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  • Original Article
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FOXO transcription factor-dependent p15INK4b and p19INK4d expression

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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References

  • Bonneau D, Longy M . (2000). Mutation of the PTEN gene. Hum Mutat 16: 109–122.

    Article  CAS  Google Scholar 

  • Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS et al. (1999). Akt promotes cell survival by phosphorylating and inhibiting a forkhead transcription factor. Cell 96: 857–868.

    Article  CAS  Google Scholar 

  • Cichy SB, Uddin S, Danilkovich A, Guo S, Klippel A, Unterman TG . (1998). Protein kinase B/Akt mediates effects of insulin on hepatic insulin-like growth factor-binding protein-1 gene expression through a conserved insulin response sequence. J Biol Chem 273: 6482–6487.

    Article  CAS  Google Scholar 

  • Collado M, Medema RH, Garcia-Cao I, Dubuisson ML, Barradas M, Glassford J et al. (2000). Inhibition of the phosphoinositide 3-kinase pathway induces a senescence-like arrest mediated by p27Kip1. J Biol Chem 276: 21960–21968.

    Article  Google Scholar 

  • Fujita N, Sato S, Katayama K, Tsuruo T . (2002). Akt-dependent phosphorylation of p27Kip1 promotes binding to 14-3-3 and cytoplasmic localization. J Biol Chem 277: 28706–28713.

    Article  CAS  Google Scholar 

  • Katayama K, Fujita N, Tsuruo T . (2005). Akt/protein kinase B-dependent phosphorylation and inactivation of WEE1Hu promote cell cycle progression at G2/M transition. Mol Cell Biol 25: 5725–5737.

    Article  CAS  Google Scholar 

  • LaBaer J, Garrett MD, Stevenson LF, Slingerland JM, Sandhu C, Chou HS et al. (1997). New functional activities for the p21 family of CDK inhibitors. Genes Dev 11: 847–862.

    Article  CAS  Google Scholar 

  • Latres E, Malumbres M, Sotillo R, Martin J, Ortega S, Martin-Caballero J et al. (2000). Limited overlapping roles of P15INK4b and P18INK4c cell cycle inhibitors in proliferation and tumorigenesis. EMBO J 19: 3496–3506.

    Article  CAS  Google Scholar 

  • Matsushima-Nishiu M, Unoki M, Ono K, Tsunoda T, Minaguchi T, Kuramoto H et al. (2001). Growth and gene expression profile analyses of endometrial cancer cells expressing exogenous PTEN. Cancer Res 61: 3741–3749.

    CAS  Google Scholar 

  • Matsuura I, Denissova NG, Wang G, He D, Long J, Liu F . (2004). Cyclin-dependent kinases regulate the antiproliferative function of Smads. Nature 430: 226–231.

    Article  CAS  Google Scholar 

  • Mayo LD, Donner DB . (2001). A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus. Proc Natl Acad Sci USA 98: 11598–11603.

    Article  CAS  Google Scholar 

  • Medema RH, Kops GJ, Bos JL, Burgering BM . (2000). AFX-like forkhead transcription factors mediate cell-cycle regulation by Ras and PKB thorough p27Kip1. Nature 404: 782–787.

    Article  CAS  Google Scholar 

  • Ogasawara T, Kawaguchi H, Jinno S, Hoshi K, Itaka K, Takato T et al. (2004). Bone morphogenetic protein 2-induced osteoblast differentiation requires Smad-mediated down-regulation of Cdk6. Mol Cell Biol 24: 6560–6568.

    Article  CAS  Google Scholar 

  • Puisieux A, Galvin K, Troalen F, Bressac B, Marcais C, Galun E et al. (1993). Retinoblastoma and p53 tumor suppressor genes in human hepatoma cell lines. FASEB J 7: 1407–1413.

    Article  CAS  Google Scholar 

  • Rodier G, Montagnoli A, Di Marcotullio L, Coulombe P, Draetta GF, Pagano M et al. (2001). p27 cytoplasmic localization is regulated by phosphorylation on Ser10 and is not a prerequisite for its proteolysis. EMBO J 20: 6672–6682.

    Article  CAS  Google Scholar 

  • Rokudai S, Fujita N, Kitahara O, Nakamura Y, Tsuruo T . (2002). Involvement of FKHR-dependent TRADD expression in chemotherapeutic drug-induced apoptosis. Mol Cell Biol 22: 8695–8708.

    Article  CAS  Google Scholar 

  • Ruas M, Peters G . (1998). The p16INK4a/CDKN2A tumor suppressor and its relatives. Biochim Biophys Acta 1378: F115–F177.

    CAS  Google Scholar 

  • Sherr CJ, Roberts JM . (1995). Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev 9: 1149–1163.

    Article  CAS  Google Scholar 

  • Stahl M, Dijkers PF, Kops GJ, Les SM, Coffer PJ, Burgering BM et al. (2002). The forkhead transcription factor FoxO regulates transcription of p27Kip1 and Bim in response to IL-2. J Immunol 168: 5024–5031.

    Article  CAS  Google Scholar 

  • Stott FJ, Bates S, James MC, McConnell BB, Starborg M, Brookes S et al. (1998). The alternative product from the human CDKN2A locus, p14ARF, participates in a regulatory feedback loop with p53 and MDM2. EMBO J 17: 5001–5014.

    Article  CAS  Google Scholar 

  • Suhara T, Kim HS, Kirshenbaum LA, Walsh K . (2002). Suppression of Akt signaling induces Fas ligand expression: involvement of caspase and Jun kinase activation in Akt-mediated Fas ligand regulation. Mol Cell Biol 22: 680–691.

    Article  CAS  Google Scholar 

  • Tang ED, Nunez G, Barr FG, Guan KL . (1999). Negative regulation of the forkhead transcription factor FKHR by Akt. J Biol Chem 274: 16741–16746.

    Article  CAS  Google Scholar 

  • Tsuruo T, Naito M, Tomida A, Fujita N, Mashima T, Sakamoto H et al. (2003). Molecular targeting therapy of cancer: drug resistance, apoptosis and survival signal. Cancer Sci 94: 15–21.

    Article  CAS  Google Scholar 

  • Vanhaesebroeck B, Alessi DR . (2000). The PI3K-PDK1 connection: more than just a road to PKB. Biochem J 346: 561–576.

    CAS  Google Scholar 

  • Wells J, Yan PS, Cechvala M, Huang T, Farnham PJ . (2003). Identification of novel pRb binding sites using CpG microarrays suggests that E2F recruits pRb to specific genomic sites during S phase. Oncogene 22: 1445–1460.

    Article  CAS  Google Scholar 

  • Woods YL, Rena G . (2002). Effect of multiple phosphorylation events on the transcription factors FKHR, FKHRL1, and AFX. Biochem Soc Trans 30: 391–397.

    Article  CAS  Google Scholar 

  • Zariwala M, Liu E, Xiong Y . (1996). Mutational analysis of the p16 family cyclin-dependent kinase inhibitors p15INK4b and p18INK4c in tumor-derived cell lines and primary tumors. Oncogene 12: 451–455.

    CAS  Google Scholar 

  • Zhou BP, Liao Y, Xia W, Spohn B, Lee MH, Hung MC . (2001). Cytoplasmic localization of p21Cip1/WAF1 by Akt-induced phosphorylation in HER-2/neu-overexpressing cells. Nat Cell Biol 3: 245–252.

    Article  CAS  Google Scholar 

  • Zindy F, van Deursen J, Grosveld G, Sherr CJ, Roussel MF . (2000). INK4d-deficient mice are fertile despite testicular atrophy. Mol Cell Biol 20: 372–378.

    Article  CAS  Google Scholar 

Download references

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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Correspondence to N Fujita.

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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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