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FOXO transcription factor-dependent p15(INK4b) and p19(INK4d) expression
K Katayama1, A Nakamura, Y Sugimoto
1Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
Oncogene
|September 18, 2007
Summary
Forkhead box O (FOXO) transcription factors induce cell-cycle arrest by regulating p15(INK4b) and p19(INK4d) gene expression. Akt inactivation enhances FOXO activity, promoting G1 cell-cycle arrest.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- Forkhead box O (FOXO) transcription factors regulate critical cellular processes like cell-cycle arrest and apoptosis.
- Akt/protein kinase B signaling pathway promotes cell proliferation and inhibits apoptosis, partly through FOXO phosphorylation and subsequent nuclear export.
Purpose of the Study:
- To investigate the role of FOXO transcription factors in mediating G1 cell-cycle arrest.
- To elucidate the mechanism by which Akt signaling influences FOXO-dependent gene transcription.
Main Methods:
- Inhibition of Akt signaling using PI3K and PDK1 inhibitors, and dominant-negative Akt transfection.
- Ectopic expression of wild-type and mutant FOXO proteins.
- Analysis of p15(INK4b), p19(INK4d), p16(INK4a), and p18(INK4c) gene expression.
- Chromatin immunoprecipitation assays to assess FOXO binding to gene promoters.
- Cell-cycle analysis in wild-type and knockout murine embryonic fibroblasts.
Main Results:
- Inhibition of Akt signaling led to increased transcription of p15(INK4b) and p19(INK4d), but not p16(INK4a) or p18(INK4c).
- Ectopic expression of active FOXO proteins upregulated p15(INK4b) and p19(INK4d) levels.
- FOXO proteins directly bound to the promoter regions of p15(INK4b) and p19(INK4d), inducing their transcription.
- Loss of p15(INK4b) or p19(INK4d) abrogated the G1 cell-cycle arrest induced by Akt inactivation.
Conclusions:
- FOXO transcription factors are key mediators of G1 cell-cycle arrest.
- Akt inactivation promotes G1 arrest through FOXO-dependent transcription of p15(INK4b) and p19(INK4d).
- This pathway represents a critical regulatory mechanism in cell-cycle control.
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