|
1
|
Li J, Ruan Y, Jiang C, Sun J, An D, Zhou B, Liu H, Li Z, Xu H. Tissue-Specific Expression of the Porcine DHRS3 Gene and Its Impact on the Proliferation and Differentiation of Myogenic Cells. Animals (Basel) 2025; 15:1101. [PMID: 40281935 PMCID: PMC12023973 DOI: 10.3390/ani15081101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2025] [Revised: 04/08/2025] [Accepted: 04/08/2025] [Indexed: 04/29/2025] Open
Abstract
The DHRS3 gene, a member of the short-chain dehydrogenase/reductase (SDR) family, is involved in critical metabolic processes in animals. This study investigated the expression patterns of DHRS3 across various tissues of developmental stages in pigs and preliminarily evaluated its effects on myoblast proliferation, apoptosis, and differentiation. RT-qPCR (real-time quantitative PCR) was employed to analyze DHRS3 expression in the heart, liver, spleen, lungs, kidneys, longissimus dorsi, foreleg, and hind leg of pigs at 3 days, 6 months, and 12 months of age. Cell proliferation was analyzed using EdU (5-ethynyl-2'-deoxyuridine) assays, RT-qPCR, and flow cytometry, while the expression changes of proliferation-, apoptosis-, and differentiation-related genes were assessed via RT-qPCR. The results indicated that DHRS3 was expressed in all eight tissues at all three developmental stages. At 3 days, DHRS3 expression was the highest in the kidneys; at 6 months, it peaked in the liver; and at 12 months, it was again the highest in the kidneys. Across all stages, the liver and kidneys exhibited the highest DHRS3 expression levels. Functional studies revealed that DHRS3 overexpression suppressed myoblast proliferation and differentiation while promoting apoptosis. In contrast, DHRS3 inhibition enhanced myoblast proliferation and differentiation and reduced apoptosis. These findings underscore the regulatory role of DHRS3 in myogenesis and provide insights into its metabolic and developmental functions in pigs.
Collapse
Affiliation(s)
- Jifeng Li
- Key Laboratory of Animal Genetics, Breeding and Reproduction in the Plateau Mountainous Region, Ministry of Education, Guizhou University, Guiyang 550025, China
- College of Animal Science, Guizhou University, Guiyang 550025, China
| | - Yong Ruan
- Key Laboratory of Animal Genetics, Breeding and Reproduction in the Plateau Mountainous Region, Ministry of Education, Guizhou University, Guiyang 550025, China
- College of Animal Science, Guizhou University, Guiyang 550025, China
| | - Chuanmei Jiang
- Key Laboratory of Animal Genetics, Breeding and Reproduction in the Plateau Mountainous Region, Ministry of Education, Guizhou University, Guiyang 550025, China
- College of Animal Science, Guizhou University, Guiyang 550025, China
| | - Jinkui Sun
- Key Laboratory of Animal Genetics, Breeding and Reproduction in the Plateau Mountainous Region, Ministry of Education, Guizhou University, Guiyang 550025, China
- College of Animal Science, Guizhou University, Guiyang 550025, China
| | - Dongwei An
- Key Laboratory of Animal Genetics, Breeding and Reproduction in the Plateau Mountainous Region, Ministry of Education, Guizhou University, Guiyang 550025, China
- College of Animal Science, Guizhou University, Guiyang 550025, China
| | - Bo Zhou
- Key Laboratory of Animal Genetics, Breeding and Reproduction in the Plateau Mountainous Region, Ministry of Education, Guizhou University, Guiyang 550025, China
- College of Animal Science, Guizhou University, Guiyang 550025, China
| | - Huan Liu
- Key Laboratory of Animal Genetics, Breeding and Reproduction in the Plateau Mountainous Region, Ministry of Education, Guizhou University, Guiyang 550025, China
- College of Animal Science, Guizhou University, Guiyang 550025, China
| | - Ziyang Li
- Key Laboratory of Animal Genetics, Breeding and Reproduction in the Plateau Mountainous Region, Ministry of Education, Guizhou University, Guiyang 550025, China
- College of Animal Science, Guizhou University, Guiyang 550025, China
| | - Houqiang Xu
- Key Laboratory of Animal Genetics, Breeding and Reproduction in the Plateau Mountainous Region, Ministry of Education, Guizhou University, Guiyang 550025, China
- College of Animal Science, Guizhou University, Guiyang 550025, China
| |
Collapse
|
|
2
|
Varshosaz P, O'Connor C, Moise AR. Feedback regulation of retinaldehyde reductase DHRS3, a critical determinant of retinoic acid homeostasis. FEBS Lett 2025; 599:340-351. [PMID: 39420244 PMCID: PMC11808460 DOI: 10.1002/1873-3468.15038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 09/13/2024] [Accepted: 09/18/2024] [Indexed: 10/19/2024]
Abstract
Retinoic acid is crucial for vertebrate embryogenesis, influencing anterior-posterior patterning and organogenesis through its interaction with nuclear hormone receptors comprising heterodimers of retinoic acid receptors (RARα, β, or γ) and retinoid X receptors (RXRα, β, or γ). Tissue retinoic acid levels are tightly regulated since both its excess and deficiency are deleterious. Dehydrogenase/reductase 3 (DHRS3) plays a critical role in this regulation by converting retinaldehyde to retinol, preventing excessive retinoic acid formation. Mutations in DHRS3 can result in embryonic lethality and congenital defects. This study shows that mouse Dhrs3 expression is responsive to vitamin A status and is directly regulated by the RAR/RXR complex through cis-regulatory elements. This highlights a negative feedback mechanism that ensures retinoic acid homeostasis.
Collapse
Affiliation(s)
- Parisa Varshosaz
- Biology and Biomolecular Sciences Ph.D. Program, Northern Ontario School of MedicineLaurentian UniversitySudburyCanada
| | - Catherine O'Connor
- Medical Sciences DivisionNorthern Ontario School of MedicineSudburyCanada
| | - Alexander R. Moise
- Medical Sciences DivisionNorthern Ontario School of MedicineSudburyCanada
- Department of Biology and Biomolecular Sciences ProgramLaurentian UniversitySudburyCanada
| |
Collapse
|
|
3
|
Overexpressed miRNA-nov-1 promotes manganese-induced apoptosis in N27 cells by regulating Dhrs3 to activate mTOR signaling pathway. Toxicology 2023; 489:153472. [PMID: 36868551 DOI: 10.1016/j.tox.2023.153472] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 02/20/2023] [Accepted: 02/28/2023] [Indexed: 03/05/2023]
Abstract
Environmental and occupational chronic manganese exposure can cause neurotoxicity and apoptosis. Moreover, microRNAs (miRNAs) are extensively involved in the process of neuronal apoptosis. Therefore, it is crucial to study the mechanism of miRNA in manganese-induced neuronal apoptosis and to find potential targets. In the present study, we found that the expression of miRNA-nov-1 was increased after N27 cells were exposed to MnCl2. Then, seven different cell groups were constructed by lentiviral infection of cells, and the overexpression of miRNA-nov-1 promoted the apoptosis process of N27 cells. Further studies showed a negative regulatory relationship between miRNA-nov-1 and dehydrogenase/reductase 3 (Dhrs3). The up-regulation of miRNA-nov-1 reduced the protein level of Dhrs3 in N27 cells exposed to manganese, increased the expression of a caspase-3 protein, activated the rapamycin (mTOR) signaling pathway, and increased cell apoptosis. Furthermore, we found that the expression of the Caspase-3 protein was decreased after the low expression of miRNA-nov-1, the mTOR signaling pathway was inhibited, and reduced cell apoptosis. However, these effects were reversed by the knockdown of Dhrs3. Taken together, these results suggested that overexpression of miRNA-nov-1 can promote manganese-induced apoptosis in N27 cells by activating the mTOR signaling pathway and negatively regulating Dhrs3.
Collapse
|
|
4
|
Li Z, Tan Y, Li X, Quan J, Bode AM, Cao Y, Luo X. DHRS2 inhibits cell growth and metastasis in ovarian cancer by downregulation of CHKα to disrupt choline metabolism. Cell Death Dis 2022; 13:845. [PMID: 36192391 PMCID: PMC9530226 DOI: 10.1038/s41419-022-05291-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 09/20/2022] [Accepted: 09/22/2022] [Indexed: 01/23/2023]
Abstract
The short-chain dehydrogenase/reductase (SDR) superfamily has essential roles in lipid metabolism and redox sensing. In recent years, accumulating evidence highlights the emerging association between SDR family enzymes and cancer. Dehydrogenase/reductase member 2(DHRS2) belongs to the NADH/NADPH-dependent SDR family, and extensively participates in the regulation of the proliferation, migration, and chemoresistance of cancer cells. However, the underlying mechanism has not been well defined. In the present study, we have demonstrated that DHRS2 inhibits the growth and metastasis of ovarian cancer (OC) cells in vitro and in vivo. Mechanistically, the combination of transcriptome and metabolome reveals an interruption of choline metabolism by DHRS2. DHRS2 post-transcriptionally downregulates choline kinase α (CHKα) to inhibit AKT signaling activation and reduce phosphorylcholine (PC)/glycerophosphorylcholine (GPC) ratio, impeding choline metabolism reprogramming in OC. These actions mainly account for the tumor-suppressive role of DHRS2 in OC. Overall, our findings establish the mechanistic connection among metabolic enzymes, metabolites, and the malignant phenotype of cancer cells. This could result in further development of novel pharmacological tools against OC by the induction of DHRS2 to disrupt the choline metabolic pathway.
Collapse
Affiliation(s)
- Zhenzhen Li
- grid.216417.70000 0001 0379 7164Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Nuclear Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410078 PR China ,grid.216417.70000 0001 0379 7164Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan 410078 PR China
| | - Yue Tan
- grid.412017.10000 0001 0266 8918Hengyang Medical College, University of South China, Hengyang, 421001 Hunan PR China
| | - Xiang Li
- grid.216417.70000 0001 0379 7164Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan 410078 PR China
| | - Jing Quan
- grid.216417.70000 0001 0379 7164Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Nuclear Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410078 PR China ,grid.216417.70000 0001 0379 7164Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan 410078 PR China
| | - Ann M. Bode
- grid.17635.360000000419368657The Hormel Institute, University of Minnesota, Austin, MN 55912 USA
| | - Ya Cao
- grid.216417.70000 0001 0379 7164Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Nuclear Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410078 PR China ,grid.216417.70000 0001 0379 7164Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan 410078 PR China ,grid.216417.70000 0001 0379 7164Molecular Imaging Research Center of Central South University, Changsha, Hunan 410078 China
| | - Xiangjian Luo
- grid.216417.70000 0001 0379 7164Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Nuclear Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410078 PR China ,grid.216417.70000 0001 0379 7164Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan 410078 PR China ,grid.216417.70000 0001 0379 7164Molecular Imaging Research Center of Central South University, Changsha, Hunan 410078 China ,grid.216417.70000 0001 0379 7164Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410078 China ,grid.216417.70000 0001 0379 7164Key Laboratory of Biological Nanotechnology of National Health Commission, Central South University, Changsha, Hunan 410078 China ,grid.216417.70000 0001 0379 7164National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410078 China
| |
Collapse
|
|
5
|
Hamsanathan S, Gurkar AU. Lipids as Regulators of Cellular Senescence. Front Physiol 2022; 13:796850. [PMID: 35370799 PMCID: PMC8965560 DOI: 10.3389/fphys.2022.796850] [Citation(s) in RCA: 57] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Accepted: 01/03/2022] [Indexed: 12/11/2022] Open
Abstract
Lipids are key macromolecules that perform a multitude of biological functions ranging from maintaining structural integrity of membranes, energy storage, to signaling molecules. Unsurprisingly, variations in lipid composition and its levels can influence the functional and physiological state of the cell and its milieu. Cellular senescence is a permanent state of cell cycle arrest and is a hallmark of the aging process, as well as several age-related pathologies. Senescent cells are often characterized by alterations in morphology, metabolism, chromatin remodeling and exhibit a complex pro-inflammatory secretome (SASP). Recent studies have shown that the regulation of specific lipid species play a critical role in senescence. Indeed, some lipid species even contribute to the low-grade inflammation associated with SASP. Many protein regulators of senescence have been well characterized and are associated with lipid metabolism. However, the link between critical regulators of cellular senescence and senescence-associated lipid changes is yet to be elucidated. Here we systematically review the current knowledge on lipid metabolism and dynamics of cellular lipid content during senescence. We focus on the roles of major players of senescence in regulating lipid metabolism. Finally, we explore the future prospects of lipid research in senescence and its potential to be targeted as senotherapeutics.
Collapse
Affiliation(s)
- Shruthi Hamsanathan
- Aging Institute of UPMC, The University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Aditi U. Gurkar
- Aging Institute of UPMC, The University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
- Division of Geriatric Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
- Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA, United States
- *Correspondence: Aditi U. Gurkar,
| |
Collapse
|
|
6
|
Laubach K, Zhang J, Chen X. The p53 Family: A Role in Lipid and Iron Metabolism. Front Cell Dev Biol 2021; 9:715974. [PMID: 34395447 PMCID: PMC8358664 DOI: 10.3389/fcell.2021.715974] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 07/08/2021] [Indexed: 12/11/2022] Open
Abstract
The p53 family of tumor suppressors, which includes p53, p63, and p73, has a critical role in many biological processes, such as cell cycle arrest, apoptosis, and differentiation. In addition to tumor suppression, the p53 family proteins also participate in development, multiciliogenesis, and fertility, indicating these proteins have diverse roles. In this review, we strive to cover the relevant studies that demonstrate the roles of p53, p63, and p73 in lipid and iron metabolism.
Collapse
Affiliation(s)
| | | | - Xinbin Chen
- Comparative Oncology Laboratory, Schools of Veterinary Medicine and Medicine, University of California, Davis, Davis, CA, United States
| |
Collapse
|
|
7
|
Pokorná Z, Vysloužil J, Hrabal V, Vojtěšek B, Coates PJ. The foggy world(s) of p63 isoform regulation in normal cells and cancer. J Pathol 2021; 254:454-473. [PMID: 33638205 DOI: 10.1002/path.5656] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 02/10/2021] [Accepted: 02/24/2021] [Indexed: 12/19/2022]
Abstract
The p53 family member p63 exists as two major protein variants (TAp63 and ΔNp63) with distinct expression patterns and functional properties. Whilst downstream target genes of p63 have been studied intensively, how p63 variants are themselves controlled has been relatively neglected. Here, we review advances in understanding ΔNp63 and TAp63 regulation, highlighting their distinct pathways. TAp63 has roles in senescence and metabolism, and in germ cell genome maintenance, where it is activated post-transcriptionally by phosphorylation cascades after DNA damage. The function and regulation of TAp63 in mesenchymal and haematopoietic cells is less clear but may involve epigenetic control through DNA methylation. ΔNp63 functions to maintain stem/progenitor cells in various epithelia and is overexpressed in squamous and certain other cancers. ΔNp63 is transcriptionally regulated through multiple enhancers in concert with chromatin modifying proteins. Many signalling pathways including growth factors, morphogens, inflammation, and the extracellular matrix influence ΔNp63 levels, with inconsistent results reported. There is also evidence for reciprocal regulation, including ΔNp63 activating its own transcription. ΔNp63 is downregulated during cell differentiation through transcriptional regulation, while post-transcriptional events cause proteasomal degradation. Throughout the review, we identify knowledge gaps and highlight discordances, providing potential explanations including cell-context and cell-matrix interactions. Identifying individual p63 variants has roles in differential diagnosis and prognosis, and understanding their regulation suggests clinically approved agents for targeting p63 that may be useful combination therapies for selected cancer patients. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Collapse
Affiliation(s)
- Zuzana Pokorná
- Research Centre of Applied Molecular Oncology (RECAMO), Masaryk Memorial Cancer Institute, Brno, Czech Republic
| | - Jan Vysloužil
- Research Centre of Applied Molecular Oncology (RECAMO), Masaryk Memorial Cancer Institute, Brno, Czech Republic
| | - Václav Hrabal
- Research Centre of Applied Molecular Oncology (RECAMO), Masaryk Memorial Cancer Institute, Brno, Czech Republic.,Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic
| | - Borˇivoj Vojtěšek
- Research Centre of Applied Molecular Oncology (RECAMO), Masaryk Memorial Cancer Institute, Brno, Czech Republic
| | - Philip J Coates
- Research Centre of Applied Molecular Oncology (RECAMO), Masaryk Memorial Cancer Institute, Brno, Czech Republic
| |
Collapse
|
|
8
|
Yang L, Yu H, Touna A, Yin X, Zhang Q, Leng T. Identification of differentially expressed genes and biological pathways in sanguinarine-treated ovarian cancer by integrated bioinformatics analysis. Pharmacogn Mag 2021. [DOI: 10.4103/pm.pm_111_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
|
|
9
|
Zhuang G, Zeng Y, Tang Q, He Q, Luo G. Identifying M1 Macrophage-Related Genes Through a Co-expression Network to Construct a Four-Gene Risk-Scoring Model for Predicting Thyroid Cancer Prognosis. Front Genet 2020; 11:591079. [PMID: 33193731 PMCID: PMC7658400 DOI: 10.3389/fgene.2020.591079] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Accepted: 09/28/2020] [Indexed: 12/18/2022] Open
Abstract
Macrophages are key innate immune cells in the tumor microenvironment that regulate primary tumor growth, vascularization, metastatic spread and response to therapies. Macrophages can polarize into two different states (M1 and M2) with distinct phenotypes and functions. To investigate the known tumoricidal effects of M1 macrophages, we obtained RNA expression profiles and clinical data from The Cancer Genome Atlas Thyroid Cancer (TCGA-THCA). The proportions of immune cells in tumor samples were assessed using CIBERSORT, and weighted gene co-expression network analysis (WGCNA) was used to identify M1 macrophage-related modules. Univariate Cox analysis and LASSO-Cox regression analysis were performed, and four genes (SPP1, DHRS3, SLC11A1, and CFB) with significant differential expression were selected through GEPIA. These four genes can be considered hub genes. The four-gene risk-scoring model may be an independent prognostic factor for THCA patients. The validation cohort and the entire cohort confirmed the results. Univariate and multivariate Cox analysis was performed to identify independent prognostic factors for THCA. Finally, a prognostic nomogram was built based on the entire cohort, and the nomogram combining the risk score and clinical prognostic factors was superior to the nomogram with individual clinical prognostic factors in predicting overall survival. Time-dependent ROC curves and DCA confirmed that the combined nomogram is useful. Gene set enrichment analysis (GSEA) was used to elucidate the potential molecular functions of the high-risk group. Our study identified four genes associated with M1 macrophages and established a prognostic nomogram that predicts overall survival for patients with THCA, which may help determine clinical treatment options for different patients.
Collapse
Affiliation(s)
- Gaojian Zhuang
- The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
| | - Yu Zeng
- Department of Thyroid and Neck Tumor, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
| | - Qun Tang
- Department of Pathology, Hunan University of Chinese Medicine, Changsha, China
| | - Qian He
- Department of Neurosurgery, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Guoqing Luo
- The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
| |
Collapse
|
|
10
|
Abstract
Generation of the autacoid all-trans-retinoic acid (ATRA) from retinol (vitamin A) relies on a complex metabolon that includes retinol binding-proteins and enzymes from the short-chain dehydrogenase/reductase and aldehyde dehydrogenase gene families. Serum retinol binding-protein delivers all-trans-retinol (vitamin A) from blood to cells through two membrane receptors, Stra6 and Rbpr2. Stra6 and Rbpr2 convey retinol to cellular retinol binding-protein type 1 (Crbp1). Holo-Crbp1 delivers retinol to lecithin: retinol acyl transferase (Lrat) for esterification and storage. Lrat channels retinol directly into its active site from holo-Crbp1 by protein-protein interaction. The ratio apo-Crbp1/holo-Crbp1 directs flux of retinol into and out of retinyl esters, through regulating esterification vs ester hydrolysis. Multiple retinol dehydrogenases (Rdh1, Rdh10, Dhrs9, Rdhe2, Rdhe2s) channel retinol from holo-Crbp1 to generate retinal for ATRA biosynthesis. β-Carotene oxidase type 1 generates retinal from carotenoids, delivered by the scavenger receptor-B1. Retinal reductases (Dhrs3, Dhrs4, Rdh11) reduce retinal into retinol, thereby restraining ATRA biosynthesis. Retinal dehydrogenases (Raldh1, 2, 3) dehydrogenate retinal irreversibly into ATRA. ATRA regulates its own concentrations by inducing Lrat and ATRA degradative enzymes. ATRA exhibits hormesis. Its effects relate to its concentration as an inverted J-shaped curve, transitioning from beneficial in the "goldilocks" zone to toxicity, as concentrations increase. Hormesis has distorted understanding physiological effects of ATRA post-nataly using chow-diet fed, ATRA-dosed animal models. Cancer, immune deficiency and metabolic abnormalities result from mutations and/or insufficiency in Crbp1 and retinoid metabolizing enzymes.
Collapse
Affiliation(s)
- Joseph L Napoli
- Graduate Program in Metabolic Biology, Nutritional Sciences and Toxicology, University of California, Berkeley, CA, United States.
| |
Collapse
|
|
11
|
Lacroix M, Riscal R, Arena G, Linares LK, Le Cam L. Metabolic functions of the tumor suppressor p53: Implications in normal physiology, metabolic disorders, and cancer. Mol Metab 2020; 33:2-22. [PMID: 31685430 PMCID: PMC7056927 DOI: 10.1016/j.molmet.2019.10.002] [Citation(s) in RCA: 221] [Impact Index Per Article: 44.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 09/24/2019] [Accepted: 10/05/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The TP53 gene is one of the most commonly inactivated tumor suppressors in human cancers. p53 functions during cancer progression have been linked to a variety of transcriptional and non-transcriptional activities that lead to the tight control of cell proliferation, senescence, DNA repair, and cell death. However, converging evidence indicates that p53 also plays a major role in metabolism in both normal and cancer cells. SCOPE OF REVIEW We provide an overview of the current knowledge on the metabolic activities of wild type (WT) p53 and highlight some of the mechanisms by which p53 contributes to whole body energy homeostasis. We will also pinpoint some evidences suggesting that deregulation of p53-associated metabolic activities leads to human pathologies beyond cancer, including obesity, diabetes, liver, and cardiovascular diseases. MAJOR CONCLUSIONS p53 is activated when cells are metabolically challenged but the origin, duration, and intensity of these stresses will dictate the outcome of the p53 response. p53 plays pivotal roles both upstream and downstream of several key metabolic regulators and is involved in multiple feedback-loops that ensure proper cellular homeostasis. The physiological roles of p53 in metabolism involve complex mechanisms of regulation implicating both cell autonomous effects as well as autocrine loops. However, the mechanisms by which p53 coordinates metabolism at the organismal level remain poorly understood. Perturbations of p53-regulated metabolic activities contribute to various metabolic disorders and are pivotal during cancer progression.
Collapse
Affiliation(s)
- Matthieu Lacroix
- Institut de Recherche en Cancérologie de Montpellier, INSERM, Université de Montpellier, Institut Régional du Cancer de Montpellier, Montpellier, France; Equipe labélisée Ligue Contre le Cancer, France
| | - Romain Riscal
- Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Giuseppe Arena
- Gustave Roussy Cancer Campus, INSERM U1030, Villejuif, France
| | - Laetitia Karine Linares
- Institut de Recherche en Cancérologie de Montpellier, INSERM, Université de Montpellier, Institut Régional du Cancer de Montpellier, Montpellier, France; Equipe labélisée Ligue Contre le Cancer, France
| | - Laurent Le Cam
- Institut de Recherche en Cancérologie de Montpellier, INSERM, Université de Montpellier, Institut Régional du Cancer de Montpellier, Montpellier, France; Equipe labélisée Ligue Contre le Cancer, France.
| |
Collapse
|
|
12
|
Sirbu IO, Chiş AR, Moise AR. Role of carotenoids and retinoids during heart development. Biochim Biophys Acta Mol Cell Biol Lipids 2020; 1865:158636. [PMID: 31978553 DOI: 10.1016/j.bbalip.2020.158636] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 01/15/2020] [Accepted: 01/16/2020] [Indexed: 02/08/2023]
Abstract
The nutritional requirements of the developing embryo are complex. In the case of dietary vitamin A (retinol, retinyl esters and provitamin A carotenoids), maternal derived nutrients serve as precursors to signaling molecules such as retinoic acid, which is required for embryonic patterning and organogenesis. Despite variations in the composition and levels of maternal vitamin A, embryonic tissues need to generate a precise amount of retinoic acid to avoid congenital malformations. Here, we summarize recent findings regarding the role and metabolism of vitamin A during heart development and we survey the association of genes known to affect retinoid metabolism or signaling with various inherited disorders. A better understanding of the roles of vitamin A in the heart and of the factors that affect retinoid metabolism and signaling can help design strategies to meet nutritional needs and to prevent birth defects and disorders associated with altered retinoid metabolism. This article is part of a Special Issue entitled Carotenoids recent advances in cell and molecular biology edited by Johannes von Lintig and Loredana Quadro.
Collapse
Affiliation(s)
- Ioan Ovidiu Sirbu
- Biochemistry Department, Victor Babes University of Medicine and Pharmacy, Eftimie Murgu Nr. 2, 300041 Timisoara, Romania; Timisoara Institute of Complex Systems, V. Lucaciu 18, 300044 Timisoara, Romania.
| | - Aimée Rodica Chiş
- Biochemistry Department, Victor Babes University of Medicine and Pharmacy, Eftimie Murgu Nr. 2, 300041 Timisoara, Romania
| | - Alexander Radu Moise
- Medical Sciences Division, Northern Ontario School of Medicine, Sudbury, ON P3E 2C6, Canada; Department of Chemistry and Biochemistry, Biology and Biomolecular Sciences Program, Laurentian University, Sudbury, ON P3E 2C6, Canada.
| |
Collapse
|
|
13
|
Lin-Shiao E, Lan Y, Welzenbach J, Alexander KA, Zhang Z, Knapp M, Mangold E, Sammons M, Ludwig KU, Berger SL. p63 establishes epithelial enhancers at critical craniofacial development genes. SCIENCE ADVANCES 2019; 5:eaaw0946. [PMID: 31049400 PMCID: PMC6494499 DOI: 10.1126/sciadv.aaw0946] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Accepted: 03/19/2019] [Indexed: 05/15/2023]
Abstract
The transcription factor p63 is a key mediator of epidermal development. Point mutations in p63 in patients lead to developmental defects, including orofacial clefting. To date, knowledge on how pivotal the role of p63 is in human craniofacial development is limited. Using an inducible transdifferentiation model, combined with epigenomic sequencing and multicohort meta-analysis of genome-wide association studies data, we show that p63 establishes enhancers at craniofacial development genes to modulate their transcription. Disease-specific substitution mutation in the DNA binding domain or sterile alpha motif protein interaction domain of p63, respectively, eliminates or reduces establishment of these enhancers. We show that enhancers established by p63 are highly enriched for single-nucleotide polymorphisms associated with nonsyndromic cleft lip ± cleft palate (CL/P). These orthogonal approaches indicate a strong molecular link between p63 enhancer function and CL/P, illuminating molecular mechanisms underlying this developmental defect and revealing vital regulatory elements and new candidate causative genes.
Collapse
Affiliation(s)
- Enrique Lin-Shiao
- Departments of Cell and Developmental Biology and Epigenetics Institute, Philadelphia, PA 19104, USA
- Biochemistry and Molecular Biophysics, Biomedical Sciences Graduate Program, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Yemin Lan
- Departments of Cell and Developmental Biology and Epigenetics Institute, Philadelphia, PA 19104, USA
| | - Julia Welzenbach
- Institute of Human Genetics, University Bonn, School of Medicine and University Hospital Bonn, Bonn, Germany
| | - Katherine A Alexander
- Departments of Cell and Developmental Biology and Epigenetics Institute, Philadelphia, PA 19104, USA
| | - Zhen Zhang
- Departments of Cell and Developmental Biology and Epigenetics Institute, Philadelphia, PA 19104, USA
| | - Michael Knapp
- Institute of Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany
| | - Elisabeth Mangold
- Institute of Human Genetics, University Bonn, School of Medicine and University Hospital Bonn, Bonn, Germany
| | - Morgan Sammons
- Departments of Cell and Developmental Biology and Epigenetics Institute, Philadelphia, PA 19104, USA
| | - Kerstin U Ludwig
- Institute of Human Genetics, University Bonn, School of Medicine and University Hospital Bonn, Bonn, Germany
| | - Shelley L Berger
- Departments of Cell and Developmental Biology and Epigenetics Institute, Philadelphia, PA 19104, USA
| |
Collapse
|
|
14
|
Yarrow supercritical extract exerts antitumoral properties by targeting lipid metabolism in pancreatic cancer. PLoS One 2019; 14:e0214294. [PMID: 30913248 PMCID: PMC6435158 DOI: 10.1371/journal.pone.0214294] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Accepted: 03/11/2019] [Indexed: 12/15/2022] Open
Abstract
Metabolic reprogramming is considered a hallmark of cancer. Currently, the altered lipid metabolism in cancer is a topic of interest due to the prominent role of lipids regulating the progression of various types of tumors. Lipids and lipid-derived molecules have been shown to activate growth regulatory pathways and to promote malignancy in pancreatic cancer. In a previous work, we have described the antitumoral properties of Yarrow (Achillea Millefolium) CO2 supercritical extract (Yarrow SFE) in pancreatic cancer. Herein, we aim to investigate the underlaying molecular mechanisms by which Yarrow SFE induces cytotoxicity in pancreatic cancer cells. Yarrow SFE downregulates SREBF1 and downstream molecular targets of this transcription factor, such as fatty acid synthase (FASN) and stearoyl-CoA desaturase (SCD). Importantly, we demonstrate the in vivo effect of Yarrow SFE diminishing the tumor growth in a xenograft mouse model of pancreatic cancer. Our data suggest that Yarrow SFE can be proposed as a complementary adjuvant or nutritional supplement in pancreatic cancer therapy.
Collapse
|
|
15
|
Ochiai A, Kuroda K, Ozaki R, Ikemoto Y, Murakami K, Muter J, Matsumoto A, Itakura A, Brosens JJ, Takeda S. Resveratrol inhibits decidualization by accelerating downregulation of the CRABP2-RAR pathway in differentiating human endometrial stromal cells. Cell Death Dis 2019; 10:276. [PMID: 30894514 PMCID: PMC6427032 DOI: 10.1038/s41419-019-1511-7] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 02/19/2019] [Accepted: 03/07/2019] [Indexed: 12/20/2022]
Abstract
Pregnancy critically depends on the transformation of the human endometrium into a decidual matrix that controls embryo implantation and placenta formation, a process driven foremost by differentiation and polarization of endometrial stromal cells into mature and senescent decidual cells. Perturbations in the decidual process underpin a spectrum of prevalent reproductive disorders, including implantation failure and early pregnancy loss, emphasizing the need for new therapeutic interventions. Resveratrol is a naturally occurring polyphenol, widely used for its antioxidant and anti-inflammatory properties. Using primary human endometrial stromal cell (HESC) cultures, we demonstrate that resveratrol has anti-deciduogenic properties, repressing not only the induction of the decidual marker genes PRL and IGFBP1 but also abrogating decidual senescence. Knockdown of Sirtuin 1, a histone deacetylase activated by resveratrol, restored the expression of IGFBP1 but not the induction of PRL or senescence markers in decidualizing HESCs, suggesting involvement of other pathways. We demonstrate that resveratrol interferes with the reprogramming of the retinoic acid signaling pathway in decidualizing HESCs by accelerating down-regulation of cellular retinoic acid-binding protein 2 (CRABP2) and retinoic acid receptor (RAR). Notably, knockdown of CRABP2 or RAR in HESCs was sufficient to recapitulate the anti-deciduogenic effects of resveratrol. Thus, while resveratrol has been advanced as a potential fertility drug, our results indicate it may have detrimental effects on embryo implantation by interfering with decidual remodeling of the endometrium.
Collapse
Affiliation(s)
- Asako Ochiai
- Department of Obstetrics and Gynaecology, Faculty of Medicine, Juntendo University, Tokyo, 113-8421, Japan
| | - Keiji Kuroda
- Department of Obstetrics and Gynaecology, Faculty of Medicine, Juntendo University, Tokyo, 113-8421, Japan.
- Center for Reproductive Medicine and Implantation Research, Sugiyama Clinic Shinjuku, Tokyo, 116-0023, Japan.
| | - Rie Ozaki
- Department of Obstetrics and Gynaecology, Faculty of Medicine, Juntendo University, Tokyo, 113-8421, Japan
| | - Yuko Ikemoto
- Department of Obstetrics and Gynaecology, Faculty of Medicine, Juntendo University, Tokyo, 113-8421, Japan
| | - Keisuke Murakami
- Department of Obstetrics and Gynaecology, Faculty of Medicine, Juntendo University, Tokyo, 113-8421, Japan
| | - Joanne Muter
- The Division of Biomedical Sciences, Clinical Science Research Laboratories, Warwick Medical School, Coventry, CV2 2DX, UK
| | - Akemi Matsumoto
- Department of Obstetrics and Gynaecology, Faculty of Medicine, Juntendo University, Tokyo, 113-8421, Japan
| | - Atsuo Itakura
- Department of Obstetrics and Gynaecology, Faculty of Medicine, Juntendo University, Tokyo, 113-8421, Japan
| | - Jan J Brosens
- The Division of Biomedical Sciences, Clinical Science Research Laboratories, Warwick Medical School, Coventry, CV2 2DX, UK
- Tommy's National Centre for Miscarriage Research, University Hospitals Coventry & Warwickshire, Coventry, CV2 2DX, UK
| | - Satoru Takeda
- Department of Obstetrics and Gynaecology, Faculty of Medicine, Juntendo University, Tokyo, 113-8421, Japan
| |
Collapse
|
|
16
|
Mutant p53 Protein and the Hippo Transducers YAP and TAZ: A Critical Oncogenic Node in Human Cancers. Int J Mol Sci 2017; 18:ijms18050961. [PMID: 28467351 PMCID: PMC5454874 DOI: 10.3390/ijms18050961] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Revised: 04/11/2017] [Accepted: 04/24/2017] [Indexed: 02/07/2023] Open
Abstract
p53 protein is a well-known tumor suppressor factor that regulates cellular homeostasis. As it has several and key functions exerted, p53 is known as “the guardian of the genome” and either loss of function or gain of function mutations in the TP53 coding protein sequence are involved in cancer onset and progression. The Hippo pathway is a key regulator of developmental and regenerative physiological processes but if deregulated can induce cell transformation and cancer progression. The p53 and Hippo pathways exert a plethora of fine-tuned functions that can apparently be in contrast with each other. In this review, we propose that the p53 status can affect the Hippo pathway function by switching its outputs from tumor suppressor to oncogenic activities. In detail, we discuss: (a) the oncogenic role of the protein complex mutant p53/YAP; (b) TAZ oncogenic activation mediated by mutant p53; (c) the therapeutic potential of targeting mutant p53 to impair YAP and TAZ oncogenic functions in human cancers.
Collapse
|
|
17
|
Wang H, Guo J, Jiang J, Wu W, Chang X, Zhou H, Li Z, Zhao J. New genes associated with rheumatoid arthritis identified by gene expression profiling. Int J Immunogenet 2017; 44:107-113. [PMID: 28371410 DOI: 10.1111/iji.12313] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2016] [Revised: 12/16/2016] [Accepted: 02/23/2017] [Indexed: 12/25/2022]
Affiliation(s)
- H. Wang
- The Key Laboratory of Genome Sciences and Information; Beijing Institute of Genomics, Chinese Academy of Sciences; Beijing China
| | - J. Guo
- Department of Rheumatology and Immunology; Peking University People's Hospital; Beijing China
| | - J. Jiang
- The Key Laboratory of Genome Sciences and Information; Beijing Institute of Genomics, Chinese Academy of Sciences; Beijing China
| | - W. Wu
- The Key Laboratory of Genome Sciences and Information; Beijing Institute of Genomics, Chinese Academy of Sciences; Beijing China
| | - X. Chang
- Department of Rheumatology and Immunology; Qianfoshan Hospital; Jinan China
| | - H. Zhou
- Department of Rheumatology and Immunology; Shenzhen Second People's Hospital; Shenzhen China
| | - Z. Li
- Department of Rheumatology and Immunology; Peking University People's Hospital; Beijing China
| | - J. Zhao
- The Key Laboratory of Genome Sciences and Information; Beijing Institute of Genomics, Chinese Academy of Sciences; Beijing China
| |
Collapse
|
|
18
|
Parrales A, Iwakuma T. p53 as a Regulator of Lipid Metabolism in Cancer. Int J Mol Sci 2016; 17:ijms17122074. [PMID: 27973397 PMCID: PMC5187874 DOI: 10.3390/ijms17122074] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2016] [Revised: 12/01/2016] [Accepted: 12/06/2016] [Indexed: 12/13/2022] Open
Abstract
Enhanced proliferation and survival are common features of cancer cells. Cancer cells are metabolically reprogrammed which aids in their survival in nutrient-poor environments. Indeed, changes in metabolism of glucose and glutamine are essential for tumor progression. Thus, metabolic reprogramming is now well accepted as a hallmark of cancer. Recent findings suggest that reprogramming of lipid metabolism also occurs in cancer cells, since lipids are used for biosynthesis of membranes, post-translational modifications, second messengers for signal transduction, and as a source of energy during nutrient deprivation. The tumor suppressor p53 is a transcription factor that controls the expression of proteins involved in cell cycle arrest, DNA repair, apoptosis, and senescence. p53 also regulates cellular metabolism, which appears to play a key role in its tumor suppressive activities. In this review article, we summarize non-canonical functions of wild-type and mutant p53 on lipid metabolism and discuss their association with cancer progression.
Collapse
Affiliation(s)
- Alejandro Parrales
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA.
| | - Tomoo Iwakuma
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA.
| |
Collapse
|
|
19
|
Mammadova A, Zhou H, Carels CE, Von den Hoff JW. Retinoic acid signalling in the development of the epidermis, the limbs and the secondary palate. Differentiation 2016; 92:326-335. [DOI: 10.1016/j.diff.2016.05.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Revised: 04/20/2016] [Accepted: 05/02/2016] [Indexed: 01/06/2023]
|
|
20
|
Candelaria NR, Weldon R, Muthusamy S, Nguyen-Vu T, Addanki S, Yoffou PH, Karaboga H, Blessing AM, Bollu LR, Miranda RC, Lin CY. Alcohol Regulates Genes that Are Associated with Response to Endocrine Therapy and Attenuates the Actions of Tamoxifen in Breast Cancer Cells. PLoS One 2015; 10:e0145061. [PMID: 26661278 PMCID: PMC4681367 DOI: 10.1371/journal.pone.0145061] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2015] [Accepted: 11/29/2015] [Indexed: 01/25/2023] Open
Abstract
Hereditary, hormonal, and behavioral factors contribute to the development of breast cancer. Alcohol consumption is a modifiable behavior that is linked to increased breast cancer risks and is associated with the development of hormone-dependent breast cancers as well as disease progression and recurrence following endocrine treatment. In this study we examined the molecular mechanisms of action of alcohol by applying molecular, genetic, and genomic approaches in characterizing its effects on estrogen receptor (ER)-positive breast cancer cells. Treatments with alcohol promoted cell proliferation, increased growth factor signaling, and up-regulated the transcription of the ER target gene GREB1 but not the canonical target TFF1/pS2. Microarray analysis following alcohol treatment identified a large number of alcohol-responsive genes, including those which function in apoptotic and cell proliferation pathways. Furthermore, expression profiles of the responsive gene sets in tumors were strongly associated with clinical outcomes in patients who received endocrine therapy. Correspondingly, alcohol treatment attenuated the anti-proliferative effects of the endocrine therapeutic drug tamoxifen in ER-positive breast cancer cells. To determine the contribution and functions of responsive genes, their differential expression in tumors were assessed between outcome groups. The proto-oncogene BRAF was identified as a novel alcohol- and estrogen-induced gene that showed higher expression in patients with poor outcomes. Knock-down of BRAF, moreover, prevented the proliferation of breast cancer cells. These findings not only highlight the mechanistic basis of the effects of alcohol on breast cancer cells and increased risks for disease incidents and recurrence, but may facilitate the discovery and characterization of novel oncogenic pathways and markers in breast cancer research and therapeutics.
Collapse
Affiliation(s)
- Nicholes R. Candelaria
- Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, Texas, United States of America
| | - Ryan Weldon
- Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, Texas, United States of America
| | - Selvaraj Muthusamy
- Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, Texas, United States of America
| | - Trang Nguyen-Vu
- Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, Texas, United States of America
| | - Sridevi Addanki
- Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, Texas, United States of America
| | - Paule-Helena Yoffou
- Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, Texas, United States of America
| | - Husna Karaboga
- Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, Texas, United States of America
| | - Alicia M. Blessing
- Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, Texas, United States of America
| | - Lakshmi Reddy Bollu
- Department of Biology and Biochemistry, University of Houston, Houston, Texas, United States of America
| | - Rajesh C. Miranda
- Department of Neuroscience and Experimental Therapeutics and Women's Health in Neuroscience Program, College of Medicine, Texas A&M Health Science Center, Bryan, Texas, United States of America
| | - Chin-Yo Lin
- Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, Texas, United States of America
| |
Collapse
|
|
21
|
Chang J, Lu Y, Boswell WT, Boswell M, Caballero KL, Walter RB. Molecular genetic response to varied wavelengths of light in Xiphophorus maculatus skin. Comp Biochem Physiol C Toxicol Pharmacol 2015; 178:104-115. [PMID: 26460196 PMCID: PMC4662885 DOI: 10.1016/j.cbpc.2015.10.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2015] [Revised: 10/01/2015] [Accepted: 10/05/2015] [Indexed: 12/14/2022]
Abstract
Xiphophorus fishes represent a model often utilized to study UVB induced tumorigenesis. Recently, varied genetic responses to UVB exposure have been documented in the skin of female and male Xiphophorus, as have differences in UVB response in the skin of different parental species and for interspecies hybrids produced from crossing them. Additionally, it has been shown that exposure to "cool white" fluorescent light induces a shift in the genetic profiles of Xiphophorus skin that is nearly as robust as the UVB response, but involves a fundamentally different set of genes. Given these results and the use of Xiphophorus interspecies hybrids as an experimental model for UVB inducible melanoma, it is of interest to characterize genes that may be transcriptionally modulated in a wavelength specific manner. The global molecular genetic response of skin upon exposure of the intact animal to specific wavelengths of light has not been investigated. Herein, we report results of RNA-Seq experiments from the skin of male Xiphophorus maculatus Jp 163 B following exposure to varied 50nm wavelengths of light ranging from 300-600nm. We identify two specific wavelength regions, 350-400nm (88 genes) and 500-550nm (276 genes), that exhibit transcriptional modulation of a significantly greater number of transcripts than any of the other 50nm regions in the 300-600nm range. Observed functional sets of genes modulated within these two transcriptionally active light regions suggest different mechanisms of gene modulation.
Collapse
Affiliation(s)
- Jordan Chang
- Molecular Bioscience Research Group and Xiphophorus Genetic Stock Center, Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX 78666, USA.
| | - Yuan Lu
- Molecular Bioscience Research Group and Xiphophorus Genetic Stock Center, Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX 78666, USA.
| | - William T Boswell
- Molecular Bioscience Research Group and Xiphophorus Genetic Stock Center, Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX 78666, USA.
| | - Mikki Boswell
- Molecular Bioscience Research Group and Xiphophorus Genetic Stock Center, Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX 78666, USA.
| | - Kaela L Caballero
- Molecular Bioscience Research Group and Xiphophorus Genetic Stock Center, Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX 78666, USA.
| | - Ronald B Walter
- Molecular Bioscience Research Group and Xiphophorus Genetic Stock Center, Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX 78666, USA.
| |
Collapse
|
|
22
|
Applegate CC, Lane MA. Role of retinoids in the prevention and treatment of colorectal cancer. World J Gastrointest Oncol 2015; 7:184-203. [PMID: 26483874 PMCID: PMC4606174 DOI: 10.4251/wjgo.v7.i10.184] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2015] [Revised: 07/10/2015] [Accepted: 09/16/2015] [Indexed: 02/05/2023] Open
Abstract
Vitamin A and its derivatives, retinoids, have been widely studied for their use as cancer chemotherapeutic agents. With respect to colorectal cancer (CRC), several critical mutations dysregulate pathways implicated in progression and metastasis, resulting in aberrant Wnt/β-catenin signaling, gain-of-function mutations in K-ras and phosphatidylinositol-3-kinase/Akt, cyclooxygenase-2 over-expression, reduction of peroxisome proliferator-activated receptor γ activation, and loss of p53 function. Dysregulation leads to increased cellular proliferation and invasion and decreased cell-cell interaction and differentiation. Retinoids affect these pathways by various mechanisms, many involving retinoic acid receptors (RAR). RAR bind to all-trans-retinoic acid (ATRA) to induce the transcription of genes responsible for cellular differentiation. Although most research concerning the chemotherapeutic efficacy of retinoids focuses on the ability of ATRA to decrease cancer cell proliferation, increase differentiation, or promote apoptosis; as CRC progresses, RAR expression is often lost, rendering treatment of CRCs with ATRA ineffective. Our laboratory focuses on the ability of dietary vitamin A to decrease CRC cell proliferation and invasion via RAR-independent pathways. This review discusses our research and others concerning the ability of retinoids to ameliorate the defective signaling pathways listed above and decrease tumor cell proliferation and invasion through both RAR-dependent and RAR-independent mechanisms.
Collapse
|
|
23
|
Wong DY, Ranganath T, Kasko AM. Low-Dose, Long-Wave UV Light Does Not Affect Gene Expression of Human Mesenchymal Stem Cells. PLoS One 2015; 10:e0139307. [PMID: 26418040 PMCID: PMC4587745 DOI: 10.1371/journal.pone.0139307] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2015] [Accepted: 09/12/2015] [Indexed: 01/14/2023] Open
Abstract
Light is a non-invasive tool that is widely used in a range of biomedical applications. Techniques such as photopolymerization, photodegradation, and photouncaging can be used to alter the chemical and physical properties of biomaterials in the presence of live cells. Long-wave UV light (315 nm–400 nm) is an easily accessible and commonly used energy source for triggering biomaterial changes. Although exposure to low doses of long-wave UV light is generally accepted as biocompatible, most studies employing this wavelength only establish cell viability, ignoring other possible (non-toxic) effects. Since light exposure of wavelengths longer than 315 nm may potentially induce changes in cell behavior, we examined changes in gene expression of human mesenchymal stem cells exposed to light under both 2D and 3D culture conditions, including two different hydrogel fabrication techniques, decoupling UV exposure and radical generation. While exposure to long-wave UV light did not induce significant changes in gene expression regardless of culture conditions, significant changes were observed due to scaffold fabrication chemistry and between cells plated in 2D versus encapsulated in 3D scaffolds. In order to facilitate others in searching for more specific changes between the many conditions, the full data set is available on Gene Expression Omnibus for querying.
Collapse
Affiliation(s)
- Darice Y. Wong
- Department of Bioengineering, Henry Samueli School of Engineering, University of California Los Angeles, Los Angeles, California, United States of America
| | - Thanmayi Ranganath
- Department of Bioengineering, Henry Samueli School of Engineering, University of California Los Angeles, Los Angeles, California, United States of America
| | - Andrea M. Kasko
- Department of Bioengineering, Henry Samueli School of Engineering, University of California Los Angeles, Los Angeles, California, United States of America
- * E-mail:
| |
Collapse
|
|
24
|
Lundová T, Zemanová L, Malčeková B, Skarka A, Štambergová H, Havránková J, Šafr M, Wsól V. Molecular and biochemical characterisation of human short-chain dehydrogenase/reductase member 3 (DHRS3). Chem Biol Interact 2014; 234:178-87. [PMID: 25451588 DOI: 10.1016/j.cbi.2014.10.018] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2014] [Revised: 10/11/2014] [Accepted: 10/17/2014] [Indexed: 12/22/2022]
Abstract
Dehydrogenase/reductase (SDR family) member 3 (DHRS3), also known as retinal short-chain dehydrogenase/reductase (retSDR1) is a member of SDR16C family. This family is thought to be NADP(H) dependent and to have multiple substrates; however, to date, only all-trans-retinal has been identified as a DHRS3 substrate. The reductive reaction catalysed by DHRS3 seems to be physiological, and recent studies proved the importance of DHRS3 for maintaining suitable retinoic acid levels during embryonic development in vivo. Although it seems that DHRS3 is an important protein, knowledge of the protein and its properties is quite limited, with the majority of information being more than 15 years old. This study aimed to generate a more comprehensive characterisation of the DHRS3 protein. Recombinant enzyme was prepared and demonstrated to be a microsomal, integral-membrane protein with the C-terminus oriented towards the cytosol, consistent with its preference of NADPH as a cofactor. It was determined that DHRS3 also participates in the metabolism of other endogenous compounds, such as androstenedione, estrone, and DL-glyceraldehyde, and in the biotransformation of xenobiotics (e.g., NNK and acetohexamide) in addition to all-trans-retinal. Purified and reconstituted enzyme was prepared for the first time and will be used for further studies. Expression of DHRS3 was shown at the level of both mRNA and protein in the human liver, testis and small intestine. This new information could open other areas of DHRS3 protein research.
Collapse
Affiliation(s)
- Tereza Lundová
- Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic.
| | - Lucie Zemanová
- Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic.
| | - Beata Malčeková
- Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic.
| | - Adam Skarka
- Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic.
| | - Hana Štambergová
- Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic.
| | - Jana Havránková
- Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic.
| | - Miroslav Šafr
- Institute of Legal Medicine, Faculty of Medicine, Charles University and University Hospital in Hradec Králové, Sokolská 581, 500 05 Hradec Králové, Czech Republic.
| | - Vladimír Wsól
- Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic.
| |
Collapse
|
|
25
|
Pardini B, Bermejo JL, Naccarati A, Di Gaetano C, Rosa F, Legrand C, Novotny J, Vodicka P, Kumar R. Inherited variability in a master regulator polymorphism (rs4846126) associates with survival in 5-FU treated colorectal cancer patients. Mutat Res 2014; 766-767:7-13. [PMID: 25847265 DOI: 10.1016/j.mrfmmm.2014.05.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2013] [Revised: 04/23/2014] [Accepted: 05/30/2014] [Indexed: 06/04/2023]
Abstract
BACKGROUND Treatment with 5-fluorouracil (5-FU) is known to improve survival in many cancers including colorectal cancer. Response to the treatment, overall survival and recurrence show inter-individual variation. METHODS In this study we employed a strategy to search eQTL variants influencing the expression of a large number of genes. We identified four single nucleotide polymorphisms, defined as master regulators of transcription, and genotyped them in a set of 218 colorectal cancer patients undergoing adjuvant 5-FU based therapy. RESULTS Our results showed that the minor allele variant of the rs4846126 polymorphism was associated with poor overall and progression-free survival. Patients that were homozygous for the variant allele showed an over two fold increased risk of death (HR 2.20 95%CI 1.05-4.60) and progression (HR 2.88, 95% 1.47-5.63). The integration of external information from publicly available gene expression repositories suggested that the rs4846126 polymorphism deserves further investigation. This variant potentially regulates the gene expression of 273 genes with some of them possibly associated to the patient's response to 5-FU treatment or colorectal cancer. CONCLUSIONS Present results show that mining of public data repositories in combination with own data can be a fruitful approach to identify markers that affect therapy outcome. In particular, a genetic screen of master regulators may help in order to search for the polymorphisms involved in treatment response in cancer patients.
Collapse
Affiliation(s)
- Barbara Pardini
- Human Genetics Foundation, Turin, Italy; Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
| | - Justo Lorenzo Bermejo
- Institute of Medical Biometry and Informatics, University Hospital Heidelberg, Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Alessio Naccarati
- Human Genetics Foundation, Turin, Italy; Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic
| | - Cornelia Di Gaetano
- Human Genetics Foundation, Turin, Italy; Department of Medical Sciences, University of Turin, Turin, Italy
| | | | - Carine Legrand
- Institute of Medical Biometry and Informatics, University Hospital Heidelberg, Heidelberg, Germany
| | - Jan Novotny
- Department of Oncology, General Teaching Hospital, Prague, Czech Republic
| | - Pavel Vodicka
- Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic; First Medical Faculty, Charles University, Prague, Czech Republic
| | - Rajiv Kumar
- German Cancer Research Center (DKFZ), Heidelberg, Germany
| |
Collapse
|
|
26
|
Fischer M, Steiner L, Engeland K. The transcription factor p53: not a repressor, solely an activator. Cell Cycle 2014; 13:3037-58. [PMID: 25486564 PMCID: PMC4612452 DOI: 10.4161/15384101.2014.949083] [Citation(s) in RCA: 115] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2014] [Accepted: 07/10/2014] [Indexed: 12/12/2022] Open
Abstract
The predominant function of the tumor suppressor p53 is transcriptional regulation. It is generally accepted that p53-dependent transcriptional activation occurs by binding to a specific recognition site in promoters of target genes. Additionally, several models for p53-dependent transcriptional repression have been postulated. Here, we evaluate these models based on a computational meta-analysis of genome-wide data. Surprisingly, several major models of p53-dependent gene regulation are implausible. Meta-analysis of large-scale data is unable to confirm reports on directly repressed p53 target genes and falsifies models of direct repression. This notion is supported by experimental re-analysis of representative genes reported as directly repressed by p53. Therefore, p53 is not a direct repressor of transcription, but solely activates its target genes. Moreover, models based on interference of p53 with activating transcription factors as well as models based on the function of ncRNAs are also not supported by the meta-analysis. As an alternative to models of direct repression, the meta-analysis leads to the conclusion that p53 represses transcription indirectly by activation of the p53-p21-DREAM/RB pathway.
Collapse
Key Words
- CDE, cell cycle-dependent element
- CDKN1A
- CHR, cell cycle genes homology region
- ChIP, chromatin immunoprecipitation
- DREAM complex
- DREAM, DP, RB-like, E2F4, and MuvB complex
- E2F/RB complex
- HPV, human papilloma virus
- NF-Y, Nuclear factor Y
- cdk, cyclin-dependent kinase
- genome-wide meta-analysis
- p53
Collapse
Affiliation(s)
- Martin Fischer
- Molecular Oncology; Medical School; University of Leipzig; Leipzig, Germany
| | - Lydia Steiner
- Center for Complexity & Collective Computation; Wisconsin Institute for Discovery; Madison, WI USA
- Computational EvoDevo Group & Bioinformatics Group; Department of Computer Science and Interdisciplinary Center for Bioinformatics; University of Leipzig; Leipzig, Germany
| | - Kurt Engeland
- Molecular Oncology; Medical School; University of Leipzig; Leipzig, Germany
| |
Collapse
|
|
27
|
Billings SE, Pierzchalski K, Butler Tjaden NE, Pang XY, Trainor PA, Kane MA, Moise AR. The retinaldehyde reductase DHRS3 is essential for preventing the formation of excess retinoic acid during embryonic development. FASEB J 2013; 27:4877-89. [PMID: 24005908 DOI: 10.1096/fj.13-227967] [Citation(s) in RCA: 99] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Oxidation of retinol via retinaldehyde results in the formation of the essential morphogen all-trans-retinoic acid (ATRA). Previous studies have identified critical roles in the regulation of embryonic ATRA levels for retinol, retinaldehyde, and ATRA-oxidizing enzymes; however, the contribution of retinaldehyde reductases to ATRA metabolism is not completely understood. Herein, we investigate the role of the retinaldehyde reductase Dhrs3 in embryonic retinoid metabolism using a Dhrs3-deficient mouse. Lack of DHRS3 leads to a 40% increase in the levels of ATRA and a 60% and 55% decrease in the levels of retinol and retinyl esters, respectively, in Dhrs3(-/-) embryos compared to wild-type littermates. Furthermore, accumulation of excess ATRA is accompanied by a compensatory 30-50% reduction in the expression of ATRA synthetic genes and a 120% increase in the expression of the ATRA catabolic enzyme Cyp26a1 in Dhrs3(-/-) embryos vs. controls. Excess ATRA also leads to alterations (40-80%) in the expression of several developmentally important ATRA target genes. Consequently, Dhrs3(-/-) embryos die late in gestation and display defects in cardiac outflow tract formation, atrial and ventricular septation, skeletal development, and palatogenesis. These data demonstrate that the reduction of retinaldehyde by DHRS3 is critical for preventing formation of excess ATRA during embryonic development.
Collapse
Affiliation(s)
- Sara E Billings
- 1Department of Pharmacology and Toxicology, School of Pharmacy, 5060-Malott Hall, 1251 Wescoe Hall Dr., University of Kansas, Lawrence, KS 66045, USA.
| | | | | | | | | | | | | |
Collapse
|
|
28
|
Kedishvili NY. Enzymology of retinoic acid biosynthesis and degradation. J Lipid Res 2013; 54:1744-60. [PMID: 23630397 PMCID: PMC3679379 DOI: 10.1194/jlr.r037028] [Citation(s) in RCA: 145] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2013] [Revised: 04/17/2013] [Indexed: 12/18/2022] Open
Abstract
All-trans-retinoic acid is a biologically active derivative of vitamin A that regulates numerous physiological processes. The concentration of retinoic acid in the cells is tightly regulated, but the exact mechanisms responsible for this regulation are not completely understood, largely because the enzymes involved in the biosynthesis of retinoic acid have not been fully defined. Recent studies using in vitro and in vivo models suggest that several members of the short-chain dehydrogenase/reductase superfamily of proteins are essential for retinoic acid biosynthesis and the maintenance of retinoic acid homeostasis. However, the exact roles of some of these recently identified enzymes are yet to be characterized. The properties of the known contributors to retinoid metabolism have now been better defined and allow for more detailed understanding of their interactions with retinoid-binding proteins and other retinoid enzymes. At the same time, further studies are needed to clarify the interactions between the cytoplasmic and membrane-bound proteins involved in the processing of hydrophobic retinoid metabolites. This review summarizes current knowledge about the roles of various biosynthetic and catabolic enzymes in the regulation of retinoic acid homeostasis and outlines the remaining questions in the field.
Collapse
Affiliation(s)
- Natalia Y Kedishvili
- Department of Biochemistry and Molecular Genetics, Schools of Medicine and Dentistry, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
| |
Collapse
|
|
29
|
Monti P, Russo D, Bocciardi R, Foggetti G, Menichini P, Divizia MT, Lerone M, Graziano C, Wischmeijer A, Viadiu H, Ravazzolo R, Inga A, Fronza G. EEC- and ADULT-associated TP63 mutations exhibit functional heterogeneity toward P63 responsive sequences. Hum Mutat 2013; 34:894-904. [PMID: 23463580 DOI: 10.1002/humu.22304] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2012] [Accepted: 02/22/2013] [Indexed: 01/05/2023]
Abstract
TP63 germ-line mutations are responsible for a group of human ectodermal dysplasia syndromes, underlining the key role of P63 in the development of ectoderm-derived tissues. Here, we report the identification of two TP63 alleles, G134V (p.Gly173Val) and insR155 (p.Thr193_Tyr194insArg), associated to ADULT and EEC syndromes, respectively. These alleles, along with previously identified G134D (p.Gly173Asp) and R204W (p.Arg243Trp), were functionally characterized in yeast, studied in a mammalian cell line and modeled based on the crystal structure of the P63 DNA-binding domain. Although the p.Arg243Trp mutant showed both complete loss of transactivation function and ability to interfere over wild-type P63, the impact of p.Gly173Asp, p.Gly173Val, and p.Thr193_Tyr194insArg varied depending on the response element (RE) tested. Interestingly, p.Gly173Asp and p.Gly173Val mutants were characterized by a severe defect in transactivation along with interfering ability on two DN-P63α-specific REs derived from genes closely related to the clinical manifestations of the TP63-associated syndromes, namely PERP and COL18A1. The modeling of the mutations supported the distinct functional effect of each mutant. The present results highlight the importance of integrating different functional endpoints that take in account the features of P63 proteins' target sequences to examine the impact of TP63 mutations and the associated clinical variability.
Collapse
Affiliation(s)
- Paola Monti
- Molecular Mutagenesis and DNA Repair Unit, Istituto di Ricerca e Cura a Carattere Scientifico Azienda Ospedaliera Universitaria San Martino-IST-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
30
|
APR-246/PRIMA-1(MET) rescues epidermal differentiation in skin keratinocytes derived from EEC syndrome patients with p63 mutations. Proc Natl Acad Sci U S A 2013; 110:2157-62. [PMID: 23355676 DOI: 10.1073/pnas.1201993110] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
p53 and p63 share extensive sequence and structure homology. p53 is frequently mutated in cancer, whereas mutations in p63 cause developmental disorders manifested in ectodermal dysplasia, limb defects, and orofacial clefting. We have established primary adult skin keratinocytes from ectrodactyly, ectodermal dysplasia, and cleft lip/palate (EEC) syndrome patients with p63 mutations as an in vitro human model to study the disease mechanism in the skin of EEC patients. We show that these patient keratinocytes cultured either in submerged 2D cultures or in 3D skin equivalents have impaired epidermal differentiation and stratification. Treatment of these patient keratinocytes with the mutant p53-targeting compound APR-246/PRIMA-1(MET) (p53 reactivation and induction of massive apoptosis) that has been successfully tested in a phase I/II clinical trial in cancer patients partially but consistently rescued morphological features and gene expression during epidermal stratification in both 2D and 3D models. This rescue coincides with restoration of p63 target-gene expression. Our data show that EEC patient keratinocytes with p63 mutations can be used for characterization of the abnormal molecular circuitry in patient skin and may open possibilities for the design of novel pharmacological treatment strategies for patients with mutant p63-associated developmental abnormalities.
Collapse
|
|
31
|
Quaas M, Müller GA, Engeland K. p53 can repress transcription of cell cycle genes through a p21(WAF1/CIP1)-dependent switch from MMB to DREAM protein complex binding at CHR promoter elements. Cell Cycle 2012. [PMID: 23187802 PMCID: PMC3562311 DOI: 10.4161/cc.22917] [Citation(s) in RCA: 90] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
The tumor suppressor p53 plays an important role in cell cycle arrest by downregulating transcription. Many genes repressed by p53 code for proteins with functions in G₂/M. A large portion of these genes is controlled by cell cycle-dependent elements (CDE) and cell cycle genes homology regions (CHR) in their promoters. Cyclin B2 is an example of such a gene, with a function at the transition from G₂ to mitosis. We find that p53-dependent downregulation of cyclin B2 promoter activity is dependent on an intact CHR element. In the presence of high levels of p53 or p21WAF1/CIP1, protein binding to the CHR switches from MMB to DREAM complex by shifting MuvB core-associated proteins from B-Myb to E2F4/DP1/p130. The results suggest a model for p53-dependent transcriptional repression by which p53 directly activates p21WAF1/CIP1. The inhibitor then prevents further phosphorylation of p130 by cyclin-dependent kinases. The presence of hypophosphorylated pocket proteins shifts the equilibrium for complex formation from MMB to DREAM. In the case of promoters that do not hold CDE or E2F elements, binding of DREAM and MMB solely relies on a CHR site. Thus, p53 can repress target genes indirectly through CHR elements.
Collapse
Affiliation(s)
- Marianne Quaas
- Department of Molecular Oncology, Medical School, University of Leipzig, Leipzig, Germany
| | | | | |
Collapse
|
|
32
|
Goldstein I, Rotter V. Regulation of lipid metabolism by p53 - fighting two villains with one sword. Trends Endocrinol Metab 2012; 23:567-75. [PMID: 22819212 DOI: 10.1016/j.tem.2012.06.007] [Citation(s) in RCA: 96] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2012] [Revised: 06/19/2012] [Accepted: 06/20/2012] [Indexed: 01/01/2023]
Abstract
Both cellular and systemic metabolism of lipids are paramount for homeostasis, and their malfunction leads to devastating pathologies. Recently, exciting findings have linked the p53 tumor suppressor to the regulation of lipid metabolism. Here, we summarize these findings showing a clear role for p53 in enhancing lipid catabolism while inhibiting its anabolism. We also describe the multitude of genes regulated by p53 that participate in or regulate systemic lipid transport. From the compilation of available data a scenario is emerging in which p53 regulates genes involved in lipid metabolism - both in a cancer-preventive effort and, intriguingly, as a means to prevent atherosclerosis. Thus, by regulating lipid metabolism, p53 fights the two major causes of death worldwide - atherosclerosis and cancer.
Collapse
Affiliation(s)
- Ido Goldstein
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, 76100 Israel
| | | |
Collapse
|
|
33
|
Zolfaghari R, Chen Q, Ross AC. DHRS3, a retinal reductase, is differentially regulated by retinoic acid and lipopolysaccharide-induced inflammation in THP-1 cells and rat liver. Am J Physiol Gastrointest Liver Physiol 2012; 303:G578-88. [PMID: 22790594 PMCID: PMC3468555 DOI: 10.1152/ajpgi.00234.2012] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2012] [Accepted: 07/10/2012] [Indexed: 01/31/2023]
Abstract
Both retinoid status and inflammation have been shown to control the level of expression of retinoid homeostatic genes. In the present study, DHRS3, previously shown to possess retinal reductase activity, was identified by microarray analysis of THP-1 monocytes as a possible gene target of all-trans-retinoic acid (RA). In these cells, DHRS3 mRNA increased 30- to 40-fold after treatment with ≤20 nM RA for 24 h, while DHRS3 protein also increased. Of several synthetic retinoids tested, only Am580, a RA receptor-α-selective retinoid, increased DHRS3 mRNA expression. The full-length DHRS3 cDNA was cloned from rat liver and subjected to in vitro transcription-translation. Two major ∼30- and 35-kDa proteins were detected. In adult rat tissues, DHRS3 mRNA was most abundant in the adrenal gland, liver, and ovary. In the liver, DHRS3 is expressed in hepatocytes and possibly in all liver cells. To evaluate whether DHRS3 is regulated in the liver by RA and/or inflammatory stimuli, we treated rats for 6 h with RA or LPS or both. DHRS3 mRNA was doubled by RA but reduced by >90% after treatment with LPS in the absence and presence of RA. On the basis of our results, DHRS3 mRNA expression is regulated by RA in a tissue- or cell-type specific manner; the RA-induced increase in DHRS3 may contribute to retinoid storage; and a reduction of DHRS3 expression in the liver during inflammation may contribute to the perturbation of whole body vitamin A metabolism that has previously been shown to occur in conditions of inflammatory stress.
Collapse
Affiliation(s)
- Reza Zolfaghari
- Department of Nutritional Sciences, Pennsylvania State University, University Park, 16802, USA
| | | | | |
Collapse
|
|
34
|
Sohr S, Engeland K. The tumor suppressor p53 induces expression of the pregnancy-supporting human chorionic gonadotropin (hCG) CGB7 gene. Cell Cycle 2011; 10:3758-67. [PMID: 22032922 DOI: 10.4161/cc.10.21.17946] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Successful pregnancy requires a functionally normal blastocyst encountering a receptive maternal endometrium. Interestingly, the cell cycle regulator and tumor suppressor p53 has been reported to support reproduction in mice by regulating the expression of the leukemia inhibitory factor gene in the maternal endometrium. However, in humans the hormonal system orchestrating successful pregnancy is considerably different from rodents. Particularly, the primate-specific dimeric glycoprotein hormone human chorionic gonadotropin (hCG) is essential for blastocyst implantation and maintenance of early human pregnancy. Here we provide evidence that p53 selectively induces expression of the hCGbeta7 (CGB7) gene. None of the other CGB genes was found to be regulated by p53. We show that expression of the CGB7 gene is upregulated upon p53 induction in human HFF, HCT116 and DLD1 cells as well as in cell preparations enriched in human primary first-trimester trophoblasts. The increase in CGB7 levels upon doxorubicin treatment is lost after siRNA-directed knockdown of p53. Furthermore, we describe CGB7 as a direct transcriptional target gene of p53 by identifying a p53-responsive element in the CGB7 promoter using reporter assays, electrophoretic mobility shift assays and chromatin immunoprecipitations. With these results we provide a new link between p53 transcriptional activity and human reproduction.
Collapse
Affiliation(s)
- Sindy Sohr
- Molecular Oncology, Medical School, University of Leipzig, Leipzig, Germany
| | | |
Collapse
|
|
35
|
Ackermans MMG, Zhou H, Carels CEL, Wagener FADTG, Von den Hoff JW. Vitamin A and clefting: putative biological mechanisms. Nutr Rev 2011; 69:613-24. [DOI: 10.1111/j.1753-4887.2011.00425.x] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
|
|
36
|
Deisenroth C, Itahana Y, Tollini L, Jin A, Zhang Y. p53-Inducible DHRS3 is an endoplasmic reticulum protein associated with lipid droplet accumulation. J Biol Chem 2011; 286:28343-56. [PMID: 21659514 DOI: 10.1074/jbc.m111.254227] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
The transcription factor p53 plays a critical role in maintaining homeostasis as it relates to cellular growth, proliferation, and metabolism. In an effort to identify novel p53 target genes, a microarray approach was utilized to identify DHRS3 (also known as retSDR1) as a robust candidate gene. DHRS3 is a highly conserved member of the short chain alcohol dehydrogenase/reductase superfamily with a reported role in lipid and retinoid metabolism. Here, we demonstrate that DHRS3 is an endoplasmic reticulum (ER) protein that is shuttled to the ER via an N-terminal endoplasmic reticulum targeting signal. One important function of the ER is synthesis of neutral lipids that are packaged into lipid droplets whose biogenesis occurs from ER-derived membranes. DHRS3 is enriched at focal points of lipid droplet budding where it also localizes to the phospholipid monolayer of ER-derived lipid droplets. p53 promotes lipid droplet accumulation in a manner consistent with DHRS3 enrichment in the ER. As a p53 target gene, the observations of Dhrs3 location and potential function provide novel insight into an unexpected role for p53 in lipid droplet dynamics with implications in cancer cell metabolism and obesity.
Collapse
Affiliation(s)
- Chad Deisenroth
- Department of Radiation Oncology, School of Medicine, University of North Carolina at Chapel Hill,Chapel Hill, North Carolina 27599, USA
| | | | | | | | | |
Collapse
|