FOXO transcription factor-dependent p15(INK4b) and p19(INK4d) expression

Oncogene. 2008 Mar 13;27(12):1677-86. doi: 10.1038/sj.onc.1210813. Epub 2007 Sep 17.

Abstract

FOXO (Forkhead box O) transcription factors are involved in cell-cycle arrest or apoptosis induction by transcripting cell-cycle inhibitor p27(KIP1) 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 p15(INK4b) and p19(INK4d) 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 p15(INK4b) and p19(INK4d) but not p16(INK4a) and p18(INK4c). Ectopic expression of wild type or active FOXO but not inactive form also increased p15(INK4b) and p19(INK4d) 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 p15(INK4b) and p19(INK4d) transcription.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Chromones / pharmacology
  • Cyclin-Dependent Kinase Inhibitor p15 / biosynthesis
  • Cyclin-Dependent Kinase Inhibitor p15 / genetics*
  • Cyclin-Dependent Kinase Inhibitor p19 / biosynthesis
  • Cyclin-Dependent Kinase Inhibitor p19 / genetics*
  • Enzyme Inhibitors / pharmacology
  • Forkhead Transcription Factors / physiology*
  • G1 Phase / drug effects
  • G1 Phase / physiology
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology*
  • Humans
  • Mice
  • Mice, Knockout
  • Morpholines / pharmacology
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Up-Regulation / drug effects
  • Up-Regulation / physiology

Substances

  • CDKN2B protein, human
  • CDKN2D protein, human
  • Chromones
  • Cyclin-Dependent Kinase Inhibitor p15
  • Cyclin-Dependent Kinase Inhibitor p19
  • Enzyme Inhibitors
  • Forkhead Transcription Factors
  • Morpholines
  • Phosphoinositide-3 Kinase Inhibitors
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Proto-Oncogene Proteins c-akt