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

30 Citations (Scopus)

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
Article numberra77
JournalScience Signaling
Volume5
Issue number247
DOIs
StatePublished - Oct 23 2012

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Phosphorylation
Tumors
Hematopoietic Stem Cells
Polycomb-Group Proteins
Cells
Neoplasms
1-Phosphatidylinositol 4-Kinase
Ubiquitination
Crosstalk
Phosphatidylinositols
Stem cells
Histones
Chromatin
Cell Cycle
Carcinogenesis
Phosphotransferases
Cell Proliferation
Growth

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Akt phosphorylates the transcriptional repressor Bmi1 to block its effects on the tumor-suppressing Ink4a-Arf locus. / Liu, Yan; Liu, Fan; Yu, Hao; Zhao, Xinyang; Sashida, Goro; Deblasio, Anthony; Harr, Michael; She, Qing Bai; Chen, Zhenbang; Lin, Hui Kuan; Di Giandomenico, Silvana; Elf, Shannon E.; Yang, Youyang; Miyata, Yasuhiko; Huang, Gang; Menendez, Silvia; Mellinghoff, Ingo K.; Rosen, Neal; Pandolfi, Pier Paolo; Hedvat, Cyrus V.; Nimer, Stephen D.

In: Science Signaling, Vol. 5, No. 247, ra77, 23.10.2012.

Research output: Contribution to journalArticle

Liu, Y, Liu, F, Yu, H, Zhao, X, Sashida, G, Deblasio, A, Harr, M, She, QB, Chen, Z, Lin, HK, Di Giandomenico, S, Elf, SE, Yang, Y, Miyata, Y, Huang, G, Menendez, S, Mellinghoff, IK, Rosen, N, Pandolfi, PP, Hedvat, CV & Nimer, SD 2012, 'Akt phosphorylates the transcriptional repressor Bmi1 to block its effects on the tumor-suppressing Ink4a-Arf locus', Science Signaling, vol. 5, no. 247, ra77. https://doi.org/10.1126/scisignal.2003199
Liu, Yan ; Liu, Fan ; Yu, Hao ; Zhao, Xinyang ; Sashida, Goro ; Deblasio, Anthony ; Harr, Michael ; She, Qing Bai ; Chen, Zhenbang ; Lin, Hui Kuan ; Di Giandomenico, Silvana ; Elf, Shannon E. ; Yang, Youyang ; Miyata, Yasuhiko ; Huang, Gang ; Menendez, Silvia ; Mellinghoff, Ingo K. ; Rosen, Neal ; Pandolfi, Pier Paolo ; Hedvat, Cyrus V. ; Nimer, Stephen D. / Akt phosphorylates the transcriptional repressor Bmi1 to block its effects on the tumor-suppressing Ink4a-Arf locus. In: Science Signaling. 2012 ; Vol. 5, No. 247.
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AU - Deblasio, Anthony

AU - Harr, Michael

AU - She, Qing Bai

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AU - Di Giandomenico, Silvana

AU - Elf, Shannon E.

AU - Yang, Youyang

AU - Miyata, Yasuhiko

AU - Huang, Gang

AU - Menendez, Silvia

AU - Mellinghoff, Ingo K.

AU - Rosen, Neal

AU - Pandolfi, Pier Paolo

AU - Hedvat, Cyrus V.

AU - Nimer, Stephen D.

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