Abstract
FOXO (Forkhead box O) transcription factors are involved in cell-cycle arrest or apoptosis induction by transcripting cell-cycle inhibitor p27KIP1 or apoptosis-related genes, respectively. Akt/protein kinase B promotes cell proliferation and suppresses apoptosis, in part, by phosphorylating FOXOs. Phosphorylated FOXOs could not exhibit transcriptional activity because of their nuclear export. Here we show that p15INK4b and p19INK4d transcription is associated with FOXO-mediated G1 cell-cycle arrest. Inhibition of Akt signaling by PI3K inhibitors, a PDK1 inhibitor, or dominant-negative Akt transfection increased expression of p15INK4b and p19INK4d but not p16INK4a and p18INK4c. Ectopic expression of wild type or active FOXO but not inactive form also increased p15INK4b and p19INK4d levels. FOXOs bound to promoter regions and induced transcription of these genes. No increase in the G1-arrested cell population, mediated by PI3K inhibitor LY294002, was observed in INK4b−/− or INK4d−/− murine embryonic fibroblasts. In summary, FOXOs are involved in G1 arrest caused by Akt inactivation via p15INK4b and p19INK4d transcription.
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Acknowledgements
This study was supported in part by special grants from the Ministry of Education, Culture, Sports, Science and Technology, Japan 17016012 and 18015008 (to TT and NF). NF is also supported by the Araki Memorial Foundation for Medical and Biochemical Researches, by the Vehicle Racing Commemorative Foundation and by the Uehara Memorial Foundation.
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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).
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Katayama, K., Nakamura, A., Sugimoto, Y. et al. FOXO transcription factor-dependent p15INK4b and p19INK4d expression. Oncogene 27, 1677–1686 (2008). https://doi.org/10.1038/sj.onc.1210813
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DOI: https://doi.org/10.1038/sj.onc.1210813
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