Akt phosphorylates the transcriptional repressor Bmi1 to block its effects on the tumor-suppressing Ink4a-Arf locus Journal Article
| Authors: | Liu, Y.; Liu, F.; Yu, H.; Zhao, X.; Sashida, G.; Deblasio, A.; Harr, M.; She, Q. B.; Chen, Z.; Lin, H. K.; Di Giandomenico, S.; Elf, S. E.; Yang, Y.; Miyata, Y.; Huang, G.; Menendez, S.; Mellinghoff, I. K.; Rosen, N.; Pandolfi, P. P.; Hedvat, C. V.; Nimer, S. D. |
| Article Title: | Akt phosphorylates the transcriptional repressor Bmi1 to block its effects on the tumor-suppressing Ink4a-Arf locus |
| 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 Ser 316 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 ofBmi1 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 mechanismfor the increased abundance of p16 Ink4a and p19 Arfseen in cancer cells with an activated phosphoinositide 3-kinase to Akt signaling pathway and identifies crosstalk between phosphorylation events and chromatin structure. |
| Keywords: | signal transduction; protein kinase b; controlled study; human tissue; protein phosphorylation; human cell; protein function; cell proliferation; protein p16; serine; gene locus; phosphatidylinositol 3 kinase; cell regeneration; hematopoietic stem cell; protein p19; cyclin dependent kinase inhibitor 2a; tumor growth; histone h2a; bmi1 protein; chromatin structure; histone ubiquitination |
| Journal Title: | Science Signaling |
| Volume: | 5 |
| Issue: | 247 |
| ISSN: | 1945-0877 |
| Publisher: | American Association for the Advancement of Science |
| Date Published: | 2012-10-01 |
| Start Page: | ra77 |
| Language: | English |
| DOI: | 10.1126/scisignal.2003199 |
| PROVIDER: | scopus |
| PUBMED: | 23092893 |
| PMCID: | PMC3784651 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 3 December 2012" - "Source: Scopus" |
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