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Control of cell cycle exit and entry by protein kinase B-regulated forkhead transcription factors
Geert J P L Kops1, Rene H Medema, Janet Glassford
1Department of Physiological Chemistry, University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands.
Abstract:
AFX-like Forkhead transcription factors, which are controlled by phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB) signaling, are involved in regulating cell cycle progression and cell death. Both cell cycle arrest and induction of apoptosis are mediated in part by transcriptional regulation of p27(kip1). Here we show that the Forkheads AFX (FOXO4) and FKHR-L1 (FOXO3a) also directly control transcription of the retinoblastoma-like p130 protein and cause upregulation of p130 protein expression. Detailed analysis of p130 regulation demonstrates that following Forkhead-induced cell cycle arrest, cells enter G(0) and become quiescent. This is shown by a change in phosphorylation of p130 to G(0)-specific forms and increased p130/E2F-4 complex formation. Most importantly, long-term Forkhead activation causes a sustained but reversible inhibition of proliferation without a marked increase in apoptosis. As for the activity of the Forkheads, we also show that protein levels of p130 are controlled by endogenous PI3K/PKB signaling upon cell cycle reentry. Surprisingly, not only nontransformed cells, but also cancer cells such as human colon carcinoma cells, are forced into quiescence by Forkhead activation. We therefore propose that Forkhead inactivation by PKB signaling in quiescent cells is a crucial step in cell cycle reentry and contributes to the processes of transformation and regeneration.
Insights
Forkhead transcription factors (FOXO4, FOXO3a) induce cell cycle arrest and quiescence by upregulating p130 protein. This sustained inhibition of proliferation is reversible and occurs in both normal and cancer cells.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- AFX-like Forkhead transcription factors regulate cell cycle and apoptosis via PI3K/PKB signaling.
- Transcriptional regulation of p27(kip1) is a known mechanism for cell cycle arrest and apoptosis induction.
Purpose of the Study:
- To investigate the role of Forkhead transcription factors (FOXO4, FOXO3a) in regulating p130 protein expression.
- To determine the effects of Forkhead activation on cell cycle progression, quiescence, and apoptosis.
- To explore the influence of PI3K/PKB signaling on Forkhead activity and p130 levels.
Main Methods:
- Analysis of p130 protein expression and phosphorylation.
- Assessment of p130/E2F-4 complex formation.
- Long-term Forkhead activation studies in normal and cancer cells.
- Investigation of PI3K/PKB signaling in cell cycle reentry.
Main Results:
- Forkhead factors FOXO4 and FOXO3a directly upregulate p130 protein expression.
- Forkhead activation induces cell cycle arrest, leading to G(0) quiescence with specific p130 phosphorylation and increased p130/E2F-4 complexes.
- Sustained Forkhead activation causes reversible proliferation inhibition without significant apoptosis.
- PI3K/PKB signaling controls p130 levels during cell cycle reentry.
- Both normal and human colon carcinoma cells are induced into quiescence by Forkhead activation.
Conclusions:
- Forkhead transcription factors directly regulate p130, inducing quiescence in normal and cancer cells.
- Forkhead-mediated p130 upregulation is a key mechanism for sustained, reversible cell cycle arrest.
- Forkhead inactivation by PKB signaling is critical for cell cycle reentry, impacting transformation and regeneration.