Akt Phosphorylates the Transcriptional Repressor Bmi1 to Block Its Effects on the Tumor-Suppressing Ink4a-Arf Locus

Sci. Signal., 23 October 2012
Vol. 5, Issue 247, p. ra77
DOI: 10.1126/scisignal.2003199

Akt Phosphorylates the Transcriptional Repressor Bmi1 to Block Its Effects on the Tumor-Suppressing Ink4a-Arf Locus

  1. Yan Liu1,2,*,
  2. Fan Liu1,
  3. Hao Yu2,
  4. Xinyang Zhao1,
  5. Goro Sashida1,
  6. Anthony Deblasio1,
  7. Michael Harr1,
  8. Qing-Bai She1,
  9. Zhenbang Chen3,
  10. Hui-Kuan Lin3,
  11. Silvana Di Giandomenico1,
  12. Shannon E. Elf1,
  13. Youyang Yang1,
  14. Yasuhiko Miyata1,
  15. Gang Huang1,
  16. Silvia Menendez1,
  17. Ingo K. Mellinghoff4,
  18. Neal Rosen1,
  19. Pier Paolo Pandolfi3,
  20. Cyrus V. Hedvat5, and
  21. Stephen D. Nimer1,6,*
  1. 1Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
  2. 2Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
  3. 3Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
  4. 4Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
  5. 5Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
  6. 6Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
  1. *To whom correspondence should be addressed. E-mail: liu219{at}iupui.edu (Y.L.); snimer{at}med.miami.edu (S.D.N.)

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 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 p16Ink4a and p19Arf seen in cancer cells with an activated phosphoinositide 3-kinase to Akt signaling pathway and identifies crosstalk between phosphorylation events and chromatin structure.

Citation:

Y. Liu, F. Liu, H. Yu, X. Zhao, G. Sashida, A. Deblasio, M. Harr, Q.-B. She, Z. Chen, H.-K. Lin, S. Di Giandomenico, S. E. Elf, Y. Yang, Y. Miyata, G. Huang, S. Menendez, I. K. Mellinghoff, N. Rosen, P. P. Pandolfi, C. V. Hedvat, and S. D. Nimer, Akt Phosphorylates the Transcriptional Repressor Bmi1 to Block Its Effects on the Tumor-Suppressing Ink4a-Arf Locus. Sci. Signal. 5, ra77 (2012).

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