4.6 Article

A cyclin D-CDK6 dimer helps to reshuffle cyclin-dependent kinase inhibitors (CKI) to overcome TGF-beta-mediated arrest and maintain CDK2 activity

期刊

CELL CYCLE
卷 20, 期 8, 页码 808-818

出版社

TAYLOR & FRANCIS INC
DOI: 10.1080/15384101.2021.1909261

关键词

CDK4; CDK6; p27; Rb; g0 phase; cyclin-cdk6 dimer

资金

  1. ACS Research Scholar Award
  2. American Cancer Society

向作者/读者索取更多资源

The study focuses on the functions of cyclin D-CDK4/6 complex in cell cycle regulation, showing that CDK6 has a greater ability to overcome TGF-beta-mediated cell arrest compared to CDK4, and suggesting a potential association with p15 in this mechanism.
The cyclin D-CDK4/6 complex has two distinct functions. Its kinase-dependent role involves its ability to act as serine/threonine kinase, responsible for phosphorylation of substrates required for cell cycle transitions, while its kinase-independent function involves its ability to act as a reservoir for p27(Kip1). This association sequesters p27 from cyclin E-CDK2 complexes, allowing them to remain active. The aim of this current study is two-fold: to understand the contribution of the kinase-dependent and kinase-independent functions of CDK4 and CDK6 in epithelial cells and to directly compare CDK4 and CDK6 in a simple model system, TGF-beta treatment, where arrest is initiated by the expression of p15(Ink4b). Cells that overexpressed a catalytically inactive, p15-insensitive CDK6 variant (p27 sequestration only mutant) were able to overcome TGF-beta-mediated arrest by maintaining CDK2 activity, while cells expressing the identical mutations in CDK4 were not. This result can be partially explained by the presence of a previously unidentified cyclin D-CDK6 dimer, which serves as a sink for free p27 during TGF-beta treatment, enabling CDK2 to remain inhibitor free. The use of the TGF-beta model system and the characterization of CDK pool dynamics and p27 switching is relevant to the CDK4/6 specific inhibitors, such as palbociclib, whose mechanism of action may resemble that of p15.

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