 161:255-270.e4. [PMID: 33844988 PMCID: PMC8579492 DOI: 10.1053/j.gastro.2021.03.050] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Revised: 03/20/2021] [Accepted: 03/23/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS The molecular mechanisms underlying successful fecal microbiota transplantation (FMT) for recurrent Clostridioides difficile infection (rCDI) remain poorly understood. The primary objective of this study was to characterize alterations in microRNAs (miRs) following FMT for rCDI. METHODS Sera from 2 prospective multicenter randomized controlled trials were analyzed for miRNA levels with the use of the Nanostring nCounter platform and quantitative reverse-transcription (RT) polymerase chain reaction (PCR). In addition, rCDI-FMT and toxin-treated animals and ex vivo human colonoids were used to compare intestinal tissue and circulating miRs. miR inflammatory gene targets in colonic epithelial and peripheral blood mononuclear cells were evaluated by quantitative PCR (qPCR) and 3'UTR reporter assays. Colonic epithelial cells were used for mechanistic, cytoskeleton, cell growth, and apoptosis studies. RESULTS miRNA profiling revealed up-regulation of 64 circulating miRs 4 and 12 weeks after FMT compared with screening, of which the top 6 were validated in the discovery cohort by means of RT-qPCR. In a murine model of relapsing-CDI, RT-qPCR analyses of sera and cecal RNA extracts demonstrated suppression of these miRs, an effect reversed by FMT. In mouse colon and human colonoids, C difficile toxin B (TcdB) mediated the suppressive effects of CDI on miRs. CDI dysregulated DROSHA, an effect reversed by FMT. Correlation analyses, qPCR ,and 3'UTR reporter assays revealed that miR-23a, miR-150, miR-26b, and miR-28 target directly the 3'UTRs of IL12B, IL18, FGF21, and TNFRSF9, respectively. miR-23a and miR-150 demonstrated cytoprotective effects against TcdB. CONCLUSIONS These results provide novel and provocative evidence that modulation of the gut microbiome via FMT induces alterations in circulating and intestinal tissue miRs. These findings contribute to a greater understanding of the molecular mechanisms underlying FMT and identify new potential targets for therapeutic intervention in rCDI.
Collapse
Affiliation(s)
- Tanya M Monaghan
- National Institute for Health Research Nottingham Biomedical Research Centre, University of Nottingham, Nottingham, United Kingdom; Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, United Kingdom.
| | - Anna M Seekatz
- Department of Biological Sciences, Clemson University, Clemson, South Carolina, USA
| | - Nicholas O Markham
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA; Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Tung On Yau
- Department of Biosciences, John van Geest Cancer Research Centre, Centre for Health Aging and Understanding Disease, School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom
| | - Maria Hatziapostolou
- Department of Biosciences, John van Geest Cancer Research Centre, Centre for Health Aging and Understanding Disease, School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom
| | - Tahseen Jilani
- Advanced Data Analysis Centre, School of Computer Science, University of Nottingham, Nottingham, United Kingdom
| | - Niki Christodoulou
- Department of Biosciences, John van Geest Cancer Research Centre, Centre for Health Aging and Understanding Disease, School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom
| | - Brandi Roach
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Eleni Birli
- Department of Biosciences, John van Geest Cancer Research Centre, Centre for Health Aging and Understanding Disease, School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom
| | - Odette Pomenya
- Department of Biosciences, John van Geest Cancer Research Centre, Centre for Health Aging and Understanding Disease, School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom
| | - Thomas Louie
- Department of Microbiology and infectious Diseases, University of Calgary, Calgary, Alberta, Canada
| | - D Borden Lacy
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA; Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee, USA
| | - Peter Kim
- Department of Mathematics and Statistics, University of Guelph, Ontario, Canada
| | - Christine Lee
- Vancouver Island Health Authority, Victoria, British Columbia, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Dina Kao
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
| | - Christos Polytarchou
- Department of Biosciences, John van Geest Cancer Research Centre, Centre for Health Aging and Understanding Disease, School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom.
| |
Collapse
|
|
19
|
Pacheco JM, Canal MV, Pereyra CM, Welchen E, Martínez-Noël GMA, Estevez JM. The tip of the iceberg: emerging roles of TORC1, and its regulatory functions in plant cells. JOURNAL OF EXPERIMENTAL BOTANY 2021; 72:4085-4101. [PMID: 33462577 DOI: 10.1093/jxb/eraa603] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 12/19/2020] [Indexed: 06/12/2023]
Abstract
Target of Rapamycin (TOR) is an evolutionarily conserved protein kinase that plays a central role in coordinating cell growth with light availability, the diurnal cycle, energy availability, and hormonal pathways. TOR Complex 1 (TORC1) controls cell proliferation, growth, metabolism, and defense in plants. Sugar availability is the main signal for activation of TOR in plants, as it also is in mammals and yeast. Specific regulators of the TOR kinase pathway in plants are inorganic compounds in the form of major nutrients in the soils, and light inputs via their impact on autotrophic metabolism. The lack of TOR is embryo-lethal in plants, whilst dysregulation of TOR signaling causes major alterations in growth and development. TOR exerts control as a regulator of protein translation via the action of proteins such as S6K, RPS6, and TAP46. Phytohormones are central players in the downstream systemic physiological TOR effects. TOR has recently been attributed to have roles in the control of DNA methylation, in the abundance of mRNA splicing variants, and in the variety of regulatory lncRNAs and miRNAs. In this review, we summarize recent discoveries in the plant TOR signaling pathway in the context of our current knowledge of mammalian and yeast cells, and highlight the most important gaps in our understanding of plants that need to be addressed in the future.
Collapse
Affiliation(s)
| | - María Victoria Canal
- Instituto de Agrobiotecnología del Litoral (CONICET-UNL), Cátedra de Biología Celular y Molecular, Facultad de Bioquímica y Ciencias Biológicas,, Universidad Nacional del Litoral, Santa Fe, Argentina
| | - Cintia M Pereyra
- Instituto de Investigaciones en Biodiversidad y Biotecnología (INBIOTEC-CONICET) and Fundación para Investigaciones Biológicas Aplicadas (FIBA), Vieytes, Mar Del Plata, Argentina
| | - Elina Welchen
- Instituto de Agrobiotecnología del Litoral (CONICET-UNL), Cátedra de Biología Celular y Molecular, Facultad de Bioquímica y Ciencias Biológicas,, Universidad Nacional del Litoral, Santa Fe, Argentina
| | - Giselle M A Martínez-Noël
- Instituto de Investigaciones en Biodiversidad y Biotecnología (INBIOTEC-CONICET) and Fundación para Investigaciones Biológicas Aplicadas (FIBA), Vieytes, Mar Del Plata, Argentina
| | - José M Estevez
- Fundación Instituto Leloir and IIBBA-CONICET, Buenos Aires CP, Argentina
- Centro de Biotecnología Vegetal (CBV), Facultad de Ciencias de la Vida (FCsV), Universidad Andres Bello, Santiago, Chile and Millennium Institute for Integrative Biology (iBio), Santiago, Chile
| |
Collapse
|
|
20
|
Huang X, Dong YL, Li T, Xiong W, Zhang X, Wang PJ, Huang JQ. Dietary Selenium Regulates microRNAs in Metabolic Disease: Recent Progress. Nutrients 2021; 13:1527. [PMID: 34062793 PMCID: PMC8147315 DOI: 10.3390/nu13051527] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 04/24/2021] [Accepted: 04/27/2021] [Indexed: 02/01/2023] Open
Abstract
Selenium (Se) is an essential element for the maintenance of a healthy physiological state. However, due to environmental and dietary factors and the narrow safety range of Se, diseases caused by Se deficiency or excess have gained considerable traction in recent years. In particular, links have been identified between low Se status, cognitive decline, immune disorders, and increased mortality, whereas excess Se increases metabolic risk. Considerable evidence has suggested microRNAs (miRNAs) regulate interactions between the environment (including the diet) and genes, and play important roles in several diseases, including cancer. MiRNAs target messenger RNAs to induce changes in proteins including selenoprotein expression, ultimately generating disease. While a plethora of data exists on the epigenetic regulation of other dietary factors, nutrient Se epigenetics and especially miRNA regulated mechanisms remain unclear. Thus, this review mainly focuses on Se metabolism, pathogenic mechanisms, and miRNAs as key regulatory factors in Se-related diseases. Finally, we attempt to clarify the regulatory mechanisms underpinning Se, miRNAs, selenoproteins, and Se-related diseases.
Collapse
Affiliation(s)
- Xin Huang
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Department of Nutrition and Health, China Agricultural University, Beijing 100083, China; (X.H.); (Y.-L.D.); (T.L.); (W.X.); (X.Z.); (P.-J.W.)
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, Ministry of Education, China Agricultural University, Beijing 100083, China
| | - Yu-Lan Dong
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Department of Nutrition and Health, China Agricultural University, Beijing 100083, China; (X.H.); (Y.-L.D.); (T.L.); (W.X.); (X.Z.); (P.-J.W.)
- College of Veterinary Medicine, China Agricultural University, Beijing 100083, China
| | - Tong Li
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Department of Nutrition and Health, China Agricultural University, Beijing 100083, China; (X.H.); (Y.-L.D.); (T.L.); (W.X.); (X.Z.); (P.-J.W.)
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, Ministry of Education, China Agricultural University, Beijing 100083, China
| | - Wei Xiong
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Department of Nutrition and Health, China Agricultural University, Beijing 100083, China; (X.H.); (Y.-L.D.); (T.L.); (W.X.); (X.Z.); (P.-J.W.)
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, Ministry of Education, China Agricultural University, Beijing 100083, China
| | - Xu Zhang
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Department of Nutrition and Health, China Agricultural University, Beijing 100083, China; (X.H.); (Y.-L.D.); (T.L.); (W.X.); (X.Z.); (P.-J.W.)
| | - Peng-Jie Wang
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Department of Nutrition and Health, China Agricultural University, Beijing 100083, China; (X.H.); (Y.-L.D.); (T.L.); (W.X.); (X.Z.); (P.-J.W.)
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, Ministry of Education, China Agricultural University, Beijing 100083, China
| | - Jia-Qiang Huang
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Department of Nutrition and Health, China Agricultural University, Beijing 100083, China; (X.H.); (Y.-L.D.); (T.L.); (W.X.); (X.Z.); (P.-J.W.)
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, Ministry of Education, China Agricultural University, Beijing 100083, China
| |
Collapse
|
|
21
|
De D, Mukherjee I, Guha S, Paidi RK, Chakrabarti S, Biswas SC, Bhattacharyya SN. Rheb-mTOR activation rescues Aβ-induced cognitive impairment and memory function by restoring miR-146 activity in glial cells. MOLECULAR THERAPY. NUCLEIC ACIDS 2021; 24:868-887. [PMID: 34094708 PMCID: PMC8141608 DOI: 10.1016/j.omtn.2021.04.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Accepted: 04/09/2021] [Indexed: 12/22/2022]
Abstract
Deposition of amyloid beta plaques in adult rat or human brain is associated with increased production of proinflammatory cytokines by associated glial cells that are responsible for degeneration of the diseased tissue. The expression of these cytokines is usually under check and is controlled at the post-transcriptional level via several microRNAs. Computational analysis of gene expression profiles of cortical regions of Alzheimer’s disease patients’ brain suggests ineffective target cytokine mRNA suppression by existing micro-ribonucleoproteins (miRNPs) in diseased brain. Exploring the mechanism of amyloid beta-induced cytokine expression, we have identified how the inactivation of the repressive miR-146 miRNPs causes increased production of cytokines in amyloid beta-exposed glial cells. In exploration of the cause of miRNP inactivation, we have noted amyloid beta oligomer-induced sequestration of the mTORC1 complex to early endosomes that results in decreased Ago2 phosphorylation, limited Ago2-miRNA uncoupling, and retarded Ago2-cytokine mRNA interaction in rat astrocytes. Interestingly, constitutive activation of mTORC1 by Rheb activator restricts proinflammatory cytokine production by reactivating miR-146 miRNPs in amyloid beta-exposed glial cells to rescue the disease phenotype in the in vivo rat model of Alzheimer’s disease.
Collapse
Affiliation(s)
- Dipayan De
- RNA Biology Research Laboratory, Molecular Genetics Division, CSIR-Indian Institute of Chemical Biology, Kolkata 700032, India
| | - Ishita Mukherjee
- Structural Biology and Bio-informatics Division, CSIR-Indian Institute of Chemical Biology, Kolkata 700032, India
| | - Subhalakshmi Guha
- Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology, Kolkata 700032, India
| | - Ramesh Kumar Paidi
- Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology, Kolkata 700032, India
| | - Saikat Chakrabarti
- Structural Biology and Bio-informatics Division, CSIR-Indian Institute of Chemical Biology, Kolkata 700032, India
| | - Subhas C Biswas
- Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology, Kolkata 700032, India
| | - Suvendra N Bhattacharyya
- RNA Biology Research Laboratory, Molecular Genetics Division, CSIR-Indian Institute of Chemical Biology, Kolkata 700032, India
| |
Collapse
|
|
22
|
Xu T, Liu J, Li XR, Yu Y, Luo X, Zheng X, Cheng Y, Yu PQ, Liu Y. The mTOR/NF-κB Pathway Mediates Neuroinflammation and Synaptic Plasticity in Diabetic Encephalopathy. Mol Neurobiol 2021; 58:3848-3862. [PMID: 33860440 DOI: 10.1007/s12035-021-02390-1] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Accepted: 04/08/2021] [Indexed: 12/19/2022]
Abstract
Diabetic encephalopathy, a severe complication of diabetes mellitus, is characterized by neuroinflammation and aberrant synaptogenesis in the hippocampus leading to cognitive decline. Mammalian target of rapamycin (mTOR) is associated with cognition impairment. Nuclear factor-κB (NF-κB) is a transcription factor of proinflammatory cytokines. Although mTOR has been ever implicated in processes occurring in neuroinflammation, the role of this enzyme on NF-κB signaling pathway remains unclear in diabetic encephalopathy. In the present study, we investigated whether mTOR regulates the NF-κB signaling pathway to modulate inflammatory cytokines and synaptic plasticity in hippocampal neurons. In vitro model was constructed in mouse HT-22 hippocampal neuronal cells exposed to high glucose. With the inhibition of mTOR or NF-κB by either chemical inhibitor or short-hairpin RNA (shRNA)-expressing lentivirus-vector, we examined the effects of mTOR/NF-κB signaling on proinflammatory cytokines and synaptic proteins. The diabetic mouse model induced by a high-fat diet combined with streptozotocin injection was administrated with rapamycin (mTOR inhibitor) and PDTC (NF-κB inhibitor), respectively. High glucose significantly increased mTOR phosphorylation in HT-22 cells. While inhibiting mTOR by rapamycin or shmTOR significantly suppressed high glucose-induced activation of NF-κB and its regulators IKKβ and IκBα, suggesting mTOR is the upstream regulator of NF-κB. Furthermore, inhibiting NF-κB by PDTC and shNF-κB decreased proinflammatory cytokines expression (IL-6, IL-1β, and TNF-α) and increased brain-derived neurotrophic factor (BDNF) and synaptic proteins (synaptophysin and PSD-95) in HT-22 cells under high glucose conditions. Besides, the mTOR and NF-κB inhibitors improved cognitive decline in diabetic mice. The inhibition of mTOR and NF-κB suppressed mTOR/NF-κB signaling pathway, increased synaptic proteins, and improved ultrastructural synaptic plasticity in the hippocampus of diabetic mice. Activating mTOR/NF-κB signaling pathway regulates the pathogenesis of diabetic encephalopathy, such as neuroinflammation, synaptic proteins loss, and synaptic ultrastructure impairment. The findings provide the implication that mTOR/NF-κB is potential new drug targets to treat diabetic encephalopathy.
Collapse
Affiliation(s)
- Ting Xu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
| | - Jiao Liu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
| | - Xin-Rui Li
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
| | - Yinghua Yu
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China.,Illawarra Health and Medical Research Institute, School of Medicine, University of Wollongong, Wollongong, NSW, 2522, Australia
| | - Xuan Luo
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
| | - Xian Zheng
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
| | - Yuan Cheng
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
| | - Pei-Quan Yu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
| | - Yi Liu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China. .,Jiangsu Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China. .,Department of Biophysics, School of Life Sciences, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China.
| |
Collapse
|
|
23
|
Lee J, Lee M, Lee K. Trans-acting regulators of ribonuclease activity. J Microbiol 2021; 59:341-359. [PMID: 33779951 DOI: 10.1007/s12275-021-0650-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 12/28/2020] [Accepted: 12/28/2020] [Indexed: 12/16/2022]
Abstract
RNA metabolism needs to be tightly regulated in response to changes in cellular physiology. Ribonucleases (RNases) play an essential role in almost all aspects of RNA metabolism, including processing, degradation, and recycling of RNA molecules. Thus, living systems have evolved to regulate RNase activity at multiple levels, including transcription, post-transcription, post-translation, and cellular localization. In addition, various trans-acting regulators of RNase activity have been discovered in recent years. This review focuses on the physiological roles and underlying mechanisms of trans-acting regulators of RNase activity.
Collapse
Affiliation(s)
- Jaejin Lee
- Department of Life Science, Chung-Ang University, Seoul, 06974, Republic of Korea
| | - Minho Lee
- Department of Life Science, Chung-Ang University, Seoul, 06974, Republic of Korea.
| | - Kangseok Lee
- Department of Life Science, Chung-Ang University, Seoul, 06974, Republic of Korea.
| |
Collapse
|
|
24
|
Lam B, Nwadozi E, Haas TL, Birot O, Roudier E. High Glucose Treatment Limits Drosha Protein Expression and Alters AngiomiR Maturation in Microvascular Primary Endothelial Cells via an Mdm2-dependent Mechanism. Cells 2021; 10:742. [PMID: 33801773 PMCID: PMC8065922 DOI: 10.3390/cells10040742] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 03/20/2021] [Accepted: 03/23/2021] [Indexed: 12/21/2022] Open
Abstract
Diabetes promotes an angiostatic phenotype in the microvascular endothelium of skeletal muscle and skin. Angiogenesis-related microRNAs (angiomiRs) regulate angiogenesis through the translational repression of pro- and anti-angiogenic genes. The maturation of micro-RNA (miRs), including angiomiRs, requires the action of DROSHA and DICER proteins. While hyperglycemia modifies the expression of angiomiRs, it is unknown whether high glucose conditions alter the maturation process of angiomiRs in dermal and skeletal muscle microvascular endothelial cells (MECs). Compared to 5 mM of glucose, high glucose condition (30 mM, 6-24 h) decreased DROSHA protein expression, without changing DROSHA mRNA, DICER mRNA, or DICER protein in primary dermal MECs. Despite DROSHA decreasing, high glucose enhanced the maturation and expression of one angiomiR, miR-15a, and downregulated an miR-15a target: Vascular Endothelial Growth Factor-A (VEGF-A). The high glucose condition increased Murine Double Minute-2 (MDM2) expression and MDM2-binding to DROSHA. Inhibition of MDM2 prevented the effects evoked by high glucose on DROSHA protein and miR-15a maturation in dermal MECs. In db/db mice, blood glucose was negatively correlated with the expression of skeletal muscle DROSHA protein, and high glucose decreased DROSHA protein in skeletal muscle MECs. Altogether, our results suggest that high glucose reduces DROSHA protein and enhances the maturation of the angiostatic miR-15a through a mechanism that requires MDM2 activity.
Collapse
|
|
25
|
Lee J, Lee M, Lee K. Trans-acting regulators of ribonuclease activity. J Microbiol 2021:10.1007/s12275-021-0650-3. [PMID: 33565052 DOI: 10.1007/s12275-021-0650-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 12/28/2020] [Accepted: 12/28/2020] [Indexed: 11/29/2022]
Abstract
RNA metabolism needs to be tightly regulated in response to changes in cellular physiology. Ribonucleases (RNases) play an essential role in almost all aspects of RNA metabolism, including processing, degradation, and recycling of RNA molecules. Thus, living systems have evolved to regulate RNase activity at multiple levels, including transcription, post-transcription, post-translation, and cellular localization. In addition, various trans-acting regulators of RNase activity have been discovered in recent years. This review focuses on the physiological roles and underlying mechanisms of trans-acting regulators of RNase activity.
Collapse
Affiliation(s)
- Jaejin Lee
- Department of Life Science, Chung-Ang University, Seoul, 06974, Republic of Korea
| | - Minho Lee
- Department of Life Science, Chung-Ang University, Seoul, 06974, Republic of Korea.
| | - Kangseok Lee
- Department of Life Science, Chung-Ang University, Seoul, 06974, Republic of Korea.
| |
Collapse
|
|
26
|
Deng K, Yin H, Xiong F, Feng L, Dong P, Ren M. Genome-wide miRNA expression profiling in potato ( Solanum tuberosum L.) reveals TOR-dependent post-transcriptional gene regulatory networks in diverse metabolic pathway. PeerJ 2021; 9:e10704. [PMID: 33520467 PMCID: PMC7811781 DOI: 10.7717/peerj.10704] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 12/14/2020] [Indexed: 12/29/2022] Open
Abstract
Target of rapamycin (TOR) operates as a hub of the signal transduction that integrates nutrient and energy signaling to promote cell proliferation and growth through mediating the transcriptional and post- transcriptional regulator networks in all eukaryotic species. MicroRNAs (miRNAs) are widespread classes of small, single-stranded, non-coding endogenous RNAs and are widely found in eukaryotes, which play a vital role in regulating gene expression by degrading targeted mRNAs or translational repression at post-transcriptional level. Recent studies found that there were necessarily close connections between miRNA and TOR pathways in mammals. However, there is little information about the interplay between the miRNA and TOR in plants. Thus, the aim of this study was to identify potential TOR-miRNA-mRNA regulatory networks in TOR signaling through global mRNA and microRNA expression profiling in potato. Based on the previous high-throughput transcriptome sequencing and filtering, a total of 2,899 genes were significantly differentially expressed in potato under TOR inhibitors treatment. Pathway analysis revealed that these genes were significantly enriched in multiple metabolic processes. Similarly, in the present study, suppression of TOR resulted in 41 miRNAs up-regulated and 45 down-regulated, revealing that TOR plays a crucial role in the regulation of miRNA regulatory network. Furthermore, integrated mRNA and miRNA expression profiling uncovered that these miRNAs participated in large-scale metabolic process in the TOR signal pathway in potato, such as regulation of autophagy and ubiquitination, and biosynthesis of secondary metabolites. Overall, the results shed new insight into TOR related post-transcriptional gene regulatory networks in potato and suggesting TOR-miRNA-targeting genes relevant networks as a potential genetic resource for potato improvement.
Collapse
Affiliation(s)
- Kexuan Deng
- School of Life Sciences, Chongqing University, Chongqing, China
| | - Huan Yin
- School of Life Sciences, Chongqing University, Chongqing, China
| | - Fangjie Xiong
- School of Life Sciences, Chongqing University, Chongqing, China
| | - Li Feng
- Zhengzhou Research Base, State Key Laboratory of Cotton Biology, Zhengzhou University, Zhengzhou, China.,Institute of Urban Agriculture, Chinese Academy of Agricultural Sciences, Chengdu, China
| | - Pan Dong
- School of Life Sciences, Chongqing University, Chongqing, China.,Chongqing Key Laboratory of Biology and Genetic Breeding for Tuber and Root Crops, Chongqing, China
| | - Maozhi Ren
- School of Life Sciences, Chongqing University, Chongqing, China.,Zhengzhou Research Base, State Key Laboratory of Cotton Biology, Zhengzhou University, Zhengzhou, China.,Institute of Urban Agriculture, Chinese Academy of Agricultural Sciences, Chengdu, China
| |
Collapse
|
|
27
|
Maniyadath B, Sandra US, Kolthur-Seetharam U. Metabolic choreography of gene expression: nutrient transactions with the epigenome. J Biosci 2020. [DOI: 10.1007/s12038-019-9987-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
|
|
28
|
Annese T, Tamma R, De Giorgis M, Ribatti D. microRNAs Biogenesis, Functions and Role in Tumor Angiogenesis. Front Oncol 2020; 10:581007. [PMID: 33330058 PMCID: PMC7729128 DOI: 10.3389/fonc.2020.581007] [Citation(s) in RCA: 155] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Accepted: 10/27/2020] [Indexed: 12/19/2022] Open
Abstract
microRNAs (miRNAs) are small non-coding RNA molecules, evolutionary conserved. They target more than one mRNAs, thus influencing multiple molecular pathways, but also mRNAs may bind to a variety of miRNAs, either simultaneously or in a context-dependent manner. miRNAs biogenesis, including miRNA transcription, processing by Drosha and Dicer, transportation, RISC biding, and miRNA decay, are finely controlled in space and time. miRNAs are critical regulators in various biological processes, such as differentiation, proliferation, apoptosis, and development in both health and disease. Their dysregulation is involved in tumor initiation and progression. In tumors, they can act as onco-miRNAs or oncosuppressor-miRNA participating in distinct cellular pathways, and the same miRNA can perform both activities depending on the context. In tumor progression, the angiogenic switch is fundamental. miRNAs derived from tumor cells, endothelial cells, and cells of the surrounding microenvironment regulate tumor angiogenesis, acting as pro-angiomiR or anti-angiomiR. In this review, we described miRNA biogenesis and function, and we update the non-classical aspects of them. The most recent role in the nucleus, as transcriptional gene regulators and the different mechanisms by which they could be dysregulated, in tumor initiation and progression, are treated. In particular, we describe the role of miRNAs in sprouting angiogenesis, vessel co-option, and vasculogenic mimicry. The role of miRNAs in lymphoma angiogenesis is also discussed despite the scarcity of data. The information presented in this review reveals the need to do much more to discover the complete miRNA network regulating angiogenesis, not only using high-throughput computational analysis approaches but also morphological ones.
Collapse
Affiliation(s)
- Tiziana Annese
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, Section of Human Anatomy and Histology, University of Bari Medical School, Bari, Italy
| | - Roberto Tamma
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, Section of Human Anatomy and Histology, University of Bari Medical School, Bari, Italy
| | - Michelina De Giorgis
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, Section of Human Anatomy and Histology, University of Bari Medical School, Bari, Italy
| | - Domenico Ribatti
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, Section of Human Anatomy and Histology, University of Bari Medical School, Bari, Italy
| |
Collapse
|
|
29
|
Nobile MS, Votta G, Palorini R, Spolaor S, De Vitto H, Cazzaniga P, Ricciardiello F, Mauri G, Alberghina L, Chiaradonna F, Besozzi D. Fuzzy modeling and global optimization to predict novel therapeutic targets in cancer cells. Bioinformatics 2020; 36:2181-2188. [PMID: 31750879 PMCID: PMC7141866 DOI: 10.1093/bioinformatics/btz868] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Revised: 09/13/2019] [Accepted: 11/20/2019] [Indexed: 12/18/2022] Open
Abstract
Motivation The elucidation of dysfunctional cellular processes that can induce the onset of a disease is a challenging issue from both the experimental and computational perspectives. Here we introduce a novel computational method based on the coupling between fuzzy logic modeling and a global optimization algorithm, whose aims are to (1) predict the emergent dynamical behaviors of highly heterogeneous systems in unperturbed and perturbed conditions, regardless of the availability of quantitative parameters, and (2) determine a minimal set of system components whose perturbation can lead to a desired system response, therefore facilitating the design of a more appropriate experimental strategy. Results We applied this method to investigate what drives K-ras-induced cancer cells, displaying the typical Warburg effect, to death or survival upon progressive glucose depletion. The optimization analysis allowed to identify new combinations of stimuli that maximize pro-apoptotic processes. Namely, our results provide different evidences of an important protective role for protein kinase A in cancer cells under several cellular stress conditions mimicking tumor behavior. The predictive power of this method could facilitate the assessment of the response of other complex heterogeneous systems to drugs or mutations in fields as medicine and pharmacology, therefore paving the way for the development of novel therapeutic treatments. Availability and implementation The source code of FUMOSO is available under the GPL 2.0 license on GitHub at the following URL: https://github.com/aresio/FUMOSO Supplementary information Supplementary data are available at Bioinformatics online.
Collapse
Affiliation(s)
- Marco S Nobile
- Department of Informatics, Systems and Communication, University of Milano-Bicocca, Milano 20126, Italy.,SYSBIO.IT Centre for Systems Biology, Milano 20126, Italy.,Department of Industrial Engineering and Innovation Sciences, Eindhoven University of Technology, Eindhoven 5612 AZ, The Netherlands
| | - Giuseppina Votta
- SYSBIO.IT Centre for Systems Biology, Milano 20126, Italy.,Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milano 20126, Italy
| | - Roberta Palorini
- SYSBIO.IT Centre for Systems Biology, Milano 20126, Italy.,Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milano 20126, Italy
| | - Simone Spolaor
- Department of Informatics, Systems and Communication, University of Milano-Bicocca, Milano 20126, Italy.,SYSBIO.IT Centre for Systems Biology, Milano 20126, Italy
| | - Humberto De Vitto
- SYSBIO.IT Centre for Systems Biology, Milano 20126, Italy.,Hormel Institute, University of Minnesota, Austin, MN 55912, USA
| | - Paolo Cazzaniga
- SYSBIO.IT Centre for Systems Biology, Milano 20126, Italy.,Department of Human and Social Sciences, University of Bergamo, Bergamo 24129, Italy
| | - Francesca Ricciardiello
- SYSBIO.IT Centre for Systems Biology, Milano 20126, Italy.,Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milano 20126, Italy
| | - Giancarlo Mauri
- Department of Informatics, Systems and Communication, University of Milano-Bicocca, Milano 20126, Italy.,SYSBIO.IT Centre for Systems Biology, Milano 20126, Italy
| | - Lilia Alberghina
- SYSBIO.IT Centre for Systems Biology, Milano 20126, Italy.,Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milano 20126, Italy
| | - Ferdinando Chiaradonna
- SYSBIO.IT Centre for Systems Biology, Milano 20126, Italy.,Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milano 20126, Italy
| | - Daniela Besozzi
- Department of Informatics, Systems and Communication, University of Milano-Bicocca, Milano 20126, Italy.,SYSBIO.IT Centre for Systems Biology, Milano 20126, Italy
| |
Collapse
|
|
30
|
Ramaiah MJ. mTOR inhibition and p53 activation, microRNAs: The possible therapy against pandemic COVID-19. GENE REPORTS 2020; 20:100765. [PMID: 32835132 PMCID: PMC7324924 DOI: 10.1016/j.genrep.2020.100765] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Accepted: 06/27/2020] [Indexed: 12/12/2022]
Abstract
mTOR is a serine-threonine kinase and participates in cell proliferation, cellular metabolism was found to be activated during Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral infection and replication. During viral replication mTOR, downstream target genes such as ribosomal protein S6 kinase beta 1 (S6K1) and Eukaryotic translational initiation factor 4E-binding protein1 (4-E-BP1) are activated result in ribosome biosynthesis and efficient protein synthesis. In plasmacytoid dendritic cells (pDCs), mTOR plays a key role in the association of adapter protein myeloid differentiation primary response gene 88 (MyD88), Toll-like receptor 9 (TLR9) and interferon regulatory factor (IRF-7) leading to the transcriptional activation of type-I interferon (IFN) genes. Viruses also inactivate the interferon α (IFN-α) pathway by impairing the IRF-7 mediated activation of IFN-α gene transcription. Thus, mammalian target of rapamycin (mTOR) inhibitors can help in suppressing the early stages of viral infection and replication. Interestingly, the key tumor-suppressor p53 protein will undergo degradation by virus-encoded E3 ubiquitin ligase Ring-finger and CHY zinc-finger domain-containing 1 (RCHY1) leading to an increased viral survival in host cells. Thus, the mTOR inhibitors and p53 activators or microRNAs that functions as p53 and can target 3'-UTR of mTOR and RPS6KB1 might effectively inhibit viral replication in the human respiratory tract and lung cells.
Collapse
Affiliation(s)
- Mekala Janaki Ramaiah
- Functional Genomics and Disease Biology, School of Chemical and Biotechnology, SASTRA Deemed University, Thanjavur 613401, Tamil Nadu, India
| |
Collapse
|
|
31
|
Nelson MC, O'Connell RM. MicroRNAs: At the Interface of Metabolic Pathways and Inflammatory Responses by Macrophages. Front Immunol 2020; 11:1797. [PMID: 32922393 PMCID: PMC7456828 DOI: 10.3389/fimmu.2020.01797] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Accepted: 07/06/2020] [Indexed: 12/12/2022] Open
Abstract
Macrophages are key cells of the innate immune system with functional roles in both homeostatic maintenance of self-tissues and inflammatory responses to external stimuli, including infectious agents. Recent advances in metabolic research have revealed that macrophage functions rely upon coordinated metabolic programs to regulate gene expression, inflammation, and other important cellular processes. Polarized macrophages adjust their use of nutrients such as glucose and amino acids to meet their changing metabolic needs, and this in turn supports the functions of the activated macrophage. Metabolic and inflammatory processes have been widely studied, and a crucial role for their regulation at the post-transcriptional level by microRNAs (miRNAs) has been identified. miRNAs govern many facets of macrophage biology, including direct targeting of metabolic regulators and inflammatory pathways. This review will integrate emerging data that support an interplay between miRNAs and metabolism during macrophage inflammatory responses, highlighting critical miRNAs and miRNA families. Additionally, we will address the implications of these networks for human disease and discuss emerging areas of research in this field.
Collapse
Affiliation(s)
- Morgan C Nelson
- Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT, United States.,Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States
| | - Ryan M O'Connell
- Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT, United States.,Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States
| |
Collapse
|
|
32
|
Cao H, Chen X, Wang Z, Wang L, Xia Q, Zhang W. The role of MDM2-p53 axis dysfunction in the hepatocellular carcinoma transformation. Cell Death Discov 2020; 6:53. [PMID: 32595984 PMCID: PMC7305227 DOI: 10.1038/s41420-020-0287-y] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 05/24/2020] [Accepted: 05/28/2020] [Indexed: 12/12/2022] Open
Abstract
Liver cancer is the second most frequent cause of cancer-related death globally. The main histological subtype is hepatocellular carcinoma (HCC), which is derived from hepatocytes. According to the epidemiologic studies, the most important risk factors of HCC are chronic viral infections (HBV, HCV, and HIV) and metabolic disease (metabolic syndrome). Interestingly, these carcinogenic factors that contributed to HCC are associated with MDM2-p53 axis dysfunction, which presented with inactivation of p53 and overactivation of MDM2 (a transcriptional target and negative regulator of p53). Mechanically, the homeostasis of MDM2-p53 feedback loop plays an important role in controlling the initiation and progression of HCC, which has been found to be dysregulated in HCC tissues. To maintain long-term survival in hepatocytes, hepatitis viruses have lots of ways to destroy the defense strategies of hepatocytes by inducing TP53 mutation and silencing, promoting MDM2 overexpression, accelerating p53 degradation, and stabilizing MDM2. As a result, genetic instability, chronic ER stress, oxidative stress, energy metabolism switch, and abnormalities in antitumor genes can be induced, all of which might promote hepatocytes' transformation into hepatoma cells. In addition, abnormal proliferative hepatocytes and precancerous cells cannot be killed, because of hepatitis viruses-mediated exhaustion of Kupffer cells and hepatic stellate cells (HSCs) and CD4+T cells by disrupting their MDM2-p53 axis. Moreover, inefficiency of hepatic immune response can be further aggravated when hepatitis viruses co-infected with HIV. Unlike with chronic viral infections, MDM2-p53 axis might play a dual role in glucolipid metabolism of hepatocytes, which presented with enhancing glucolipid catabolism, but promoting hepatocyte injury at the early and late stages of glucolipid metabolism disorder. Oxidative stress, fatty degeneration, and abnormal cell growth can be detected in hepatocytes that were suffering from glucolipid metabolism disorder, and all of which could contribute to HCC initiation. In this review, we focus on the current studies of the MDM2-p53 axis in HCC, and specifically discuss the impact of MDM2-p53 axis dysfunction by viral infection and metabolic disease in the transformation of normal hepatocytes into hepatoma cells. We also discuss the therapeutic avenues and potential targets that are being developed to normalize the MDM2-p53 axis in HCC.
Collapse
Affiliation(s)
- Hui Cao
- Department of Liver Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200030 China
| | - Xiaosong Chen
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127 China
| | - Zhijun Wang
- Department of Traditional Chinese Medicine, Putuo People’s Hospital Affiliated to Tongji University, Shanghai, China
| | - Lei Wang
- Department of Liver Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200030 China
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127 China
| | - Wei Zhang
- Department of Liver Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200030 China
| |
Collapse
|
|
33
|
Chen Y, Lu Y, Ren Y, Yuan J, Zhang N, Kimball H, Zhou L, Yang M. Starvation-induced suppression of DAZAP1 by miR-10b integrates splicing control into TSC2-regulated oncogenic autophagy in esophageal squamous cell carcinoma. Theranostics 2020; 10:4983-4996. [PMID: 32308763 PMCID: PMC7163442 DOI: 10.7150/thno.43046] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2019] [Accepted: 03/21/2020] [Indexed: 12/14/2022] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) accounts for about 90% of all incident esophageal cancers, with a 5-year survival rate of < 20%. Autophagy is of particular importance in cancers; however, the detailed regulatory mechanisms of oncogenic autophagy in ESCC have not been fully elucidated. In the present study, we address how splicing control of TSC2 is involved in mTOR-regulated oncogenic autophagy. Methods: Alternative splicing events controlled by DAZAP1 in ESCC cells were identified via RNAseq. Differential phosphorylation of short or long TSC2 splicing variants by AKT and their impacts on mTOR signaling were also examined. Results: We found that starvation-induced miR-10b could enhance autophagy via silencing DAZAP1, a key regulator of pre-mRNA alternative splicing. Intriguingly, we observed a large number of significantly changed alternative splicing events, especially exon skipping, upon RNAi of DAZAP1. TSC2 was verified as one of the crucial target genes of DAZAP1. Silencing of DAZAP1 led to the exclusion of TSC2 exon 26 (from Leu947 to Arg988), producing a short TSC2 isoform. The short TSC2 isoform cannot be phosphorylated at Ser981 by AKT, which resulted in continuous activation of TSC2 in ESCC. The active TSC2 inhibited mTOR via RHEB, leading to continually stimulated oncogenic autophagy of ESCC cells. Conclusions: Our data revealed an important physiological function of tumor suppressor DAZAP1 in autophagy regulation and highlighted the potential of controlling mRNA alternative splicing as an effective therapeutic application for cancers.
Collapse
|
|
34
|
Zhu Z, Yue Q, Xie J, Zhang S, He W, Bai S, Tian S, Zhang Y, Xiong M, Sun Z, Huang C, Li Y, Zheng K, Ye L. Rapamycin-mediated mTOR inhibition impairs silencing of sex chromosomes and the pachytene piRNA pathway in the mouse testis. Aging (Albany NY) 2020; 11:185-208. [PMID: 30636722 PMCID: PMC6339782 DOI: 10.18632/aging.101740] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Accepted: 12/19/2018] [Indexed: 01/10/2023]
Abstract
Mechanistic target of rapamycin (mTOR) controls cell growth and metabolism in response to environmental and metabolic signals. Rapamycin robustly extends the lifespan in mammals and has clinical relevance in organ transplantation and cancer therapy but side effects include male infertility. Here, we report that chronic rapamycin treatment causes spermatogenic arrest in adult male mice due to defects in sex body formation and meiotic sex chromosome inactivation (MSCI). Many sex chromosome-linked genes were up-regulated in isolated pachytene spermatocytes from rapamycin-treated mice. RNA-Seq analysis also identified mRNAs encoding the core piRNA pathway components were decreased. Furthermore, rapamycin treatment was associated with a drastic reduction in pachytene piRNA populations. The inhibitory effects of rapamycin on spermatogenesis were partially reversible, with restoration of testis mass and sperm motility within 2 months of treatment cessation. Collectively, we have defined an essential role of mTOR in MSCI and identified a novel function as a regulator of small RNA homeostasis in male germ cells.
Collapse
Affiliation(s)
- Zhiping Zhu
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.,The People's Hospital of Gaochun, Nanjing, China
| | - Qiuling Yue
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China
| | - Jie Xie
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China
| | - Shuya Zhang
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China
| | - Wenxiu He
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China
| | - Shun Bai
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China
| | - Suwen Tian
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China
| | - Yingwen Zhang
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China
| | - Mengneng Xiong
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China
| | - Zheng Sun
- Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Chaoyang Huang
- Heart and Vascular Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzho, Zhejiang 310003, China
| | - Yuebei Li
- The First Medical School of Nanjing Medical University, Nanjing, China
| | - Ke Zheng
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China
| | - Lan Ye
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China
| |
Collapse
|
|
35
|
DROSHA-Dependent miRNA and AIM2 Inflammasome Activation in Idiopathic Pulmonary Fibrosis. Int J Mol Sci 2020; 21:ijms21051668. [PMID: 32121297 PMCID: PMC7084700 DOI: 10.3390/ijms21051668] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 02/23/2020] [Accepted: 02/27/2020] [Indexed: 12/11/2022] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease. Chronic lung inflammation is linked to the pathogenesis of IPF. DROSHA, a class 2 ribonuclease III enzyme, has an important role in the biogenesis of microRNA (miRNA). The function of miRNAs has been identified in the regulation of the target gene or protein related to inflammatory responses via degradation of mRNA or inhibition of translation. The absent-in-melanoma-2 (AIM2) inflammasome is critical for inflammatory responses against cytosolic double stranded DNA (dsDNA) from pathogen-associated molecular patterns (PAMPs) and self-DNA from danger-associated molecular patterns (DAMPs). The AIM2 inflammasome senses double strand DNA (dsDNA) and interacts with the adaptor apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), which recruits pro-caspase-1 and regulates the maturation and secretion of interleukin (IL)-1β and IL-18. A recent study showed that inflammasome activation contributes to lung inflammation and fibrogenesis during IPF. In the current review, we discuss recent advances in our understanding of the DROSHA-miRNA-AIM2 inflammasome axis in the pathogenesis of IPF.
Collapse
|
|
36
|
Loss of TSC complex enhances gluconeogenesis via upregulation of Dlk1-Dio3 locus miRNAs. Proc Natl Acad Sci U S A 2020; 117:1524-1532. [PMID: 31919282 DOI: 10.1073/pnas.1918931117] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Loss of the tumor suppressor tuberous sclerosis complex 1 (Tsc1) in the liver promotes gluconeogenesis and glucose intolerance. We asked whether this could be attributed to aberrant expression of small RNAs. We performed small-RNA sequencing on liver of Tsc1-knockout mice, and found that miRNAs of the delta-like homolog 1 (Dlk1)-deiodinase iodothyronine type III (Dio3) locus are up-regulated in an mTORC1-dependent manner. Sustained mTORC1 signaling during development prevented CpG methylation and silencing of the Dlk1-Dio3 locus, thereby increasing miRNA transcription. Deletion of miRNAs encoded by the Dlk1-Dio3 locus reduced gluconeogenesis, glucose intolerance, and fasting blood glucose levels. Thus, miRNAs contribute to the metabolic effects observed upon loss of TSC1 and hyperactivation of mTORC1 in the liver. Furthermore, we show that miRNA is a downstream effector of hyperactive mTORC1 signaling.
Collapse
|
|
37
|
Tong X, Yu N, Han R, Wang T. Function of Dicer with regard to Energy Homeostasis Regulation, Structural Modification, and Cellular Distribution. Int J Endocrinol 2020; 2020:6420816. [PMID: 32774363 PMCID: PMC7397435 DOI: 10.1155/2020/6420816] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Revised: 05/30/2020] [Accepted: 07/03/2020] [Indexed: 12/17/2022] Open
Abstract
As a type III ribonuclease (RNase III) specifically cleaving double-stranded RNA substrates into short fragments, Dicer is indispensable in a range of physi/pathologic processes, e.g., nutrient deprivation, hypoxia, or DNA damage. Therefore, much interest has been paid to the research of this protein as well as its products like microRNAs (miRNAs). The close relationship between Dicer levels and fluctuations of nutrient availability suggests that the protein participates in the regulation of systemic energy homeostasis. Through miRNAs, Dicer regulates the hypothalamic melanocortin-4 system and central autophagy promoting energy expenditure. Moreover, by influencing canonical energy sensors like adenosine monophosphate-activated protein kinase (AMPK) or mammalian target of rapamycin (mTOR), Dicer favors catabolism in the periphery. Taken together, Dicer might be targeted in the control of energy dysregulation. However, factors affecting its RNase activity should be noted. Firstly, modulation of structural integrity affects its role as a ribonuclease. Secondly, although previously known as a cytosolic endoribonuclease, evidence suggests Dicer can relocalize into the nucleus where it could also produce small RNAs. In this review, we probe into involvement of Dicer in energy homeostasis as well as its structural integrity or cellular distribution which affects its ability to produce miRNAs, in the hope of providing novel insights into its mechanism of action for future application.
Collapse
Affiliation(s)
- Xiaohui Tong
- School of Life Sciences, Anhui University of Chinese Medicine, Hefei, China
| | - Nianjun Yu
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China
| | - Rongchun Han
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China
| | - Tongsheng Wang
- School of Life Sciences, Anhui University of Chinese Medicine, Hefei, China
| |
Collapse
|
|
38
|
Maniyadath B, Sandra US, Kolthur-Seetharam U. Metabolic choreography of gene expression: nutrient transactions with the epigenome. J Biosci 2020; 45:7. [PMID: 31965985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Eukaryotic complexity and thus their ability to respond to diverse cues are largely driven by varying expression of gene products, qualitatively and quantitatively. Protein adducts in the form of post-translational modifications, most of which are derived from metabolic intermediates, allow fine tuning of gene expression at multiple levels. With the advent of high-throughput and high-resolution mapping technologies there has been an explosion in terms of the kind of modifications on chromatin and other factors that govern gene expression. Moreover, even the classical notion of acetylation and methylation dependent regulation of transcription is now known to be intrinsically coupled to biochemical pathways, which were otherwise regarded as 'mundane'. Here we have not only reviewed some of the recent literature but also have highlighted the dependence of gene regulatory mechanisms on metabolic inputs, both direct and indirect. We have also tried to bring forth some of the open questions, and how our understanding of gene expression has changed dramatically over the last few years, which has largely become metabolism centric. Finally, metabolic regulation of epigenome and gene expression has gained much traction due to the increased incidence of lifestyle and age-related diseases.
Collapse
Affiliation(s)
- Babukrishna Maniyadath
- Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India
| | | | | |
Collapse
|
|
39
|
Rapamycin-upregulated miR-29b promotes mTORC1-hyperactive cell growth in TSC2-deficient cells by downregulating tumor suppressor retinoic acid receptor β (RARβ). Oncogene 2019; 38:7367-7383. [PMID: 31420607 DOI: 10.1038/s41388-019-0957-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 07/25/2019] [Accepted: 08/05/2019] [Indexed: 12/23/2022]
Abstract
miR-29b has been identified as a rapamycin-induced microRNA (miRNA) in Tsc2-deficient, mTORC1-hyperactive cells. The biological significance of this induction of miR-29b is unknown. We have found that miR-29b acts as an oncogenic miRNA in Tsc2-deficient cells: inhibition of miR-29b suppressed cell proliferation, anchorage-independent cell growth, cell migration, invasion, and the growth of Tsc2-deficient tumors in vivo. Importantly, the combination of miR-29b inhibition with rapamycin treatment further inhibited these tumor-associated cellular processes. To gain insight into the molecular mechanisms by which miR-29b promotes tumorigenesis, we used RNA sequencing to identify the tumor suppressor retinoid receptor beta (RARβ) as a target gene of miR-29b. We found that miR-29b directly targeted the 3'UTR of RARβ. Forced expression of RARβ reversed the effects of miR-29b overexpression in proliferation, migration, and invasion, indicating that it is a critical target. miR-29b expression correlated with low RARβ expression in renal clear cell carcinomas and bladder urothelial carcinomas, tumors associated with TSC gene mutations. We further identified growth family member 4 (ING4) as a novel interacting partner of RARβ. Overexpression of ING4 inhibited the migration and invasion of Tsc2-deficient cells while silencing of ING4 reversed the RARβ-mediated suppression of cell migration and invasion. Taken together, our findings reveal a novel miR-29b/RARβ/ING4 pathway that regulates tumorigenic properties of Tsc2-deficient cells, and that may serve as a potential therapeutic target for TSC, lymphangioleiomyomatosis (LAM), and other mTORC1-hyperactive tumors.
Collapse
|
|
40
|
Fabris G, Dumortier O, Pisani DF, Gautier N, Van Obberghen E. Amino acid-induced regulation of hepatocyte growth: possible role of Drosha. Cell Death Dis 2019; 10:566. [PMID: 31332188 PMCID: PMC6646398 DOI: 10.1038/s41419-019-1779-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Revised: 05/23/2019] [Accepted: 06/21/2019] [Indexed: 12/14/2022]
Abstract
In an adult healthy liver, hepatocytes are in a quiescent stage unless a physical injury, such as ablation, or a toxic attack occur. Indeed, to maintain their crucial organismal homeostatic role, the damaged or remaining hepatocytes will start proliferating to restore their functional mass. One of the limiting conditions for cell proliferation is amino-acid availability, necessary both for the synthesis of proteins important for cell growth and division, and for the activation of the mTOR pathway, known for its considerable role in the regulation of cell proliferation. The overarching aim of our present work was to investigate the role of amino acids in the regulation of the switch between quiescence and growth of adult hepatocytes. To do so we used non-confluent primary adult rat hepatocytes as a model of partially ablated liver. We discovered that the absence of amino acids induces in primary rat hepatocytes the entrance in a quiescence state together with an increase in Drosha protein, which does not involve the mTOR pathway. Conversely, Drosha knockdown allows the hepatocytes, quiescent after amino-acid deprivation, to proliferate again. Further, hepatocyte proliferation appears to be independent of miRNAs, the canonical downstream partners of Drosha. Taken together, our observations reveal an intriguing non-canonical action of Drosha in the control of growth regulation of adult hepatocytes responding to a nutritional strain, and they may help to design novel preventive and/or therapeutic approaches for hepatic failure.
Collapse
Affiliation(s)
- Gaia Fabris
- Université Côte d'Azur, Inserm, CNRS, IRCAN, Nice, France.,Université Côte d'Azur, CNRS, LP2M, Nice, France
| | | | | | - Nadine Gautier
- Université Côte d'Azur, Inserm, CNRS, IRCAN, Nice, France.,Université Côte d'Azur, CNRS, Inserm, iBV, Nice, France
| | - Emmanuel Van Obberghen
- Université Côte d'Azur, CHU, Inserm, CNRS, IRCAN, Nice, France. .,Université Côte d'Azur, CHU, CNRS, LP2M, Nice, France.
| |
Collapse
|
|
41
|
Kostyniuk DJ, Marandel L, Jubouri M, Dias K, de Souza RF, Zhang D, Martyniuk CJ, Panserat S, Mennigen JA. Profiling the rainbow trout hepatic miRNAome under diet-induced hyperglycemia. Physiol Genomics 2019; 51:411-431. [PMID: 31282806 DOI: 10.1152/physiolgenomics.00032.2019] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Abstract
Carnivorous rainbow trout exhibit prolonged postprandial hyperglycemia when fed a diet exceeding 20% carbohydrate content. This poor capacity to utilize carbohydrates has led to rainbow trout being classified as "glucose-intolerant" (GI). The metabolic phenotype has spurred research to identify the underlying cellular and molecular mechanisms of glucose intolerance, largely because carbohydrate-rich diets provide economic and ecological advantages over traditionally used fish meal, considered unsustainable for rainbow trout aquaculture operations. Evidence points to a contribution of hepatic intermediary carbohydrate and lipid metabolism, as well as upstream insulin signaling. Recently, microRNAs (miRNAs), small noncoding RNAs acting as negative posttranscriptional regulators affecting target mRNA stability and translation, have emerged as critical regulators of hepatic control of glucose-homeostasis in mammals, revealing that dysregulated hepatic miRNAs might play a role in organismal hyperglycemia in metabolic disease. To determine whether hepatic regulatory miRNA networks may contribute to GI in rainbow trout, we induced prolonged postprandial hyperglycemia in rainbow trout by using a carbohydrate-rich diet and profiled genome-wide hepatic miRNAs in hyperglycemic rainbow trout compared with fasted trout and trout fed a diet devoid of carbohydrates. Using small RNA next-generation sequencing and real-time RT-PCR validation, we identified differentially regulated hepatic miRNAs between these groups and used an in silico approach to predict bona fide mRNA targets and enriched pathways. Diet-induced hyperglycemia resulted in differential regulation of hepatic miRNAs compared with fasted fish. Some of the identified miRNAs, such as miRNA-27b-3p and miRNA-200a-3p, are known to be responsive to hyperglycemia in the liver of hyperglycemic glucose-tolerant fish and mammals, suggesting an evolutionary conserved regulation. Using Gene Ontology term-based enrichment analysis, we identify intermediate carbohydrate and lipid metabolism and insulin signaling as potential targets of posttranscriptional regulation by hyperglycemia-regulated miRNAs and provide correlative expression analysis of specific predicted miRNA-target pairs. This study identifies hepatic miRNAs in rainbow trout that exhibit differential postprandial expression in response to diets with different carbohydrate content and predicts posttranscriptionally regulated target mRNAs enriched for pathways involved in glucoregulation. Together, these results provide a framework for testable hypotheses of functional involvement of specific hepatic miRNAs in GI in rainbow trout.
Collapse
Affiliation(s)
| | - Lucie Marandel
- INRA, Université de Pau et Pays d'Adour, UMR 1419, Nutrition, Metabolism and Aquaculture, E2S UPPA, Saint Pée-sur-Nivelle, France
| | - Mais Jubouri
- Department of Biology, University of Ottawa, Ottawa, Ontario, Canada
| | - Karine Dias
- INRA, Université de Pau et Pays d'Adour, UMR 1419, Nutrition, Metabolism and Aquaculture, E2S UPPA, Saint Pée-sur-Nivelle, France
| | - Robson F de Souza
- Microbiology Department, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Dapeng Zhang
- Department of Biology, Saint Louis University, Saint Louis, Missouri
| | - Christopher J Martyniuk
- Department of Physiological Sciences and Center for Environmental and Human Toxicology, UF Genetics Institute, College of Veterinary Medicine, University of Florida, Gainesville, Florida
| | - Stéphane Panserat
- INRA, Université de Pau et Pays d'Adour, UMR 1419, Nutrition, Metabolism and Aquaculture, E2S UPPA, Saint Pée-sur-Nivelle, France
| | - Jan A Mennigen
- Department of Biology, University of Ottawa, Ottawa, Ontario, Canada
| |
Collapse
|
|
42
|
Ferro F, Spelat R, Shaw G, Duffy N, Islam MN, O'Shea PM, O'Toole D, Howard L, Murphy JM. Survival/Adaptation of Bone Marrow-Derived Mesenchymal Stem Cells After Long-Term Starvation Through Selective Processes. Stem Cells 2019; 37:813-827. [PMID: 30835892 DOI: 10.1002/stem.2998] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 02/04/2019] [Accepted: 02/17/2019] [Indexed: 12/25/2022]
Abstract
After in vivo transplantation, mesenchymal stem cells (MSC) face an ischemic microenvironment, characterized by nutrient deprivation and reduced oxygen tension, which reduces their viability and thus their therapeutic potential. Therefore, MSC response to models of in vitro ischemia is of relevance for improving their survival and therapeutic efficacy. The aim of this study was to understand the survival/adaptive response mechanism that MSC use to respond to extreme culture conditions. Specifically, the effect of a long-term starvation on human bone marrow (hBM)-derived MSC cultured in a chemically defined medium (fetal bovine serum-free [SF] and human SF), either in hypoxic or normoxic conditions. We observed that hBM-MSC that were isolated and cultured in SF medium and subjected to a complete starvation for up to 75 days transiently changed their behavior and phenotype. However, at the end of that period, hBM-MSC retained their characteristics as determined by their morphology, DNA damage resistance, proliferation kinetic, and differentiation potential. This survival mode involved a quiescent state, confirmed by increased expression of cell cycle regulators p16, p27, and p57 and decreased expression of proliferating cell nuclear antigen (PCNA), Ki-67, mTOR, and Nanog. In addition, Jak/STAT (STAT6) antiapoptotic activity selected which cells conserved stemness and that supported metabolic, bioenergetic, and scavenging requirements. We also demonstrated that hBM-MSC exploited an autophagic process which induced lipid β-oxidation as an alternative energy source. Priming MSC by concomitant starvation and culture in hypoxic conditions to induce their quiescence would be of benefit to increase MSC survival when transplanted in vivo. Stem Cells 2019;37:813-827.
Collapse
Affiliation(s)
- Federico Ferro
- Regenerative Medicine Institute (REMEDI), School of Medicine, National University of Ireland Galway (NUIG), Galway, Ireland
| | - Renza Spelat
- Neuroscience Area, International School for Advanced Studies (SISSA), Trieste, Italy
| | - Georgina Shaw
- Regenerative Medicine Institute (REMEDI), School of Medicine, National University of Ireland Galway (NUIG), Galway, Ireland
| | - Niamh Duffy
- Regenerative Medicine Institute (REMEDI), School of Medicine, National University of Ireland Galway (NUIG), Galway, Ireland
| | - Md Nahidul Islam
- Regenerative Medicine Institute (REMEDI), School of Medicine, National University of Ireland Galway (NUIG), Galway, Ireland.,Department of Clinical Biochemistry, Saolta University Health Care Group (SUHCG), Galway University Hospitals, Galway, Ireland
| | - Paula M O'Shea
- Department of Clinical Biochemistry, Saolta University Health Care Group (SUHCG), Galway University Hospitals, Galway, Ireland
| | - Daniel O'Toole
- Regenerative Medicine Institute (REMEDI), School of Medicine, National University of Ireland Galway (NUIG), Galway, Ireland
| | - Linda Howard
- Regenerative Medicine Institute (REMEDI), School of Medicine, National University of Ireland Galway (NUIG), Galway, Ireland
| | - J Mary Murphy
- Regenerative Medicine Institute (REMEDI), School of Medicine, National University of Ireland Galway (NUIG), Galway, Ireland
| |
Collapse
|
|
43
|
Zhou Y, Hu Y, Sun Q, Xie N. Non-coding RNA in Fragile X Syndrome and Converging Mechanisms Shared by Related Disorders. Front Genet 2019; 10:139. [PMID: 30881383 PMCID: PMC6405884 DOI: 10.3389/fgene.2019.00139] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2018] [Accepted: 02/11/2019] [Indexed: 12/12/2022] Open
Abstract
Fragile X syndrome (FXS) is one of the most common forms of hereditary intellectual disability. It is also a well-known monogenic cause of autism spectrum disorders (ASD). Repetitive trinucleotide expansion of CGG repeats in the 5'-UTR of FMR1 is the pathological mutation. Full mutation CGG repeats epigenetically silence FMR1 and thus lead to the absence of its product, fragile mental retardation protein (FMRP), which is an indispensable translational regulator at synapsis. Loss of FMRP causes abnormal neural morphology, dysregulated protein translation, and distorted synaptic plasticity, giving rise to FXS phenotypes. Non-coding RNAs, including siRNA, miRNA, and lncRNA, are transcribed from DNA but not meant for protein translation. They are not junk sequence but play indispensable roles in diverse cellular processes. FXS is the first neurological disorder being linked to miRNA pathway dysfunction. Since then, insightful knowledge has been gained in this field. In this review, we mainly focus on how non-coding RNAs, especially the siRNAs, miRNAs, and lncRNAs, are involved in FXS pathogenesis. We would also like to discuss several potential mechanisms mediated by non-coding RNAs that may be shared by FXS and other related disorders.
Collapse
Affiliation(s)
- Yafang Zhou
- Department of Geriatric Neurology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Central South University, Changsha, China
| | - Yacen Hu
- Department of Geriatric Neurology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Central South University, Changsha, China
| | - Qiying Sun
- Department of Geriatric Neurology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Central South University, Changsha, China
| | - Nina Xie
- Department of Geriatric Neurology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Central South University, Changsha, China
| |
Collapse
|
|
44
|
Ogórek B, Lam HC, Khabibullin D, Liu HJ, Nijmeh J, Triboulet R, Kwiatkowski DJ, Gregory RI, Henske EP. TSC2 regulates microRNA biogenesis via mTORC1 and GSK3β. Hum Mol Genet 2019; 27:1654-1663. [PMID: 29509898 DOI: 10.1093/hmg/ddy073] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Accepted: 02/26/2018] [Indexed: 12/21/2022] Open
Abstract
Tuberous sclerosis complex (TSC) is an autosomal dominant disease caused by germline inactivating mutations of TSC1 or TSC2. In TSC-associated tumors of the brain, heart, skin, kidney and lung, inactivation of both alleles of TSC1 or TSC2 leads to hyperactivation of the mTORC1 pathway. The TSC/mTORC1 pathway is a key regulator of cellular processes related to growth, proliferation and autophagy. We and others have previously found that mTORC1 regulates microRNA biogenesis, but the mechanisms are not fully understood. Microprocessor, a multi-protein complex including the nuclease Drosha, processes the primary miR transcript. Using a dual-luciferase reporter, we found that inhibition of mTORC1 or downregulation of Raptor decreased Microprocessor activity, while loss of TSC2 led to a striking increase (∼5-fold) in Microprocessor activity. To determine the global impact of TSC2 on microRNAs we quantitatively analyzed 752 microRNAs in Tsc2-expressing and Tsc2-deficient cells. Out of 259 microRNAs expressed in both cell lines, 137 were significantly upregulated and 24 were significantly downregulated in Tsc2-deficient cells, consistent with the increased Microprocessor activity. Microprocessor activity is known to be regulated in part by GSK3β. We found that total GSK3β levels were higher in Tsc2-deficient cells, and the increase in Microprocessor activity associated with Tsc2 loss was reversed by three different GSK3β inhibitors. Furthermore, mTOR inhibition increased the levels of phospho-GSK3β (S9), which negatively affects Microprocessor activity. Taken together these data reveal that TSC2 regulates microRNA biogenesis and Microprocessor activity via GSK3β.
Collapse
Affiliation(s)
- Barbara Ogórek
- Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Hilaire C Lam
- Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Damir Khabibullin
- Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Heng-Jia Liu
- Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Julie Nijmeh
- Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Robinson Triboulet
- Stem Cell Program, Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA.,Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
| | - David J Kwiatkowski
- Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Richard I Gregory
- Stem Cell Program, Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA.,Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
| | - Elizabeth P Henske
- Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| |
Collapse
|
|
45
|
de la Cruz López KG, Toledo Guzmán ME, Sánchez EO, García Carrancá A. mTORC1 as a Regulator of Mitochondrial Functions and a Therapeutic Target in Cancer. Front Oncol 2019; 9:1373. [PMID: 31921637 PMCID: PMC6923780 DOI: 10.3389/fonc.2019.01373] [Citation(s) in RCA: 121] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2019] [Accepted: 11/21/2019] [Indexed: 02/05/2023] Open
Abstract
Continuous proliferation of tumor cells requires constant adaptations of energy metabolism to rapidly fuel cell growth and division. This energetic adaptation often comprises deregulated glucose uptake and lactate production in the presence of oxygen, a process known as the "Warburg effect." For many years it was thought that the Warburg effect was a result of mitochondrial damage, however, unlike this proposal tumor cell mitochondria maintain their functionality, and is essential for integrating a variety of signals and adapting the metabolic activity of the tumor cell. The mammalian/mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of numerous cellular processes implicated in proliferation, metabolism, and cell growth. mTORC1 controls cellular metabolism mainly by regulating the translation and transcription of metabolic genes, such as peroxisome proliferator activated receptor γ coactivator-1 α (PGC-1α), sterol regulatory element-binding protein 1/2 (SREBP1/2), and hypoxia inducible factor-1 α (HIF-1α). Interestingly it has been shown that mTORC1 regulates mitochondrial metabolism, thus representing an important regulator in mitochondrial function. Here we present an overview on the role of mTORC1 in the regulation of mitochondrial functions in cancer, considering new evidences showing that mTORC1 regulates the translation of nucleus-encoded mitochondrial mRNAs that result in an increased ATP mitochondrial production. Moreover, we discuss the relationship between mTORC1 and glutaminolysis, as well as mitochondrial metabolites. In addition, mitochondrial fission processes regulated by mTORC1 and its impact on cancer are discussed. Finally, we also review the therapeutic efficacy of mTORC1 inhibitors in cancer treatments, considering its use in combination with other drugs, with particular focus on cellular metabolism inhibitors, that could help improve their anti neoplastic effect and eliminate cancer cells in patients.
Collapse
Affiliation(s)
- Karen Griselda de la Cruz López
- Posgrado en Ciencias Biomédicas, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | | | | | - Alejandro García Carrancá
- Unidad de Investigación Biomédica en Cáncer, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México & Instituto Nacional de Cancerología, Secretaría de Salud, Mexico City, Mexico
- *Correspondence: Alejandro García Carrancá
| |
Collapse
|
|
46
|
Podshivalova K, Wang EA, Hart T, Salomon DR. Expression of the miR-150 tumor suppressor is restored by and synergizes with rapamycin in a human leukemia T-cell line. Leuk Res 2018; 74:1-9. [PMID: 30269036 PMCID: PMC6290994 DOI: 10.1016/j.leukres.2018.09.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Revised: 07/21/2018] [Accepted: 09/18/2018] [Indexed: 02/06/2023]
Abstract
miR-150 functions as a tumor suppressor in malignancies of the lymphocyte lineage and its expression is significantly reduced in these cells. However, the mechanism of miR-150 repression is unknown and so are pharmacological interventions that can reverse it. Here, we report that reduced expression of miR-150 in human Jurkat T-cell acute lymphoblastic leukemia (T-ALL) cells is mediated by constitutive mTOR signaling, a common characteristic of T-ALL cell lines and clinical isolates. Activating mTOR signaling in non-malignant T cells also resulted in a significant miR-150 down-regulation. Conversely, treatment with a pharmacological mTOR inhibitor, rapamycin, increased miR-150 expression in a dose-dependent manner in Jurkat cells, as well as in other leukemia cells. Interestingly, ectopic over-expression of miR-150 acted in a feed-forward loop and further sensitized Jurkat cells to a rapamycin-induced cell cycle arrest by targeting a large network of cell cycle genes. These findings suggest that miR-150 is normally expressed in quiescent T lymphocytes to reinforce an anti-proliferative state, and that mTOR signaling promotes cell proliferation in part by inhibiting miR-150 expression. Restoration of the miR-150-dependent anti-proliferative loop constitutes a novel mechanism underlying the efficacy of rapamycin in a T-ALL cell line. Further investigation of this mechanism in clinical isolates of T-ALL and other hematopoietic malignancies could help better guide development of targeted therapies.
Collapse
Affiliation(s)
- Katie Podshivalova
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, United States.
| | - Eileen A Wang
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, United States
| | - Traver Hart
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, United States
| | - Daniel R Salomon
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, United States
| |
Collapse
|
|
47
|
Treiber T, Treiber N, Meister G. Regulation of microRNA biogenesis and its crosstalk with other cellular pathways. Nat Rev Mol Cell Biol 2018; 20:5-20. [DOI: 10.1038/s41580-018-0059-1] [Citation(s) in RCA: 628] [Impact Index Per Article: 89.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
|
|
48
|
Nie X, Zheng J, Ricupero CL, He L, Jiao K, Mao JJ. mTOR acts as a pivotal signaling hub for neural crest cells during craniofacial development. PLoS Genet 2018; 14:e1007491. [PMID: 29975682 PMCID: PMC6049956 DOI: 10.1371/journal.pgen.1007491] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Revised: 07/17/2018] [Accepted: 06/14/2018] [Indexed: 12/14/2022] Open
Abstract
mTOR is a highly conserved serine/threonine protein kinase that is critical for diverse cellular processes in both developmental and physiological settings. mTOR interacts with a set of molecules including Raptor and Rictor to form two distinct functional complexes, namely the mTORC1 and mTORC2. Here, we used novel genetic models to investigate functions of the mTOR pathway for cranial neural crest cells (NCCs), which are a temporary type of cells arising from the ectoderm layer and migrate to the pharyngeal arches participating craniofacial development. mTOR deletion elicited a proliferation deficit and excessive apoptosis of post-migratory NCCs, leading to growth arrest of the facial primordia along with midline orofacial clefts. Furthermore, NCC differentiation was impaired. Thus, NCC derivatives, such as skeletons, vasculatures and neural tissues were either rudimentary or malformed. We further demonstrate that disruption of mTOR caused P53 hyperactivity and cell cycle arrest in cranial NCCs, and lowering P53 activity by one copy reduction attenuated the severity of craniofacial phenotype in NCC-mTOR knockout mice. Remarkably, NCC-Rptor disruption caused a spectrum of defects mirroring that of the NCC-mTOR deletion, whereas NCC-Rictor disruption only caused a mild craniofacial phenotype compared to the mTOR and Rptor conditional knockout models. Altogether, our data demonstrate that mTOR functions mediated by mTORC1 are indispensable for multiple processes of NCC development including proliferation, survival, and differentiation during craniofacial morphogenesis and organogenesis, and P53 hyperactivity in part accounts for the defective craniofacial development in NCC-mTOR knockout mice.
Collapse
Affiliation(s)
- Xuguang Nie
- Center for Craniofacial Regeneration, College of Dental Medicine, Columbia University, New York, New York, United States of America
| | - Jinxuan Zheng
- Center for Craniofacial Regeneration, College of Dental Medicine, Columbia University, New York, New York, United States of America
| | - Christopher L. Ricupero
- Center for Craniofacial Regeneration, College of Dental Medicine, Columbia University, New York, New York, United States of America
| | - Ling He
- Center for Craniofacial Regeneration, College of Dental Medicine, Columbia University, New York, New York, United States of America
| | - Kai Jiao
- University of Alabama at Birmingham, Department of Genetics, Birmingham, Alabama, United States of America
| | - Jeremy J. Mao
- Center for Craniofacial Regeneration, College of Dental Medicine, Columbia University, New York, New York, United States of America
- Department of Pathology and Cell Biology, Columbia University, New York, New York, United States of America
| |
Collapse
|
|
49
|
Loss of Drosha underlies dopaminergic neuron toxicity in models of Parkinson's disease. Cell Death Dis 2018; 9:693. [PMID: 29880811 PMCID: PMC5992196 DOI: 10.1038/s41419-018-0716-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Revised: 04/26/2018] [Accepted: 05/17/2018] [Indexed: 01/06/2023]
Abstract
MiRNAs, a group of powerful modulator of gene expression, participate in multiple cellular processes under physiological and pathological conditions. Emerging evidence shows that Drosha, which controls the initial step in canonical miRNA biogenesis, is involved in modulating cell survival and death in models of several diseases. However, the role of Drosha in Parkinson’s disease (PD) has not been well established. Here, we show that the level of Drosha decreases in 6-OHDA-induced cellular and animal models of PD. 6-OHDA induced a p38 MAPK-dependent phosphorylation of Drosha. This triggered Drosha degradation. Enhancing the level of Drosha protected the dopaminergic (DA) neurons from 6-OHDA-induced toxicity in both in vitro and in vivo models of PD and alleviated the motor deficits of PD mice. These findings reveal that Drosha plays a critical role in the survival of DA neurons and suggest that stress-induced destabilization of Drosha may be part of the pathological process in PD.
Collapse
|
|
50
|
Neuronal activity regulates DROSHA via autophagy in spinal muscular atrophy. Sci Rep 2018; 8:7907. [PMID: 29784949 PMCID: PMC5962575 DOI: 10.1038/s41598-018-26347-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Accepted: 05/10/2018] [Indexed: 02/06/2023] Open
Abstract
Dysregulated miRNA expression and mutation of genes involved in miRNA biogenesis have been reported in motor neuron diseases including spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS). Therefore, identifying molecular mechanisms governing miRNA expression is important to understand these diseases. Here, we report that expression of DROSHA, which is a critical enzyme in the microprocessor complex and essential for miRNA biogenesis, is reduced in motor neurons from an SMA mouse model. We show that DROSHA is degraded by neuronal activity induced autophagy machinery, which is also dysregulated in SMA. Blocking neuronal activity or the autophagy-lysosome pathway restores DROSHA levels in SMA motor neurons. Moreover, reducing DROSHA levels enhances axonal growth. As impaired axonal growth is a well described phenotype of SMA motor neurons, these data suggest that DROSHA reduction by autophagy may mitigate the phenotype of SMA. In summary, these findings suggest that autophagy regulates RNA metabolism and neuronal growth via the DROSHA/miRNA pathway and this pathway is dysregulated in SMA.
Collapse
|