Akt phosphorylates the transcriptional repressor Bmi1 to block its effects on the tumor-suppressing Ink4a-Arf locus

Yan Liu, Fan Liu, Hao Yu, Xinyang Zhao, Goro Sashida, Anthony Deblasio, Michael Harr, Qing Bai She, Zhenbang Chen, Hui Kuan Lin, Silvana Di Giandomenico, Shannon E. Elf, Youyang Yang, Yasuhiko Miyata, Gang Huang, Silvia Menendez, Ingo K. Mellinghoff, Neal Rosen, Pier Paolo Pandolfi, Cyrus V. HedvatStephen D. Nimer

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

The Polycomb group protein Bmi1 is a transcriptional silencer of the Ink4a-Arf locus, which encodes the cell cycle regulator p16Ink4a and the tumor suppressor p19Arf. 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 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 p16Ink4a and p19Arfseen in cancer cells with an activated phosphoinositide 3-kinase to Akt signaling pathway and identifies crosstalk between phosphorylation events and chromatin structure.

Original languageEnglish (US)
Article numberra77
JournalScience Signaling
Volume5
Issue number247
DOIs
StatePublished - Oct 23 2012

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    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., ... Nimer, S. D. (2012). Akt phosphorylates the transcriptional repressor Bmi1 to block its effects on the tumor-suppressing Ink4a-Arf locus. Science Signaling, 5(247), [ra77]. https://doi.org/10.1126/scisignal.2003199