Related Experiment Videos
Cell cycle inhibition by FoxO forkhead transcription factors involves downregulation of cyclin D
Marc Schmidt1, Silvia Fernandez de Mattos, Armando van der Horst
1Division of Molecular Biology, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
Abstract:
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.
Insights
Forkhead box O (FoxO) transcription factors inhibit cell proliferation through a novel mechanism. They reduce D-type cyclin expression, independent of p27(kip1), impacting cell cycle progression.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- FoxO transcription factors are key regulators of cellular responses to PI3K/PKB signaling.
- FoxO factors antagonize cellular proliferation, partly via p27(kip1) induction.
- A p27(kip1)-independent mechanism for FoxO-mediated cell cycle arrest was investigated.
Purpose of the Study:
- To identify and characterize novel mechanisms of FoxO-mediated cell cycle arrest.
- To elucidate the role of D-type cyclins and CDK4/pRb pathway in FoxO function.
Main Methods:
- Overexpression and conditional activation of FoxO factors.
- Analysis of D-type cyclin (D1, D2) and p27(kip1) protein expression.
- Assessment of CDK4 activity and pRb phosphorylation.
- Ectopic expression of cyclin D1 to evaluate rescue effects.
Main Results:
- FoxO factor activation reduces D-type cyclin D1 and D2 protein levels via transcriptional repression.
- This downregulation is independent of p27(kip1).
- Reduced D-type cyclins impair CDK4-mediated pRb inactivation, contributing to cell cycle arrest.
Conclusions:
- FoxO factors employ a p27(kip1)-independent pathway involving downregulation of D-type cyclins to inhibit cell proliferation.
- This mechanism highlights a critical role for D-type cyclins in FoxO-mediated cell cycle control.