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Cited by 117

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

Uxa, Sigrid, Bernhart, Stephan H, Mages, Christina F S, Fischer, Martin, Kohler, Robin, Hoffmann, Steve, Stadler, Peter F, Engeland, Kurt, Müller, Gerd A·2019·Nucleic Acids Research
DOI 10.1093/nar/gkz635
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Abstract

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.

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Metadata

Authors
Uxa, S., Bernhart, S. H., Mages, C. F. S., Fischer, M., Kohler, R., Hoffmann, S., Stadler, P. F., Engeland, K., & Müller, G. A.
Affiliations
  • Molecular Oncology, Department of Gynaecology, Medical School, Leipzig University, 04103 Leipzig, Germany
  • Transcriptome Bioinformatics Group, Department of Computer Science and Interdisciplinary Center for Bioinformatics, Leipzig University, 04107 Leipzig, Germany
  • Computational Biology Group, Leibniz Institute on Aging – Fritz Lipmann Institute (FLI), 07745 Jena, Germany
ORCID
Venue
Nucleic Acids Research
Publisher
Oxford University Press (OUP)
Published
2019-08-10
Volume
47
Issue
17
Pages
9087-9103
ISSN
  • 0305-1048
  • 1362-4962
DOI
10.1093/nar/gkz635
Cited by
117
References
19
Language
en
Licence
creativecommons.org/licenses/by-nc/4.0/ (vor)
Funders
  • German Research Foundation (MU 3798/1-1)
  • MF (FI 1993/2-1)
  • German BMBF (01KU1505-C)
  • University of Leipzig
  • German Academic Scholarship Foundation
  • Christiane Nüsslein-Volhard Foundation

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CoChat. (2026). Citation check: DREAM and RB cooperate to induce gene repression and cell-cycle arrest in response to p53 activation. https://app.cochat.ai/papers/10.1093/nar/gkz635
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Uxa, S., Bernhart, S. H., Mages, C. F. S., Fischer, M., Kohler, R., Hoffmann, S., Stadler, P. F., Engeland, K., & Müller, G. A. (2019). DREAM and RB cooperate to induce gene repression and cell-cycle arrest in response to p53 activation. Nucleic Acids Research. https://doi.org/10.1093/nar/gkz635

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