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Cancer Discov. 2018 Jul;8(7):884-897. doi: 10.1158/2159-8290.CD-17-0912. Epub 2018 Jun 13.

CDK6 Antagonizes p53-Induced Responses during Tumorigenesis.

Author information

1
Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria.
2
Platform Bioinformatics and Biostatistics, University of Veterinary Medicine, Vienna, Austria.
3
MLL Munich Leukemia Laboratory, Munich, Germany.
4
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
5
Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
6
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
7
Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, and Tufts Cancer Center, Boston, Massachusetts.
8
Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria.
9
Medical University of Vienna, Vienna, Austria.
10
Research Institute of Molecular Pathology (IMP), Vienna, Austria.
11
CNIO, Madrid, Spain.
12
Innsbruck Medical University, Innsbruck, Austria.
13
Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria. veronika.sexl@vetmeduni.ac.at.

Abstract

Tumor formation is a multistep process during which cells acquire genetic and epigenetic changes until they reach a fully transformed state. We show that CDK6 contributes to tumor formation by regulating transcriptional responses in a stage-specific manner. In early stages, the CDK6 kinase induces a complex transcriptional program to block p53 in hematopoietic cells. Cells lacking CDK6 kinase function are required to mutate TP53 (encoding p53) to achieve a fully transformed immortalized state. CDK6 binds to the promoters of genes including the p53 antagonists Prmt5, Ppm1d, and Mdm4 The findings are relevant to human patients: Tumors with low levels of CDK6 have mutations in TP53 significantly more often than expected.Significance: CDK6 acts at the interface of p53 and RB by driving cell-cycle progression and antagonizing stress responses. While sensitizing cells to p53-induced cell death, specific inhibition of CDK6 kinase activity may provoke the outgrowth of p53-mutant clones from premalignant cells. Cancer Discov; 8(7); 884-97. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 781.

PMID:
29899063
PMCID:
PMC6031305
[Available on 2019-01-01]
DOI:
10.1158/2159-8290.CD-17-0912

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