CDK6 Antagonizes p53-Induced Responses during Tumorigenesis

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinogenesis*
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic
  • Cyclin-Dependent Kinase 6 / metabolism*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Mice
  • Mutation*
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Tumor Suppressor Protein p53 / genetics*


  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • CDK6 protein, human
  • Cyclin-Dependent Kinase 6