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