Open AccessCell Cycle Inhibition by FoxO Forkhead Transcription Factors Involves Downregulation of Cyclin D
Author(s) -
Marc Schmidt,
Sylvia Fernandez de Mattos,
Armando van der Horst,
Rob Klompmaker,
Geert J. P. L. Kops,
Eric W.F. Lam,
Boudewijn M.T. Burgering,
René H. Medema
Publication year - 2002
Publication title -
molecular and cellular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.14
H-Index - 327
eISSN - 1067-8824
pISSN - 0270-7306
DOI - 10.1128/mcb.22.22.7842-7852.2002
Subject(s) - biology , transcription factor , downregulation and upregulation , cyclin , microbiology and biotechnology , ectopic expression , forkhead transcription factors , cyclin dependent kinase , cell cycle , cyclin d1 , kinase , pi3k/akt/mtor pathway , cyclin e , cyclin d3 , repressor , signal transduction , cyclin dependent kinase 2 , protein kinase a , cell , cell culture , genetics , gene
The FoxO forkhead transcription factors FoxO4 (AFX), FoxO3a (FKHR.L1), and FoxO1a (FKHR) represent important physiological targets of phosphatidylinositol-3 kinase (PI3K)/protein kinase B (PKB) signaling. Overexpression or conditional activation of FoxO factors is able to antagonize many responses to constitutive PI3K/PKB activation including its effect on cellular proliferation. It was previously shown that the FoxO-induced cell cycle arrest is partially mediated by enhanced transcription and protein expression of the cyclin-dependent kinase inhibitor p27(kip1) (R. H. Medema, G. J. Kops, J. L. Bos, and B. M. Burgering, Nature 404:782-787, 2000). Here we have identified a p27(kip1)-independent mechanism that plays an important role in the antiproliferative effect of FoxO factors. Forced expression or conditional activation of FoxO factors leads to reduced protein expression of the D-type cyclins D1 and D2 and is associated with an impaired capacity of CDK4 to phosphorylate and inactivate the S-phase repressor pRb. Downregulation of D-type cyclins involves a transcriptional repression mechanism and does not require p27(kip1) function. Ectopic expression of cyclin D1 can partially overcome FoxO factor-induced cell cycle arrest, demonstrating that downregulation of D-type cyclins represents a physiologically relevant mechanism of FoxO-induced cell cycle inhibition.