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. Hedvat; Stephen D. Nimer

doi:10.1126/scisignal.2003199

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. Hedvat

Stephen D. Nimer

Producción científica: Article › revisión exhaustiva

53 Citas (Scopus)

Resumen

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 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.

Idioma original	English (US)
Número de artículo	ra77
Publicación	Science signaling
Volumen	5
N.º	247
DOI	https://doi.org/10.1126/scisignal.2003199
Estado	Published - oct 23 2012
Publicado de forma externa	Sí

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), Artículo ra77. https://doi.org/10.1126/scisignal.2003199

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, n.º 247, ra77. https://doi.org/10.1126/scisignal.2003199

@article{eff1cae5e38a4f91be2de1a2d5e10d3f,

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 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.",

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

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doi = "10.1126/scisignal.2003199",

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AU - Sashida, Goro

AU - Deblasio, Anthony

AU - Harr, Michael

AU - She, Qing Bai

AU - Chen, Zhenbang

AU - Lin, Hui Kuan

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.

PY - 2012/10/23

Y1 - 2012/10/23

N2 - 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.

AB - 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.

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

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ASJC Scopus subject areas

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