CDK6 Antagonizes p53-Induced Responses during Tumorigenesis

Publikationen als Autor:in / Herausgeber:in der Vetmeduni

Hartenberger, Svenja Irina; Vogl, Claus; Dolezal, Marlies; Prchal-Murphy, Michaela; Sexl, Veronika; Kollmann, Karoline; Kollmann, Sebastian; Doma, Eszter

Abstrakt

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.

Dokumententyp

Originalarbeit

ISSN/eISSN

2159-8274 - 2159-8290

WoS ID

WOS:000437210800025

Projekt

Die CDK6/p16INK4A Achse - Bedeutung für Hämatopoese und Lymphom-entstehung; ERC ADG: CDK6 in Transkription –vom Feind zum Freund