DREAM and RB cooperate to induce gene repression and cell-cycle arrest in response to p53 activation.
Animals
Cell Cycle Checkpoints
/ genetics
Cells, Cultured
Crk-Associated Substrate Protein
/ genetics
Cyclin-Dependent Kinase Inhibitor p21
/ genetics
E2F Transcription Factors
/ genetics
Fibroblasts
/ metabolism
Gene Expression Regulation
Genes, cdc
HCT116 Cells
Humans
Kv Channel-Interacting Proteins
/ genetics
Mice
Repressor Proteins
/ genetics
Retinoblastoma Protein
/ genetics
Retinoblastoma-Like Protein p107
/ genetics
Trans-Activators
/ genetics
Tumor Suppressor Protein p53
/ genetics
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
26 09 2019
26 09 2019
Historique:
accepted:
16
07
2019
revised:
07
07
2019
received:
11
04
2019
pubmed:
11
8
2019
medline:
21
12
2019
entrez:
11
8
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31400114
pii: 5545733
doi: 10.1093/nar/gkz635
pmc: PMC6753476
doi:
Substances chimiques
Bcar1 protein, mouse
0
CDKN1A protein, human
0
Crk-Associated Substrate Protein
0
Cyclin-Dependent Kinase Inhibitor p21
0
E2F Transcription Factors
0
KCNIP3 protein, human
0
Kv Channel-Interacting Proteins
0
Lin37 protein, human
0
Lin37 protein, mouse
0
Rbl1 protein, mouse
0
Repressor Proteins
0
Retinoblastoma Protein
0
Retinoblastoma-Like Protein p107
0
TP53 protein, human
0
Trans-Activators
0
Tumor Suppressor Protein p53
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
9087-9103Informations de copyright
© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.
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