DREAM and RB cooperate to induce gene repression and cell-cycle arrest in response to p53 activation.

Autor:	Uxa S; Molecular Oncology, Department of Gynaecology, Medical School, Leipzig University, 04103 Leipzig, Germany., Bernhart SH; Transcriptome Bioinformatics Group, Department of Computer Science and Interdisciplinary Center for Bioinformatics, Leipzig University, 04107 Leipzig, Germany., Mages CFS; Molecular Oncology, Department of Gynaecology, Medical School, Leipzig University, 04103 Leipzig, Germany., Fischer M; Computational Biology Group, Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), 07745 Jena, Germany., Kohler R; Molecular Oncology, Department of Gynaecology, Medical School, Leipzig University, 04103 Leipzig, Germany., Hoffmann S; Computational Biology Group, Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), 07745 Jena, Germany., Stadler PF; Transcriptome Bioinformatics Group, Department of Computer Science and Interdisciplinary Center for Bioinformatics, Leipzig University, 04107 Leipzig, Germany.; German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig; Leipzig Research Center for Civilization Diseases; and Competence Center for Scalable Data Services and Solutions Dresden/Leipzig, Leipzig University, 04107 Leipzig, Germany.; Max Planck Institute for Mathematics in the Sciences, 04103 Leipzig, Germany.; Institute for Theoretical Chemistry, University of Vienna, A-1090 Wien, Austria.; Facultad de Ciencias, Universidad National de Colombia, Sede Bogota, Colombia.; Santa Fe Institute, Santa Fe, NM 87501, USA., Engeland K; Molecular Oncology, Department of Gynaecology, Medical School, Leipzig University, 04103 Leipzig, Germany., Müller GA; Molecular Oncology, Department of Gynaecology, Medical School, Leipzig University, 04103 Leipzig, Germany.; Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA 95064, USA.
Jazyk:	angličtina
Zdroj:	Nucleic acids research [Nucleic Acids Res] 2019 Sep 26; Vol. 47 (17), pp. 9087-9103.
DOI:	10.1093/nar/gkz635
Abstrakt:	Most human cancers acquire mutations causing defects in the p53 signaling pathway. The tumor suppressor p53 becomes activated in response to genotoxic stress and is essential for arresting the cell cycle to facilitate DNA repair or to initiate apoptosis. p53-induced cell cycle-arrest is mediated by expression of the CDK inhibitor p21WAF1/Cip1, which prevents phosphorylation and inactivation of the pocket proteins RB, p130, and p107. In a hypophosphorylated state, pocket proteins bind to E2F factors forming RB-E2F and DREAM transcriptional repressor complexes. Here, we analyze the influence of RB and DREAM on p53-induced gene repression and cell-cycle arrest. We show that abrogation of DREAM function by knockout of the DREAM component LIN37 results in a reduced repression of cell-cycle genes. We identify the genes repressed by the p53-DREAM pathway and describe a set of genes that is downregulated by p53 independent of LIN37/DREAM. Most strikingly, p53-dependent repression of cell-cycle genes is completely abrogated in LIN37-/-;RB-/- cells leading to a loss of the G1/S checkpoint. Taken together, we show that DREAM and RB are key factors in the p53 signaling pathway to downregulate a large number of cell-cycle genes and to arrest the cell cycle at the G1/S transition. (© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.)
Databáze:	MEDLINE
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