Akt phosphorylates the transcriptional repressor bmi1 to block its effects on the tumor-suppressing ink4a-arf locus

Sci Signal. 2012 Oct 23;5(247):ra77. doi: 10.1126/scisignal.2003199.

Abstract

The Polycomb group protein Bmi1 is a transcriptional silencer of the Ink4a-Arf locus, which encodes the cell cycle regulator p16(Ink4a) and the tumor suppressor p19(Arf). Bmi1 plays a key role in oncogenesis and stem cell self-renewal. We report that phosphorylation of human Bmi1 at Ser³¹⁶ by Akt impaired its function by triggering its dissociation from the Ink4a-Arf locus, which resulted in decreased ubiquitylation of histone H2A and the inability of Bmi1 to promote cellular proliferation and tumor growth. Moreover, Akt-mediated phosphorylation of Bmi1 also inhibited its ability to promote self-renewal of hematopoietic stem and progenitor cells. Our study provides a mechanism for the increased abundance of p16(Ink4a) and p19(Arf) seen in cancer cells with an activated phosphoinositide 3-kinase to Akt signaling pathway and identifies crosstalk between phosphorylation events and chromatin structure.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chromatin / genetics
  • Chromatin / pathology
  • Cyclin-Dependent Kinase Inhibitor p16 / biosynthesis*
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Gene Silencing
  • Genetic Loci*
  • HeLa Cells
  • Histones / genetics
  • Histones / metabolism
  • Humans
  • Mice
  • Mice, Knockout
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation
  • Polycomb Repressive Complex 1 / genetics
  • Polycomb Repressive Complex 1 / metabolism*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Signal Transduction / genetics
  • Ubiquitination / genetics

Substances

  • BMI1 protein, human
  • Bmi1 protein, mouse
  • Cdkn2a protein, mouse
  • Chromatin
  • Cyclin-Dependent Kinase Inhibitor p16
  • Histones
  • Proto-Oncogene Proteins
  • Repressor Proteins
  • Polycomb Repressive Complex 1
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt