Journal
CANCER DISCOVERY
Volume 8, Issue 7, Pages 884-897Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-17-0912
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Funding
- MLL Munich Leukemia Laboratory
- ERC
- [FWF-SFB47]
- [FWF-P24297]
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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, Ppmld, 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. (C)2018 AACR.
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