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 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 p16(Ink4a) and p19(Arf) seen in cancer cells with an activated phosphoinositide 3-kinase to Akt signaling pathway and identifies crosstalk between phosphorylation events and chromatin structure.
authors.affiliation: Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. liu219@iupui.edu
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Fan
authors.initials: F
authors.lastname: Liu
authors.forename: Hao
authors.initials: H
authors.lastname: Yu
authors.forename: Xinyang
authors.initials: X
authors.lastname: Zhao
authors.forename: Goro
authors.initials: G
authors.lastname: Sashida
authors.forename: Anthony
authors.initials: A
authors.lastname: Deblasio
authors.forename: Michael
authors.initials: M
authors.lastname: Harr
authors.forename: Qing-Bai
authors.initials: QB
authors.lastname: She
authors.forename: Zhenbang
authors.initials: Z
authors.lastname: Chen
authors.forename: Hui-Kuan
authors.initials: HK
authors.lastname: Lin
authors.forename: Silvana
authors.initials: S
authors.lastname: Di Giandomenico
authors.forename: Shannon E
authors.initials: SE
authors.lastname: Elf
authors.forename: Youyang
authors.initials: Y
authors.lastname: Yang
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Miyata
authors.forename: Gang
authors.initials: G
authors.lastname: Huang
authors.forename: Silvia
authors.initials: S
authors.lastname: Menendez
authors.forename: Ingo K
authors.initials: IK
authors.lastname: Mellinghoff
authors.forename: Neal
authors.initials: N
authors.lastname: Rosen
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
authors.forename: Cyrus V
authors.initials: CV
authors.lastname: Hedvat
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Nimer
mesh_terms: D000818:Animals; D002843:Chromatin / Q000235:genetics / Q000473:pathology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis* / Q000235:genetics; D020868:Gene Silencing; D056426:Genetic Loci; D006367:HeLa Cells; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D063150:Polycomb Repressive Complex 1 / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D054875:Ubiquitination / Q000235:genetics
chemical_list: C069077:BMI1 protein, human; C489421:Bmi1 protein, mouse; C417743:Cdkn2a protein, mouse; D002843:Chromatin; D019941:Cyclin-Dependent Kinase Inhibitor p16; D006657:Histones; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D063150:Polycomb Repressive Complex 1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt