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a systematic substrate screen links CDK4/6 to senescence suppression through FOXM1

Anders, Lars and Ke, Nan and Hydbring, Per and Zhai, Huili and Choi, Yoon and Braun, Pascal and Vidal, Marc and Sicinski, Peter (2011) a systematic substrate screen links CDK4/6 to senescence suppression through FOXM1. Cancer Cell, 20 (5). pp. 620-634. ISSN 1535-6108

Abstract

Cyclin D-CDKs (CDK4, CDK6) are critical regulators of cell cycle entry, and their aberrant expression and activation is observed in the majority of human cancers. However, it is currently not completely understood by which cellular mechanisms CDK4/6 promote tumorigenesis, largely due to the limited number of identified substrates. Here we applied a proteome-wide substrate screen and demonstrate that individual cyclin D-CDK complexes possess major differences in substrate specificity. We identified the Forkhead Box M1 (FOXM1) transcription factor as a functionally critical phosphorylation target. While modification of its N-terminal sequence is linked to stabilization of the protein by preventing CDH1/APC-mediated degradation, phosphorylation of the transactivation domain leads to direct transcriptional activation, resulting in suppression of cellular senescence. Moreover, FOXM1 is required for CDK4-induced expression of proliferation-associated genes, including cyclin E. Accordingly, acute inhibition of CDK4/6 activity in cancer cells disables FOXM1, results in downregulation of cell cycle and DNA repair genes, and enforces a ROS-dependent senescence program. Thus, pharmacological inhibition of CDK4/6 catalytic activity might be particularly effective in tumors that highly depend on FOXM1.

Item Type: Article
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Additional Information: author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used
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Date Deposited: 13 Oct 2015 13:15
Last Modified: 13 Oct 2015 13:15
URI: https://oak.novartis.com/id/eprint/3972

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