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Yang J, Zhang S, Li X, Chen Z, Xu J, Chen J, Tan Y, Li G, Yu B, Gu X, Xu L. Convergent and divergent transcriptional reprogramming of motor and sensory neurons underlying response to peripheral nerve injury. J Adv Res 2025; 72:135-150. [PMID: 39002719 DOI: 10.1016/j.jare.2024.07.008] [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: 10/15/2023] [Revised: 07/10/2024] [Accepted: 07/10/2024] [Indexed: 07/15/2024] Open
Abstract
INTRODUCTION Motor neurons differ from sensory neurons in aspects including origins and surrounding environment. Understanding the similarities and differences in molecular response to peripheral nerve injury (PNI) and regeneration between sensory and motor neurons is crucial for developing effective drug targets for CNS regeneration. However, genome-wide comparisons of molecular changes between sensory and motor neurons following PNI remains limited. OBJECTIVES This study aims to investigate genome-wide convergence and divergence of injury response between sensory and motor neurons to identify novel drug targets for neural repair. METHODS We analyzed two large-scale RNA-seq datasets of in situ captured sensory neurons (SNs) and motoneurons (MNs) upon PNI, retinal ganglion cells and spinal cord upon CNS injury. Additionally, we integrated these with other related single-cell level datasets. Bootstrap DESeq2 and WGCNA were used to detect and explore co-expression modules of differentially expressed genes (DEGs). RESULTS We found that SNs and MNs exhibited similar injury states, but with a delayed response in MNs. We identified a conserved regeneration-associated module (cRAM) with 274 shared DEGs. Of which, 47% of DEGs could be changed in injured neurons supported by single-cell resolution datasets. We also identified some less-studied candidates in cRAM, including genes associated with transcription, ubiquitination (Rnf122), and neuron-immune cells cross-talk. Further in vitro experiments confirmed a novel role of Rnf122 in axon growth. Analysis of the top 10% of DEGs with a large divergence suggested that both extrinsic (e.g., immune microenvironment) and intrinsic factors (e.g., development) contributed to expression divergence between SNs and MNs following injury. CONCLUSIONS This comprehensive analysis revealed convergent and divergent injury response genes in SNs and MNs, providing new insights into transcriptional reprogramming of sensory and motor neurons responding to axonal injury and subsequent regeneration. It also identified some novel regeneration-associated candidates that may facilitate the development of strategies for axon regeneration.
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Affiliation(s)
- Jian Yang
- Department of Neurosurgery, People's Hospital of Deyang City, Sichuan Clinical Research Center for Neurological Diseases, Deyang 618000, China; Co-innovation Center of Neuroregeneration, Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong 226000, China.
| | - Shuqiang Zhang
- Co-innovation Center of Neuroregeneration, Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong 226000, China
| | - Xiaodi Li
- Chinese Medicine Modernization and Big Data Research Center, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing 210000, China
| | - Zhifeng Chen
- Co-innovation Center of Neuroregeneration, Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong 226000, China
| | - Jie Xu
- Co-innovation Center of Neuroregeneration, Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong 226000, China
| | - Jing Chen
- Co-innovation Center of Neuroregeneration, Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong 226000, China
| | - Ya Tan
- Co-innovation Center of Neuroregeneration, Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong 226000, China
| | - Guicai Li
- Co-innovation Center of Neuroregeneration, Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong 226000, China
| | - Bin Yu
- Co-innovation Center of Neuroregeneration, Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong 226000, China
| | - Xiaosong Gu
- Co-innovation Center of Neuroregeneration, Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong 226000, China.
| | - Lian Xu
- Co-innovation Center of Neuroregeneration, Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong 226000, China; Institute for Translational Neuroscience, the Second Affiliated Hospital of Nantong University, Nantong University, Nantong, Jiangsu 226000, China.
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Martínez-López N, Pereiro P, Saco A, Lama R, Figueras A, Novoa B. Characterization of a fish-specific immunoglobulin-like domain-containing protein (Igldcp) in zebrafish (Danio rerio) induced after nodavirus infection. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2025; 162:105285. [PMID: 39515405 DOI: 10.1016/j.dci.2024.105285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Revised: 11/05/2024] [Accepted: 11/05/2024] [Indexed: 11/16/2024]
Abstract
One of the most highly induced genes in zebrafish (Danio rerio) larvae after infection with the nodavirus red-spotted grouper nervous necrosis virus (RGNNV) was a member of the immunoglobulin superfamily (IgSF), which has remained uncharacterized and erroneously annotated in zebrafish and other fish species as galectin 17 (lgals17). We characterized this gene and named it immunoglobulin (Ig)-like domain-containing protein (igldcp), a new member of the IgSF that does not possess orthologs in mammals. Igldcp expression is induced by viral infection and it belongs to the group of interferon-stimulated genes (ISGs). In vitro overexpression of igldcp decreased RGNNV replication, whereas in vivo knockdown of this gene had the opposite effect, resulting in increased larval mortality. RNA-Seq analyses of larvae overexpressing igldcp in the absence or presence of infection with RGNNV showed that the main processes affected by Igldcp could be directly involved in the regulation of various cellular processes associated with the modulation of the immune system.
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Affiliation(s)
| | | | - Amaro Saco
- Institute of Marine Research (IIM-CSIC), Vigo, Spain
| | - Raquel Lama
- Institute of Marine Research (IIM-CSIC), Vigo, Spain
| | | | - Beatriz Novoa
- Institute of Marine Research (IIM-CSIC), Vigo, Spain.
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Deng Y, Yang Y, Xiao Y, Zeng X, Xie HL, Lan R, Zhang L, Yang H. Annual Energy-Saving Smart Windows with Actively Controllable Passive Radiative Cooling and Multimode Heating Regulation. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2024; 36:e2401869. [PMID: 38641342 DOI: 10.1002/adma.202401869] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/04/2024] [Revised: 04/15/2024] [Indexed: 04/21/2024]
Abstract
Smart windows with radiative heat management capability using the sun and outer space as zero-energy thermodynamic resources have gained prominence, demonstrating a minimum carbon footprint. However, realizing on-demand thermal management throughout all seasons while reducing fossil energy consumption remains a formidable challenge. Herein, an energy-efficient smart window that enables actively tunable passive radiative cooling (PRC) and multimode heating regulation is demonstrated by integrating the emission-enhanced polymer-dispersed liquid crystal (SiO2@PRC PDLC) film and a low-emission layer deposited with carbon nanotubes. Specifically, this device can achieve a temperature close to the chamber interior ambient under solar irradiance of 700 W m-2, as well as a temperature drop of 2.3 °C at sunlight of 500 W m-2, whose multistage PRC efficiency can be rapidly adjusted by a moderate voltage. Meanwhile, synchronous cooperation of passive radiative heating (PRH), solar heating (SH), and electric heating (EH) endows this smart window with the capability to handle complicated heating situations during cold weather. Energy simulation reveals the substantial superiority of this device in energy savings compared with single-layer SiO2@PRC PDLC, normal glass, and commercial low-E glass when applied in different climate zones. This work provides a feasible pathway for year-round thermal management, presenting a huge potential in energy-saving applications.
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Affiliation(s)
- Yuan Deng
- Key Lab of Environment-friendly Chemistry and Application in Ministry of Education and Key Laboratory of Advanced Functional Polymer Materials of Colleges and Universities of Hunan Province and College of Chemistry, Xiangtan University, Xiangtan, Hunan, 411105, China
| | - Yihai Yang
- Beijing Advanced Innovation Center for Materials Genome Engineering and School of Materials Science and Engineering, Peking University, Beijing, 100871, P. R. China
| | - Yuanhang Xiao
- Key Lab of Environment-friendly Chemistry and Application in Ministry of Education and Key Laboratory of Advanced Functional Polymer Materials of Colleges and Universities of Hunan Province and College of Chemistry, Xiangtan University, Xiangtan, Hunan, 411105, China
| | - Xingping Zeng
- College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang, 330022, P. R. China
| | - He-Lou Xie
- Key Lab of Environment-friendly Chemistry and Application in Ministry of Education and Key Laboratory of Advanced Functional Polymer Materials of Colleges and Universities of Hunan Province and College of Chemistry, Xiangtan University, Xiangtan, Hunan, 411105, China
| | - Ruochen Lan
- Institute of Advanced Materials, Jiangxi Normal University, Nanchang, 330022, P. R. China
| | - Lanying Zhang
- Beijing Advanced Innovation Center for Materials Genome Engineering and School of Materials Science and Engineering, Peking University, Beijing, 100871, P. R. China
| | - Huai Yang
- Beijing Advanced Innovation Center for Materials Genome Engineering and School of Materials Science and Engineering, Peking University, Beijing, 100871, P. R. China
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Zhao H, Wei Y, Zhang J, Zhang K, Tian L, Liu Y, Zhang S, Zhou Y, Wang Z, Shi S, Fu Z, Fu J, Zhao J, Li X, Zhang L, Zhao L, Liu K. HPV16 infection promotes the malignant transformation of the esophagus and progression of esophageal squamous cell carcinoma. J Med Virol 2023; 95:e29132. [PMID: 37792307 DOI: 10.1002/jmv.29132] [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: 06/06/2023] [Revised: 07/27/2023] [Accepted: 09/05/2023] [Indexed: 10/05/2023]
Abstract
Esophageal squamous cell carcinoma (ESCC) may be correlated with HPV infection, and the mechanism underlying the ESCC formation induced by HPV16 infection remains elusive. Here, we overexpressed HPV16 E6 and E7 and coordinated the overexpression of these two genes in EPC2 and ESCC cells. We found that E7 and coordinated expression of E6 and E7 promoted the proliferation of EPC2 cells, and upregulation of shh was responsible for cell proliferation since the use of vismodegib led to the failure of organoid formation. Meanwhile, overexpression of E6 and E7 in ESCC cells promoted cell proliferation, migration, and invasion in vitro. Importantly, E6 and E7 coordinately increased the capability of tumor growth in nude mice, while vismodegib slowed the growth of tumors in NCG mice. Moreover, a series of genes and proteins changed in cell lines after overexpression of the E6 and E7 genes, the potential biological processes and pathways were systematically analyzed using a bioinformatics assay. Together, these findings suggest that the activation of the hedgehog pathway induced by HPV16 infection may initially transform basal cells in the esophagus and promote following malignant processes in ESCC cells. The application of hedgehog inhibitors may represent a therapeutic avenue for ESCC treatment.
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Affiliation(s)
- Hongzhou Zhao
- Central Laboratory, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, People's Republic of China
- School of Medicine, Xiamen University, Xiamen, Fujian, People's Republic of China
| | - Yuxuan Wei
- Central Laboratory, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, People's Republic of China
- School of Medicine, Xiamen University, Xiamen, Fujian, People's Republic of China
| | - Jiaying Zhang
- School of Life Science, Xiamen University, Xiamen, Fujian, People's Republic of China
| | - Kun Zhang
- Department of General Surgery, The First Hospital of Fuzhou, Fuzhou, Fujian, People's Republic of China
| | - Liming Tian
- Department of Gynecology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, People's Republic of China
| | - Yongpan Liu
- School of Life Science, Xiamen University, Xiamen, Fujian, People's Republic of China
| | - Shihui Zhang
- Centre for Translational Stem Cell Biology, School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong SAR, People's Republic of China
| | - Yijian Zhou
- Central Laboratory, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, People's Republic of China
- School of Medicine, Xiamen University, Xiamen, Fujian, People's Republic of China
| | - Zhuo Wang
- Central Laboratory, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, People's Republic of China
- School of Medicine, Xiamen University, Xiamen, Fujian, People's Republic of China
| | - Songlin Shi
- School of Medicine, Xiamen University, Xiamen, Fujian, People's Republic of China
| | - Zhichao Fu
- Department of Radiotherapy, 900 Hospital of the Joint Logistics Team (Dongfang Hospital, Xiamen University), Fuzhou, Fujian, People's Republic of China
| | - Jianqian Fu
- Department of Medical Oncology, The Fifth Hospital of Xiamen, Xiamen, Fujian, People's Republic of China
| | - Jing Zhao
- Central Laboratory, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, People's Republic of China
- School of Medicine, Xiamen University, Xiamen, Fujian, People's Republic of China
| | - Xinxin Li
- Central Laboratory, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, People's Republic of China
- School of Medicine, Xiamen University, Xiamen, Fujian, People's Republic of China
| | - Lijia Zhang
- Central Laboratory, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, People's Republic of China
| | - Liran Zhao
- School of Medicine, Xiamen University, Xiamen, Fujian, People's Republic of China
| | - Kuancan Liu
- Central Laboratory, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, People's Republic of China
- School of Medicine, Xiamen University, Xiamen, Fujian, People's Republic of China
- School of Life Science, Nanchang Normal University, Nanchang, Jiangxi, People's Republic of China
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Construction and Validation of an Oxaliplatin-Resistant Gene Signature in Colorectal Cancer Patients Who Underwent Chemotherapy. Pharmaceuticals (Basel) 2022; 15:ph15091139. [PMID: 36145360 PMCID: PMC9503614 DOI: 10.3390/ph15091139] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 09/02/2022] [Accepted: 09/06/2022] [Indexed: 11/16/2022] Open
Abstract
Aberrant expression of genes contributes to the chemoresistance of colorectal cancer (CRC) treatment. This study aimed to identify genes associated with the chemoresistance of oxaliplatin-based chemotherapy in CRC patients and to construct a signature. Oxaliplatin resistance-related genes were screened by analyzing the gene profiles of cell lines and tissue samples that underwent oxaliplatin-based treatment. Oxaliplatin resistance-related genes were used to establish a signature. The association of the signature had clinical significance, so the prognostic value of the signature was analyzed. Independent cohorts and CRC cell lines were used to validate the value of the gene signature and the oxaliplatin-resistant genes. There were 64 oxaliplatin resistance-related genes identified after overlapping the genes from the dataset of oxaliplatin-treated CRC cells and the dataset of patients treated with oxaliplatin-based chemotherapy. A gene signature based on five oxaliplatin resistance-related genes was established. This gene signature effectively predicted the prognosis of CRC patients who underwent chemotherapy. No significant associations were found between the gene mutations and survival of the patients; however, two genes were associated with microsatellite instability status. Two external independent cohorts and CRC cell line experiments validated the prognostic values of the signature and expression of the genes after oxaliplatin treatment. In conclusion, the oxaliplatin resistance-related gene signature involving five genes was a novel biomarker for the prediction of the chemotherapy response and prognosis of CRC patients who underwent oxaliplatin-based chemotherapy.
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Inactivation of tumor suppressor TAp63 by hepatitis B virus X protein in hepatocellular carcinoma. Chin Med J (Engl) 2022; 135:1728-1733. [PMID: 35950770 PMCID: PMC9509107 DOI: 10.1097/cm9.0000000000002283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND The hepatitis B virus X (HBx) protein plays a critical role in the initiation and progression of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC). In the early stage of the disease, HBx facilitates tumor onset by inactivating the tumor suppressor p53. The p53-encoding gene, however, is frequently mutated or deleted as the cancer progresses to the late stage and, under such circumstance, the p53 homolog TAp63 can harness HCC growth by transactivating several important p53-target genes. METHODS To determine whether HBx regulates TAp63, we performed co-immunoprecipitation assay, real-time quantitative polymerase chain reaction, immunoblotting, and flow cytometry analysis in p53-null cancer cell lines, Hep3B and H1299. RESULTS HBx interacts with the transactivation domain of TAp63, as HBx was co-immunoprecipitated with TAp63 but not with ΔNp63. The interaction between HBx and TAp63 abolished transcriptional activity of TAp63, as evidenced by the reduction of the levels of its target genes p21 and PUMA , consequently leading to restricted apoptosis and augmented proliferation of HCC cells. CONCLUSION HBV induces progression of HCC that harbors defective p53 by inhibiting the tumor suppressor TAp63.
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Gehi BR, Gadhave K, Uversky VN, Giri R. Intrinsic disorder in proteins associated with oxidative stress-induced JNK signaling. Cell Mol Life Sci 2022; 79:202. [PMID: 35325330 PMCID: PMC11073203 DOI: 10.1007/s00018-022-04230-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 03/01/2022] [Accepted: 03/03/2022] [Indexed: 01/02/2023]
Abstract
The c-Jun N-terminal kinase (JNK) signaling cascade is a mitogen-activated protein kinase (MAPK) signaling pathway that can be activated in response to a wide range of environmental stimuli. Based on the type, degree, and duration of the stimulus, the JNK signaling cascade dictates the fate of the cell by influencing gene expression through its substrate transcription factors. Oxidative stress is a result of a disturbance in the pro-oxidant/antioxidant homeostasis of the cell and is associated with a large number of diseases, such as neurodegenerative disorders, cancer, diabetes, cardiovascular diseases, and disorders of the immune system, where it activates the JNK signaling pathway. Among different biological roles ascribed to the intrinsically disordered proteins (IDPs) and hybrid proteins containing ordered domains and intrinsically disordered protein regions (IDPRs) are signaling hub functions, as intrinsic disorder allows proteins to undertake multiple interactions, each with a different consequence. In order to ensure precise signaling, the cellular abundance of IDPs is highly regulated, and mutations or changes in abundance of IDPs/IDPRs are often associated with disease. In this study, we have used a combination of six disorder predictors to evaluate the presence of intrinsic disorder in proteins of the oxidative stress-induced JNK signaling cascade, and as per our findings, none of the 18 proteins involved in this pathway are ordered. The highest level of intrinsic disorder was observed in the scaffold proteins, JIP1, JIP2, JIP3; dual specificity phosphatases, MKP5, MKP7; 14-3-3ζ and transcription factor c-Jun. The MAP3Ks, MAP2Ks, MAPKs, TRAFs, and thioredoxin were the proteins that were predicted to be moderately disordered. Furthermore, to characterize the predicted IDPs/IDPRs in the proteins of the JNK signaling cascade, we identified the molecular recognition features (MoRFs), posttranslational modification (PTM) sites, and short linear motifs (SLiMs) associated with the disordered regions. These findings will serve as a foundation for experimental characterization of disordered regions in these proteins, which represents a crucial step for a better understanding of the roles of IDPRs in diseases associated with this important pathway.
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Affiliation(s)
- Bhuvaneshwari R Gehi
- School of Basic Sciences, Indian Institute of Technology Mandi, VPO Kamand, Mandi, Himachal Pradesh, 175005, India
- Molecular Biophysics Unit (MBU), Indian Institute of Science, Bengaluru, 560012, India
| | - Kundlik Gadhave
- School of Basic Sciences, Indian Institute of Technology Mandi, VPO Kamand, Mandi, Himachal Pradesh, 175005, India
| | - Vladimir N Uversky
- Department of Molecular Medicine and Byrd Alzheimer's Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
- Laboratory of New Methods in Biology, Institute for Biological Instrumentation of the Russian Academy of Sciences, Federal Research Center "Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences", Pushchino, Moscow region, 142290, Russia.
| | - Rajanish Giri
- School of Basic Sciences, Indian Institute of Technology Mandi, VPO Kamand, Mandi, Himachal Pradesh, 175005, India.
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Huang S, Cao B, Wang J, Zhang Y, Ledet E, Sartor O, Xiong Y, Zeng SX, Lu H. Cancer-derived C-terminus-extended p53 mutation confers dominant-negative effect on its wild-type counterpart. J Mol Cell Biol 2021; 14:6464145. [PMID: 34918105 PMCID: PMC8964174 DOI: 10.1093/jmcb/mjab078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 10/25/2021] [Accepted: 10/28/2021] [Indexed: 11/24/2022] Open
Abstract
The vast majority of p53 missense mutants lose the wild-type (wt) function and/or exert ‘dominant-negative’ effects on their wt counterpart. Here, we identify a novel form of p53 mutation with an extended C-terminus (p53 long C-terminus, p53LC) in a variety of human cancers. Interestingly, the two representative mutants (named ‘p53-374*48’ and ‘p53-393*78’) as tested in this study show both loss-of-function and dominant-negative phenotypes in cell proliferation and colony formation assays. Mechanistically, p53LCs interact with and retain wt p53 in the cytoplasm and prevent it from binding to the promoters of target genes, consequently inhibiting its transcriptional activity. Also, p53LCs are very stable, though not acetylated in cells. Remarkably, the p53LCs can desensitize wt p53-containing cancer cells to p53-activating agents. Together, our results unveil a longer form of p53 mutant that possesses a dominant-negative effect on its wt counterpart, besides losing its wt activity.
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Affiliation(s)
- Shibo Huang
- Institute of Clinical Pharmacology, Nanchang University, Nanchang 330006, China.,Department of Biochemistry & Molecular Biology and Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Bo Cao
- Department of Biochemistry & Molecular Biology and Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA 70112, USA.,College of Pharmacy, Xavier University of Louisiana, New Orleans, LA 70125, USA
| | - Jieqiong Wang
- Department of Biochemistry & Molecular Biology and Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Yiwei Zhang
- Department of Biochemistry & Molecular Biology and Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Elisa Ledet
- Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Oliver Sartor
- Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Yuqin Xiong
- Institute of Clinical Pharmacology, Nanchang University, Nanchang 330006, China
| | - Shelya X Zeng
- Department of Biochemistry & Molecular Biology and Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Hua Lu
- Department of Biochemistry & Molecular Biology and Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA 70112, USA
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Comparative Transcriptomic Analysis of Regenerated Skins Provides Insights into Cutaneous Air-Breathing Formation in Fish. BIOLOGY 2021; 10:biology10121294. [PMID: 34943209 PMCID: PMC8698756 DOI: 10.3390/biology10121294] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 12/06/2021] [Accepted: 12/07/2021] [Indexed: 11/16/2022]
Abstract
Cutaneous air-breathing is one of the air-breathing patterns in bimodal respiration fishes, while little is known about its underlying formation mechanisms. Here, we first investigated the skin regeneration of loach (Misgurnus anguillicaudatus, a cutaneous air-breathing fish) and yellow catfish (Pelteobagrus fulvidraco, a water-breathing fish) through morphological and histological observations. Then, the original skins (OS: MOS, POS) and regenerated skins (RS: MRS, PRS) when their capillaries were the most abundant (the structural foundation of air-breathing in fish) during healing, of the two fish species were collected for high-throughput RNA-seq. A total of 56,054 unigenes and 53,731 unigenes were assembled in loach and yellow catfish, respectively. A total of 640 (460 up- and 180 down-regulated) and 4446 (2340 up- and 2106 down-regulated) differentially expressed genes (DEGs) were respectively observed in RS/OS of loach and yellow catfish. Subsequently, the two DEG datasets were clustered in GO, KOG and KEGG databases, and further analyzed by comparison and screening. Consequently, tens of genes and thirteen key pathways were targeted, indicating that these genes and pathways had strong ties to cutaneous skin air-breathing in loach. This study provides new insights into the formation mechanism of cutaneous air-breathing and also offers a substantial contribution to the gene expression profiles of skin regeneration in fish.
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Jung JH, Lee D, Ko HM, Jang HJ. Inhibition of CNOT2 Induces Apoptosis via MID1IP1 in Colorectal Cancer Cells by Activating p53. Biomolecules 2021; 11:biom11101492. [PMID: 34680125 PMCID: PMC8533695 DOI: 10.3390/biom11101492] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 10/08/2021] [Accepted: 10/08/2021] [Indexed: 12/13/2022] Open
Abstract
CCR4-NOT transcription complex subunit 2 (CNOT2), a subunit of the CCR4-NOT complex, has been described in cancer progression. The CNOT complex plays an important role in multiple cellular functions. Recent studies in our laboratory showed that CNOT2 promotes breast cancer cell proliferation and angiogenesis. In addition, CNOT2 signals are critically related to apoptosis induced by atorvastatin in lung cancer cells. Furthermore, depletion of CNOT2 was shown to enhance the antitumor effect of midline 1 interacting protein 1 (MID1IP1) depletion, thus inhibiting c-Myc expression in liver cancer cells. However, the molecular mechanisms related to its oncogenic role remain unclear. Herein, for the first time, we report that CNOT2 inhibition can induce apoptosis in colorectal cancer cells by activating p53. Inhibition of CNOT2 markedly induced apoptosis in various cancer cells like that of the wild-type p53. Furthermore, inhibition of CNOT2 elongated p53 s half-life. Previously, our laboratory demonstrated that MID1IP1 promoted colocalization with c-Myc mediated by CNOT2. Interestingly, inhibition of CNOT2 cannot induce p53 expression without MID1IP1 or apoptosis in cancer cells. In conclusion, our results demonstrate that CNOT2 inhibition induces apoptosis through MID1IP1 by activating p53.
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Affiliation(s)
- Ji Hoon Jung
- College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea; (H.M.K.); (H.-J.J.)
- Correspondence: ; Tel.: +82-2-961-2171
| | - Duckgue Lee
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan-si 31151, Korea;
| | - Hyun Min Ko
- College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea; (H.M.K.); (H.-J.J.)
| | - Hyeung-Jin Jang
- College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea; (H.M.K.); (H.-J.J.)
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Abstract
The tumor suppressor p53 prevents tumorigenesis, while inactivation of p53 promotes cancer development and drug resistance. Here, we identify that a long noncoding RNA, the RNA component of mitochondrial RNA-processing endoribonuclease (RMRP), promotes growth and proliferation of colorectal cancer cells by inhibiting p53 activity. Mechanistically, RMRP retains SNRPA1 in the nucleus, thus preventing its lysosomal degradation. The nuclear SNRPA1 then prompts MDM2-mediated p53 ubiquitination and degradation. Remarkably, RMRP expression is induced by poly (ADP-ribose) polymerase (PARP) inhibitors, a group of targeted anticancer drugs, through the transcription factor C/EBPβ. Targeting RMRP significantly enhances sensitivity of colorectal cancer cells to PARP inhibition by reactivating p53. Our study provides a possible mechanism underling tumor resistance to PARP inhibitors. p53 inactivation is highly associated with tumorigenesis and drug resistance. Here, we identify a long noncoding RNA, the RNA component of mitochondrial RNA-processing endoribonuclease (RMRP), as an inhibitor of p53. RMRP is overexpressed and associated with an unfavorable prognosis in colorectal cancer. Ectopic RMRP suppresses p53 activity by promoting MDM2-induced p53 ubiquitination and degradation, while depletion of RMRP activates the p53 pathway. RMRP also promotes colorectal cancer growth and proliferation in a p53-dependent fashion in vitro and in vivo. This anti-p53 action of RMRP is executed through an identified partner protein, SNRPA1. RMRP can interact with SNRPA1 and sequester it in the nucleus, consequently blocking its lysosomal proteolysis via chaperone-mediated autophagy. The nuclear SNRPA1 then interacts with p53 and enhances MDM2-induced proteasomal degradation of p53. Remarkably, ablation of SNRPA1 completely abrogates RMRP regulation of p53 and tumor cell growth, indicating that SNRPA1 is indispensable for the anti-p53 function of RMRP. Interestingly and significantly, poly (ADP-ribose) polymerase (PARP) inhibitors induce RMRP expression through the transcription factor C/EBPβ, and RMRP confers tumor resistance to PARP inhibition by preventing p53 activation. Altogether, our study demonstrates that RMRP plays an oncogenic role by inactivating p53 via SNRPA1 in colorectal cancer.
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Hao Q, Chen J, Liao J, Huang Y, Gan Y, Larisch S, Zeng SX, Lu H, Zhou X. p53 induces ARTS to promote mitochondrial apoptosis. Cell Death Dis 2021; 12:204. [PMID: 33627621 PMCID: PMC7904775 DOI: 10.1038/s41419-021-03463-8] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 01/13/2021] [Accepted: 01/19/2021] [Indexed: 11/09/2022]
Abstract
Apoptosis related protein in TGF-β signaling pathway (ARTS) was originally discovered in cells undergoing apoptosis in response to TGF-β, but ARTS also acts downstream of many other apoptotic stimuli. ARTS induces apoptosis by antagonizing the anti-apoptotic proteins XIAP and Bcl-2. Here we identified the pro-apoptotic Sept4/ARTS gene as a p53-responsive target gene. Ectopic p53 and a variety of p53-inducing agents increased both mRNA and protein levels of ARTS, whereas ablation of p53 reduced ARTS expression in response to multiple stress conditions. Also, γ-irradiation induced p53-dependent ARTS expression in mice. Consistently, p53 binds to the responsive DNA element on the ARTS promoter and transcriptionally activated the promoter-driven expression of a luciferase reporter gene. Interestingly, ARTS binds to and sequesters p53 at mitochondria, enhancing the interaction of the latter with Bcl-XL. Ectopic ARTS markedly augments DNA damage stress- or Nutlin-3-triggered apoptosis, while ablation of ARTS preferentially impairs p53-induced apoptosis. Altogether, these findings demonstrate that ARTS collaborates with p53 in mitochondria-engaged apoptosis.
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Affiliation(s)
- Qian Hao
- Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Jiaxiang Chen
- Department of Biochemistry & Molecular Biology and Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA, 70112, USA
- Department of Physiology, Medical College of Nanchang University, Nanchang, 330006, China
| | - Junming Liao
- Department of Biochemistry & Molecular Biology and Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA, 70112, USA
| | - Yingdan Huang
- Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Yu Gan
- Department of Physiology, Medical College of Nanchang University, Nanchang, 330006, China
| | - Sarit Larisch
- Cell Death and Cancer Research Laboratory, Department of Biology, University of Haifa, Haifa, 31905, Israel
| | - Shelya X Zeng
- Department of Biochemistry & Molecular Biology and Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA, 70112, USA
| | - Hua Lu
- Department of Biochemistry & Molecular Biology and Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA, 70112, USA.
| | - Xiang Zhou
- Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
- Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China.
- Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
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Xiao X, Xin C, Zhang Y, Yan J, Chen Z, Xu H, Liang M, Wu B, Fang F, Qiu W. Characterization of Odontogenic Differentiation from Human Dental Pulp Stem Cells Using TMT-Based Proteomic Analysis. BIOMED RESEARCH INTERNATIONAL 2020; 2020:3871496. [PMID: 33490242 PMCID: PMC7789479 DOI: 10.1155/2020/3871496] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 11/10/2020] [Accepted: 11/20/2020] [Indexed: 01/09/2023]
Abstract
BACKGROUND The repair of dental pulp injury relies on the odontogenic differentiation of dental pulp stem cells (DPSCs). To better understand the odontogenic differentiation of DPSCs and identify proteins involved in this process, tandem mass tags (TMTs) coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS) were applied to compare the proteomic profiles of induced and control DPSCs. METHODS The proteins expressed during osteogenic differentiation of human DPSCs were profiled using the TMT method combined with LC-MS/MS analysis. The identified proteins were subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Then, a protein-protein interaction (PPI) network was constructed. Two selected proteins were confirmed by western blotting (WB) analysis. RESULTS A total of 223 proteins that were differentially expressed were identified. Among them, 152 proteins were significantly upregulated and 71 were downregulated in the odontogenic differentiation group compared with the control group. On the basis of biological processes in GO, the identified proteins were mainly involved in cellular processes, metabolic processes, and biological regulation, which are connected with the signaling pathways highlighted by KEGG pathway analysis. PPI networks showed that most of the differentially expressed proteins were implicated in physical or functional interaction. The protein expression levels of FBN1 and TGF-β2 validated by WB were consistent with the proteomic analysis. CONCLUSIONS This is the first proteomic analysis of human DPSC odontogenesis using a TMT method. We identified many new differentially expressed proteins that are potential targets for pulp-dentin complex regeneration and repair.
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Affiliation(s)
- Xijuan Xiao
- Yuncheng Stomatological Hospital, Yuncheng Stomatological Health School, South Section of Yuxi Road, Yuncheng 044000, China
| | - Caihong Xin
- Yuncheng Stomatological Hospital, Yuncheng Stomatological Health School, South Section of Yuxi Road, Yuncheng 044000, China
| | - Yuqin Zhang
- Yuncheng Stomatological Hospital, Yuncheng Stomatological Health School, South Section of Yuxi Road, Yuncheng 044000, China
| | - Jie Yan
- Yuncheng Stomatological Hospital, Yuncheng Stomatological Health School, South Section of Yuxi Road, Yuncheng 044000, China
| | - Zhao Chen
- Guangdong Provincial Key Laboratory of Oral Diseases, Guangzhou 510055, China
- Department of Stomatology, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou 510515, China
| | - Huiyong Xu
- Department of Stomatology, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou 510515, China
| | - Min Liang
- Department of Periodontology, Guanghua School and Hospital of Stomatology and Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong 510055, China
| | - Buling Wu
- Department of Stomatology, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou 510515, China
| | - Fuchun Fang
- Guangdong Provincial Key Laboratory of Oral Diseases, Guangzhou 510055, China
- Department of Stomatology, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou 510515, China
| | - Wei Qiu
- Guangdong Provincial Key Laboratory of Oral Diseases, Guangzhou 510055, China
- Department of Stomatology, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou 510515, China
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Pan J, Li Z, Dai S, Ding H, Wang Q, Li X, Ding G, Wang P, Guan Y, Liu W. Integrative analyses of transcriptomics and metabolomics upon seed germination of foxtail millet in response to salinity. Sci Rep 2020; 10:13660. [PMID: 32788682 PMCID: PMC7423953 DOI: 10.1038/s41598-020-70520-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Accepted: 05/13/2020] [Indexed: 02/07/2023] Open
Abstract
Salinity stress has become an expanding threat to food security worldwide. Revealing the mechanisms of salinity tolerance in plants has immense significance. Foxtail millet (Setaria italica L.) has been regarded as a model crop for exploring mechanisms under stress, considering its extreme adaptation abilities to adverse ecologies. In present study, two foxtail millet cultivars of Yugu2 and An04 with contrasting salt tolerance properties were investigated through integrative analyses of transcriptomics and metabolomics. In the transcriptomics results, 8887 and 12,249 DEGs were identified in Yugu2 and An04 in response to salinity, respectively, and 3149 of which were overlapped between two varieties. These salinity-responsive genes indicated that ion transport, redox homeostasis, phytohormone metabolism, signaling and secondary metabolism were enriched in Yugu2 by GO and KEGG analyses. The integrative omics analysis implied that phenylpropanoid, flavonoid and lignin biosynthesis pathways, and lysophospholipids were vital in determining the foxtail millet salinity tolerance. Importantly, the tolerance of Yugu2 attributed to higher efficiencies of ion channel and antioxidant system. All these provide a comprehensive regulatory network of foxtail millet to cope with salinity, and shed some lights on salt tolerance which is relevant for other cereal crops.
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Affiliation(s)
- Jiaowen Pan
- Biotechnology Research Center, Key Laboratory of Genetic Improvement, Ecology and Physiology of Crops, Shandong Academy of Agricultural Sciences, Jinan, 250100, Shandong, People's Republic of China
| | - Zhen Li
- Biotechnology Research Center, Key Laboratory of Genetic Improvement, Ecology and Physiology of Crops, Shandong Academy of Agricultural Sciences, Jinan, 250100, Shandong, People's Republic of China
| | - Shaojun Dai
- Development Center of Plant Germplasm Resources, College of Life Sciences, Shanghai Normal University, Shanghai, 200234, People's Republic of China
| | - Hanfeng Ding
- Shandong Center of Crop Germplasm Resources, Shandong Academy of Agricultural Sciences, Jinan, 250100, Shandong, People's Republic of China.,College of Life Sciences, Shandong Normal University, Jinan, 250014, Shandong, People's Republic of China
| | - Qingguo Wang
- Biotechnology Research Center, Key Laboratory of Genetic Improvement, Ecology and Physiology of Crops, Shandong Academy of Agricultural Sciences, Jinan, 250100, Shandong, People's Republic of China
| | - Xiaobo Li
- School of Life Science and Technology, Harbin Normal University, Harbin, 150025, Heilongjiang, People's Republic of China
| | - Guohua Ding
- School of Life Science and Technology, Harbin Normal University, Harbin, 150025, Heilongjiang, People's Republic of China
| | - Pengfei Wang
- Shandong Engineering Research Center for Grape Cultivation and Deep-Processing, Shandong Academy of Grape, Jinan, 250100, Shandong, People's Republic of China
| | - Yanan Guan
- Crop Research Institute, Shandong Engineering Laboratory for Featured Crops, Shandong Academy of Agricultural Sciences, Jinan, 250100, Shandong, People's Republic of China. .,College of Life Sciences, Shandong Normal University, Jinan, 250014, Shandong, People's Republic of China.
| | - Wei Liu
- Biotechnology Research Center, Key Laboratory of Genetic Improvement, Ecology and Physiology of Crops, Shandong Academy of Agricultural Sciences, Jinan, 250100, Shandong, People's Republic of China. .,College of Life Sciences, Shandong Normal University, Jinan, 250014, Shandong, People's Republic of China.
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15
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Hao Q, Chen Y, Zhou X. The Janus Face of p53-Targeting Ubiquitin Ligases. Cells 2020; 9:cells9071656. [PMID: 32660118 PMCID: PMC7407405 DOI: 10.3390/cells9071656] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 07/03/2020] [Accepted: 07/06/2020] [Indexed: 12/11/2022] Open
Abstract
The tumor suppressor p53 prevents tumorigenesis and cancer progression by maintaining genomic stability and inducing cell growth arrest and apoptosis. Because of the extremely detrimental nature of wild-type p53, cancer cells usually mutate the TP53 gene in favor of their survival and propagation. Some of the mutant p53 proteins not only lose the wild-type activity, but also acquire oncogenic function, namely “gain-of-function”, to promote cancer development. Growing evidence has revealed that various E3 ubiquitin ligases are able to target both wild-type and mutant p53 for degradation or inactivation, and thus play divergent roles leading to cancer cell survival or death in the context of different p53 status. In this essay, we reviewed the recent progress in our understanding of the p53-targeting E3 ubiquitin ligases, and discussed the potential clinical implications of these E3 ubiquitin ligases in cancer therapy.
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Affiliation(s)
- Qian Hao
- Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China;
| | - Yajie Chen
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, China;
| | - Xiang Zhou
- Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China;
- Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, China
- Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
- Correspondence: ; Tel.: +86-21-54237325
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16
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Li P, Li K, Li X, Zhao F, Wang R, Wang J. Improving enzyme activity of glucosamine-6-phosphate synthase by semi-rational design strategy and computer analysis. Biotechnol Lett 2020; 42:2319-2332. [PMID: 32601959 DOI: 10.1007/s10529-020-02949-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2019] [Accepted: 06/24/2020] [Indexed: 11/30/2022]
Abstract
OBJECTIVE To improve enzyme activity of Glucosamine-6-phosphate synthase (Glms) of Bacillus subtilis by site saturation mutagenesis at Leu593, Ala594, Lys595, Ser596 and Val597 based on computer-aided semi-rational design. RESULTS The results indicated that L593S had the greatest effect on the activity of BsGlms and the enzyme activity increased from 5 to 48 U/mL. The mutation of L593S increased the yield of glucosamine by 1.6 times that of the original strain. The binding energy of the mutant with substrate was reduced from - 743.864 to - 768.246 kcal/mol. Molecular dynamics simulation results showed that Ser593 enhanced the flexibility of the protein, which ultimately led to increased enzyme activity. CONCLUSION We successfully improved BsGlms activity through computer simulation and site saturation mutagenesis. This combination of methodologies may fit into an efficient workflow for improving Glms and other proteins activity.
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Affiliation(s)
- Piwu Li
- State Key Laboratory of Biobased Material and Green Papermaking (LBMP) (Qilu University of Technology), Jinan, 250353, Shandong, People's Republic of China.,Key Laboratory of Shandong Microbial Engineering, QILU University of Technology (Shandong Academy of Sciences), Jinan, 250353, Shandong, People's Republic of China
| | - Kang Li
- Key Laboratory of Shandong Microbial Engineering, QILU University of Technology (Shandong Academy of Sciences), Jinan, 250353, Shandong, People's Republic of China
| | - Xu Li
- Key Laboratory of Shandong Microbial Engineering, QILU University of Technology (Shandong Academy of Sciences), Jinan, 250353, Shandong, People's Republic of China
| | - Fei Zhao
- Key Laboratory of Shandong Microbial Engineering, QILU University of Technology (Shandong Academy of Sciences), Jinan, 250353, Shandong, People's Republic of China
| | - Ruiming Wang
- State Key Laboratory of Biobased Material and Green Papermaking (LBMP) (Qilu University of Technology), Jinan, 250353, Shandong, People's Republic of China.,Key Laboratory of Shandong Microbial Engineering, QILU University of Technology (Shandong Academy of Sciences), Jinan, 250353, Shandong, People's Republic of China
| | - Junqing Wang
- State Key Laboratory of Biobased Material and Green Papermaking (LBMP) (Qilu University of Technology), Jinan, 250353, Shandong, People's Republic of China. .,Key Laboratory of Shandong Microbial Engineering, QILU University of Technology (Shandong Academy of Sciences), Jinan, 250353, Shandong, People's Republic of China.
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17
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Fuselier TT, Lu H. PHLD Class Proteins: A Family of New Players in the p53 Network. Int J Mol Sci 2020; 21:ijms21103543. [PMID: 32429563 PMCID: PMC7278972 DOI: 10.3390/ijms21103543] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 05/11/2020] [Accepted: 05/12/2020] [Indexed: 12/12/2022] Open
Abstract
The Pleckstrin Homology-like Domain (PHLD) class of proteins are multifunctional proteins. The class is comprised of two families of proteins, PHLDA and PHLDB, each with 3 members. All members of the families possess a pleckstrin homology (PH) domain. Though identified nearly 30 years ago, this class of proteins remains understudied with PHLDA family members receiving most of the research attention. Recent studies have also begun to reveal the functions of the PHLDB family proteins in regulation of p53 and AKT signaling pathways important for cancer and metabolism. This review will discuss current research and offer some prospects on the possible roles of both families in cancer and metabolism.
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Affiliation(s)
- Taylor T. Fuselier
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, LA 70112, USA;
- Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Hua Lu
- Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA 70112, USA
- Correspondence:
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18
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Deng X, Li S, Kong F, Ruan H, Xu X, Zhang X, Wu Z, Zhang L, Xu Y, Yuan H, Peng H, Yang D, Guan M. Long noncoding RNA PiHL regulates p53 protein stability through GRWD1/RPL11/MDM2 axis in colorectal cancer. Am J Cancer Res 2020; 10:265-280. [PMID: 31903119 PMCID: PMC6929633 DOI: 10.7150/thno.36045] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Accepted: 08/04/2019] [Indexed: 01/15/2023] Open
Abstract
We identified a novel long noncoding RNA (lncRNA) upregulated in colorectal cancer (CRC). We elucidated its role and clinical significance in CRC carcinogenesis. Methods: LncRNA candidates were identified using TCGA database. LncRNA expression profiles were studied by qRT-PCR and microarray in paired tumor and normal tissues. The independence of the signature in survival prediction was evaluated by multivariable Cox regression analysis. The mechanisms of lncRNA function and regulation in CRC were examined using molecular biological methods. Results: We identified a novel long noncoding gene (PiHL, P53 inHibiting LncRNA) from 8q24.21 as a p53 negative regulator. PiHL is drastically upregulated in CRC and is an independent predictor of CRC poor prognosis. Further in vitro and in vivo models demonstrated that PiHL was crucial in maintaining cell proliferation and inducing 5-FU chemoresistance through a p53-dependent manner. Mechanistically, PiHL acts to promote p53 ubiquitination by sequestering RPL11 from MDM2, through enhancing GRWD1 and RPL11 complex formation. We further show that p53 can directly bind to PiHL promoter and regulating its expression. Conclusion: Our study illustrates how cancer cells hijack the PiHL-p53 axis to promote CRC progression and chemoresistance. PiHL plays an oncogenic role in CRC carcinogenesis and is an independent prognostic factor as well as a potential therapeutic target for CRC patients.
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19
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Zheng L, Dong H, Zhao W, Zhang X, Duan X, Zhang H, Liu S, Sui G. An Air-Liquid Interface Organ-Level Lung Microfluidics Platform for Analysis on Molecular Mechanisms of Cytotoxicity Induced by Cancer-Causing Fine Particles. ACS Sens 2019; 4:907-917. [PMID: 30843693 DOI: 10.1021/acssensors.8b01672] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Fine particulate matter less than 2.5 μm in diameter (PM2.5) is regarded as a carcinogenic factor, but the mechanism has been left unexplored. Our goal was to reveal the carcinogenic mechanism at the gene and protein level under the inhalational air-liquid interface (ALI) condition. Herein, we developed an ALI organ-level lung microfluidic platform (ALI-OLMP) carrying lung epithelial cell line BEAS-2B and human pulmonary microvascular endothelial cells (HPMEC); the cell viability was above 98% within 14 days on this system, which was used to mimic the practical alveolar microenvironment for the multiomics analysis, to identify the global gene and protein expression after exposure to PM2.5 in Shanghai, China from 2014 to 2015. The combined RNA-Seq and iTRAQ analysis indicated that the unique set was 2532 genes at 10 μg/cm2 of PM2.5, and there were also at least 25 identical activated signal transduction cascades including bladder cancer, transcriptional dysregulation in cancer, the TP53 (p53) signaling pathway, Jak-STAT signaling pathway, and PI3K-Akt signaling pathway, which could lead to blocking of differentiation, cell proliferation and survival, and sustained angiogenesis. The images obtained by the transmission electron microscopy (TEM) showed that the particles could enter the mitochondria, and even get into the nucleus. The Pearson's correlation coefficient test elucidated that inorganics (EC), organics (OC, PAHs, and alkane), and metals (Cr, Mn, and Sb) were significantly correlated to the dysregulated oncoproteins (VEGF, IL6, MDM2, AKT1, STAT, and P53). The findings may to some extent explain the molecular mechanism of carcinogenicity caused by fine-particle exposure.
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Affiliation(s)
- Lulu Zheng
- Shanghai Key laboratory of Atmospheric Particle Pollution Prevention (LAP3), Department of Environmental Science & Engineering, Fudan University, 220 Handan Road, Shanghai 200433, P.R. China
- Engineering Research Center of Optical Instrument and System, Ministry of Education, Shanghai Key Lab of Modern Optical System, University of Shanghai for Science and Technology, 516 Jungong Road, Shanghai 200093, China
| | - Heng Dong
- Shanghai Key laboratory of Atmospheric Particle Pollution Prevention (LAP3), Department of Environmental Science & Engineering, Fudan University, 220 Handan Road, Shanghai 200433, P.R. China
| | - Wang Zhao
- Shanghai Key laboratory of Atmospheric Particle Pollution Prevention (LAP3), Department of Environmental Science & Engineering, Fudan University, 220 Handan Road, Shanghai 200433, P.R. China
| | - Xinlian Zhang
- Shanghai Key laboratory of Atmospheric Particle Pollution Prevention (LAP3), Department of Environmental Science & Engineering, Fudan University, 220 Handan Road, Shanghai 200433, P.R. China
| | - Xiaoxiao Duan
- Shanghai Key laboratory of Atmospheric Particle Pollution Prevention (LAP3), Department of Environmental Science & Engineering, Fudan University, 220 Handan Road, Shanghai 200433, P.R. China
| | - Hao Zhang
- Shanghai Key laboratory of Atmospheric Particle Pollution Prevention (LAP3), Department of Environmental Science & Engineering, Fudan University, 220 Handan Road, Shanghai 200433, P.R. China
| | - Sixiu Liu
- Shanghai Key laboratory of Atmospheric Particle Pollution Prevention (LAP3), Department of Environmental Science & Engineering, Fudan University, 220 Handan Road, Shanghai 200433, P.R. China
| | - Guodong Sui
- Shanghai Key laboratory of Atmospheric Particle Pollution Prevention (LAP3), Department of Environmental Science & Engineering, Fudan University, 220 Handan Road, Shanghai 200433, P.R. China
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Zhou X, Hao Q, Lu H. Mutant p53 in cancer therapy-the barrier or the path. J Mol Cell Biol 2019; 11:293-305. [PMID: 30508182 PMCID: PMC6487791 DOI: 10.1093/jmcb/mjy072] [Citation(s) in RCA: 168] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2018] [Revised: 11/14/2018] [Accepted: 11/14/2018] [Indexed: 12/11/2022] Open
Abstract
Since wild-type p53 is central for maintaining genomic stability and preventing oncogenesis, its coding gene TP53 is highly mutated in ~50% of human cancers, and its activity is almost abrogated in the rest of cancers. Approximately 80% of p53 mutations are single point mutations with several hotspot mutations. Besides loss of function and dominant-negative effect on the wild-type p53 activity, the hotspot p53 mutants also acquire new oncogenic functions, so-called 'gain-of-functions' (GOF). Because the GOF of mutant p53 is highly associated with late-stage malignance and drug resistance, these p53 mutants have become hot targets for developing novel cancer therapies. In this essay, we review some recent progresses in better understanding of the role of mutant p53 GOF in chemoresistance and the underlying mechanisms, and discuss the pros and cons of targeting mutant p53 for the development of anti-cancer therapies.
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Affiliation(s)
- Xiang Zhou
- Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, and Key Laboratory of Medical Epigenetics and Metabolism, Fudan University, Shanghai, China
| | - Qian Hao
- Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China
| | - Hua Lu
- Department of Biochemistry & Molecular Biology and Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA, USA
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21
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Zhao X, Song X, Zhao J, Zhu W, Hou J, Wang Y, Zhang W. Juglone Inhibits Proliferation of HPV-Positive Cervical Cancer Cells Specifically. Biol Pharm Bull 2019; 42:475-480. [DOI: 10.1248/bpb.b18-00845] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
- Xingyu Zhao
- Department of Biochemistry, Basic Medical College of Jilin Medical University
| | - Xiaoxing Song
- Department of Biochemistry, Basic Medical College of Jilin Medical University
| | - Jierui Zhao
- Department of Biochemistry, Basic Medical College of Jilin Medical University
| | - Wenhe Zhu
- Department of Biochemistry, Basic Medical College of Jilin Medical University
| | - Jiancheng Hou
- Department of Biochemistry, Basic Medical College of Jilin Medical University
| | - Yanchun Wang
- Department of Biochemistry, Basic Medical College of Jilin Medical University
| | - Wei Zhang
- Department of Biochemistry, Basic Medical College of Jilin Medical University
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22
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Thanjeem Begum ME, Baul HS, Venkatesh K, Sen D. Novel miRNA expression in the delta opioid signaling pathway mediated cell survivability in an in vitro model of ER stress. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2019; 17:150-187. [PMID: 30716419 DOI: 10.1016/j.nano.2019.01.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Revised: 12/21/2018] [Accepted: 01/11/2019] [Indexed: 10/27/2022]
Abstract
Micro RNAs (miRNAs) are small non-coding RNAs which bind to the 3'-untranslated region of a mature mRNA to induce degradation; thereby regulating gene expression. It is reported that dysregulated miRNAs involved in neurodegenerative diseases including Parkinson's disease, could play a significant role as prognostic markers and therapeutic targets. Neuroprotective effect of delta opioid receptors (DOR) and its known miRNA regulation against endoplasmic reticulum (ER) stress have been reported previously by our lab. Current study focuses on understanding the regulation of novel miRNAs by DOR under ER stress. Novel miRNAs were identified for three different samples; control, tunicamycin (ER stress inducer), and tunicamycin+DADLE (DOR agonist). Differentially regulated miRNAs between the different samples were identified and pathway/target genes analysis was carried out. The results suggest that following DOR activation novel miRNAs like xxx-m0073-3p, xxx-m0225-3p, xxx-m0088-3p, xxx-m0098-5p etc. could regulate cell survival mechanisms in neuronal cells (SH-SY5Y) under ER stress.
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Affiliation(s)
- M Erfath Thanjeem Begum
- Cellular and Molecular Therapeutics Laboratory, Centre for Biomaterials, Cellular and Molecular Theranostics, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - Himadri Shekhaar Baul
- Cellular and Molecular Therapeutics Laboratory, Centre for Biomaterials, Cellular and Molecular Theranostics, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - Katari Venkatesh
- Cellular and Molecular Therapeutics Laboratory, Centre for Biomaterials, Cellular and Molecular Theranostics, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - Dwaipayan Sen
- Cellular and Molecular Therapeutics Laboratory, Centre for Biomaterials, Cellular and Molecular Theranostics, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India..
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23
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Chen SL, Zhang CZ, Liu LL, Lu SX, Pan YH, Wang CH, He YF, Lin CS, Yang X, Xie D, Yun JP. A GYS2/p53 Negative Feedback Loop Restricts Tumor Growth in HBV-Related Hepatocellular Carcinoma. Cancer Res 2018; 79:534-545. [PMID: 30584071 DOI: 10.1158/0008-5472.can-18-2357] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Revised: 11/20/2018] [Accepted: 12/17/2018] [Indexed: 11/16/2022]
Abstract
Hepatocellular carcinogenesis is attributed to the reprogramming of cellular metabolism as a consequence of the alteration in metabolite-related gene regulation. Identifying the mechanism of aberrant metabolism is of great potential to provide novel targets for the treatment of hepatocellular carcinoma (HCC). Here, we demonstrated that glycogen synthase 2 (GYS2) restricted tumor growth in hepatitis B virus-related HCC via a negative feedback loop with p53. Expression of GYS2 was significantly downregulated in HCC and correlated with decreased glycogen content and unfavorable patient outcomes. GYS2 overexpression suppressed, whereas GYS2 knockdown facilitated cell proliferation in vitro and tumor growth in vivo via modulating p53 expression. GYS2 competitively bound to MDM2 to prevent p53 from MDM2-mediated ubiquitination and degradation. Furthermore, GYS2 enhanced the p300-induced acetylation of p53 at K373/382, which in turn inhibited the transcription of GYS2 in the support of HBx/HDAC1 complex. In summary, our findings suggest that GYS2 serves as a prognostic factor and functions as a tumor suppressor in HCC. The newly identified HBx/GYS2/p53 axis is responsible for the deregulation of glycogen metabolism and represents a promising therapeutic target for the clinical management of HCC. SIGNIFICANCE: We elucidated the clinical significance, biological function, and regulation of the HBx/GYS2/p53 axis, which supplement the understanding of tumor glycogen metabolism and provide potential prognostic and therapeutic targets for HCC treatment.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/3/534/F1.large.jpg.
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Affiliation(s)
- Shi-Lu Chen
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.,Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Chris Zhiyi Zhang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.,Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Li-Li Liu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.,Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Shi-Xun Lu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.,Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Ying-Hua Pan
- Department of Rheumatology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Chun-Hua Wang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.,Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yang-Fan He
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.,Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Cen-Shan Lin
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.,Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xia Yang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.,Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Dan Xie
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.,Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jing-Ping Yun
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. .,Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China
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24
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Fang L, Du WW, Lyu J, Dong J, Zhang C, Yang W, He A, Kwok YSS, Ma J, Wu N, Li F, Awan FM, He C, Yang BL, Peng C, MacKay HJ, Yee AJ, Yang BB. Enhanced breast cancer progression by mutant p53 is inhibited by the circular RNA circ-Ccnb1. Cell Death Differ 2018; 25:2195-2208. [PMID: 29795334 PMCID: PMC6261950 DOI: 10.1038/s41418-018-0115-6] [Citation(s) in RCA: 106] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Revised: 03/13/2018] [Accepted: 03/29/2018] [Indexed: 12/19/2022] Open
Abstract
TP53 mutations occur in many different types of cancers that produce mutant p53 proteins. The mutant p53 proteins have lost wild-type p53 activity and gained new functions that contribute to malignant tumor progression. Different p53 mutations create distinct profiles in loss of wild-type p53 activity and gain of functions. Targeting the consequences generated by the great number of p53 mutations would be extremely complex. Therefore, in this study we used a workaround and took advantage of the fact that mutant p53 cannot bind H2AX. Using this, we developed a new approach to repress the acquisition of mutant p53 functions. We show here that the delivery of a circular RNA circ-Ccnb1 inhibited the function of three p53 mutations. By microarray analysis and real-time PCR, we detected decreased circ-Ccnb1 expression levels in patients bearing breast carcinoma. Ectopic delivery of circ-Ccnb1 inhibited tumor growth and extended mouse viability. Using proteomics, we found that circ-Ccnb1 precipitated p53 in p53 wild-type cells, but instead precipitated Bclaf1 in p53 mutant cells. Further experiments showed that H2AX serves as a bridge, linking the interaction of circ-Ccnb1 and wild-type p53, thus allowing Bclaf1 to bind Bcl2 resulting in cell survival. In the p53 mutant cells, circ-Ccnb1 formed a complex with H2AX and Bclaf1, resulting in the induction of cell death. We found that this occurred in three p53 mutations. These results shed light on the possible development of new approaches to inhibit the malignancy of p53 mutations.
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Affiliation(s)
- Ling Fang
- Sunnybrook Research Institute, and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
- China-Japan Union Hospital of Jilin University, Jilin, China
| | - William W Du
- Sunnybrook Research Institute, and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
| | - Juanjuan Lyu
- Sunnybrook Research Institute, and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
| | - Jun Dong
- Sunnybrook Research Institute, and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
| | - Chao Zhang
- Sunnybrook Research Institute, and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
| | | | - Alina He
- Sunnybrook Research Institute, and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
| | - Yat Sze Sheila Kwok
- Sunnybrook Research Institute, and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
| | - Jian Ma
- Sunnybrook Research Institute, and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
| | - Nan Wu
- Sunnybrook Research Institute, and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
| | - Feiya Li
- Sunnybrook Research Institute, and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
| | - Faryal Mehwish Awan
- Sunnybrook Research Institute, and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
| | - Chengyan He
- China-Japan Union Hospital of Jilin University, Jilin, China
| | - Bing L Yang
- Sunnybrook Research Institute, Toronto, Canada
| | - Chun Peng
- Department of Biology, York University, Toronto, Canada
| | | | | | - Burton B Yang
- Sunnybrook Research Institute, and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
- Sunnybrook Research Institute, Toronto, Canada.
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25
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Fang Z, Cao B, Liao JM, Deng J, Plummer KD, Liao P, Liu T, Zhang W, Zhang K, Li L, Margolin D, Zeng SX, Xiong J, Lu H. SPIN1 promotes tumorigenesis by blocking the uL18 (universal large ribosomal subunit protein 18)-MDM2-p53 pathway in human cancer. eLife 2018; 7:31275. [PMID: 29547122 PMCID: PMC5871334 DOI: 10.7554/elife.31275] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Accepted: 03/13/2018] [Indexed: 12/14/2022] Open
Abstract
Ribosomal proteins (RPs) play important roles in modulating the MDM2-p53 pathway. However, less is known about the upstream regulators of the RPs. Here, we identify SPIN1 (Spindlin 1) as a novel binding partner of human RPL5/uL18 that is important for this pathway. SPIN1 ablation activates p53, suppresses cell growth, reduces clonogenic ability, and induces apoptosis of human cancer cells. Mechanistically, SPIN1 sequesters uL18 in the nucleolus, preventing it from interacting with MDM2, and thereby alleviating uL18-mediated inhibition of MDM2 ubiquitin ligase activity toward p53. SPIN1 deficiency increases ribosome-free uL18 and uL5 (human RPL11), which are required for SPIN1 depletion-induced p53 activation. Analysis of cancer genomic databases suggests that SPIN1 is highly expressed in several human cancers, and its overexpression is positively correlated with poor prognosis in cancer patients. Altogether, our findings reveal that the oncogenic property of SPIN1 may be attributed to its negative regulation of uL18, leading to p53 inactivation.
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Affiliation(s)
- Ziling Fang
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, United States
| | - Bo Cao
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, United States
| | - Jun-Ming Liao
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, United States.,School of Dentistry at Case Western University, Cleveland, United States
| | - Jun Deng
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, United States
| | - Kevin D Plummer
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, United States
| | - Peng Liao
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, United States
| | - Tao Liu
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, United States
| | - Wensheng Zhang
- Department of Computer Science, Bioinformatics Facility of Xavier RCMI Center of Cancer Research, Xavier University of Louisiana, New Orleans, United States
| | - Kun Zhang
- Department of Computer Science, Bioinformatics Facility of Xavier RCMI Center of Cancer Research, Xavier University of Louisiana, New Orleans, United States
| | - Li Li
- Laboratory of Translational Cancer Research, Ochsner Clinical Foundation, New Orleans, United States
| | - David Margolin
- Department of Colon and Rectal Surgery, Ochsner Clinical Foundation, New Orleans, United States
| | - Shelya X Zeng
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, United States
| | - Jianping Xiong
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Hua Lu
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, United States
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26
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Chen G, Zhou T, Li Y, Yu Z, Sun L. p53 target miR-29c-3p suppresses colon cancer cell invasion and migration through inhibition of PHLDB2. Biochem Biophys Res Commun 2017; 487:90-95. [PMID: 28392396 DOI: 10.1016/j.bbrc.2017.04.023] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2017] [Accepted: 04/06/2017] [Indexed: 12/28/2022]
Abstract
miR-29c-3p is a potential tumor suppressor microRNA that is reportedly downregulated in several types of human cancers, but its role in colon cancer remains to be elucidated. Meanwhile, TP53, one of the most important tumor suppressors, is highly mutated in colon cancer. In the attempt to connect p53 and miR-29c-3p, we found that the upstream of miR-29c-3p gene contains a functional p53 consensus responsive element that is driven by p53 transcriptional factor activity, suggesting miR-29c-3p as a direct p53 target gene. Through online software prediction and in vivo validation, we demonstrated that Pleckstrin Homology Like Domain Family Member 2 (PHLDB2) is a valid miR-29c-3p target gene. Analysis of human cancer databases available from PROGgeneV2 showed that higher expression of PHLDB2 is associated with shorter overall survival and metastasis-free survival of colon cancer patients. Further, suppression of colon cancer cell invasion and migration by miR-29c-3p was significantly attenuated in the presence of ectopic PHLDB2, indicating PHLDB2 is a critical downstream target of miR-29c-3p. Collectively, our findings present the first to elucidate that miR-29c is a direct p53 target gene, and also identify PHLDB2 as an important miR-29c target gene involved in colon cancer metastasis.
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Affiliation(s)
- Geng Chen
- Department of Pathophysiology, Basic College of Medicine, Jilin University, Changchun, 130021, China; Department of Gastroenterology, The First Hospital of Jilin University, Changchun, 130021, China
| | - Tong Zhou
- Department of Endocrinology, The First Hospital of Jilin University, Changchun, 130021, China
| | - Yang Li
- Department of Respiration, The First Hospital of Jilin University, Changchun, 130021, China
| | - Zhenxiang Yu
- Department of Respiration, The First Hospital of Jilin University, Changchun, 130021, China
| | - Liankun Sun
- Department of Pathophysiology, Basic College of Medicine, Jilin University, Changchun, 130021, China.
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