CDK6 Antagonizes p53-Induced Responses during Tumorigenesis

Tumor formation is a multi-step 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 CDK6 kinase induces a complex transcriptional program to block p53 in hematopoietic cells. Cells lacking CDK6 kinase function are required to mutate 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 p53 significantly more often than expected.