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PMID: 22505453 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Akt-mediated phosphorylation of Bmi1 modulates its oncogenic potential, E3 ligase activity, and DNA damage repair activity in mouse prostate cancer.

The Journal of clinical investigation ·Vol. 122 ·No. 5 ·2012-05-00 ·Pages 1920-32

Nacerddine K, Beaudry JB, Ginjala V, Westerman B, Mattiroli F, Song JY, van der Poel H, Ponz OB, Pritchard C, Cornelissen-Steijger P, Zevenhoven J, Tanger E, Sixma TK, Ganesan S, van Lohuizen M

Abstract

Prostate cancer (PCa) is a major lethal malignancy in men, but the molecular events and their interplay underlying prostate carcinogenesis remain poorly understood. Epigenetic events and the upregulation of polycomb group silencing proteins including Bmi1 have been described to occur during PCa progression. Here, we found that conditional overexpression of Bmi1 in mice induced prostatic intraepithelial neoplasia, and elicited invasive adenocarcinoma when combined with PTEN haploinsufficiency. In addition, Bmi1 and the PI3K/Akt pathway were coactivated in a substantial fraction of human high-grade tumors. We found that Akt mediated Bmi1 phosphorylation, enhancing its oncogenic potential in an Ink4a/Arf-independent manner. This process also modulated the DNA damage response and affected genomic stability. Together, our findings demonstrate the etiological role of Bmi1 in PCa, unravel an oncogenic collaboration between Bmi1 and the PI3K/Akt pathway, and provide mechanistic insights into the modulation of Bmi1 function by phosphorylation during prostate carcinogenesis.

MeSH Terms
Adenocarcinoma/enzymology,metabolism,pathology Animals Cell Line, Tumor Cell Transformation, Neoplastic DNA Breaks, Double-Stranded DNA Repair Enzyme Activation Genomic Instability Haploinsufficiency Histones/metabolism Humans Male Mice Mice, Inbred BALB C Mice, Nude Mice, Transgenic Neoplasm Grading Neoplasm Transplantation Nuclear Proteins/genetics,metabolism PTEN Phosphohydrolase/genetics,metabolism Phosphorylation Polycomb Repressive Complex 1 Prostate/metabolism,pathology Prostatic Intraepithelial Neoplasia/enzymology,metabolism,pathology Prostatic Neoplasms/enzymology,metabolism,pathology Protein Processing, Post-Translational Proto-Oncogene Proteins/genetics,metabolism Proto-Oncogene Proteins c-akt/metabolism Repressor Proteins/genetics,metabolism Signal Transduction Ubiquitin-Protein Ligases/metabolism Ubiquitination
Chemicals
Bmi1 protein, mouse Histones Nuclear Proteins Proto-Oncogene Proteins Repressor Proteins Polycomb Repressive Complex 1 Ubiquitin-Protein Ligases Proto-Oncogene Proteins c-akt PTEN Phosphohydrolase Pten protein, mouse
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Nacerddine Karim
Division of Molecular Genetics and Center for Biomedical Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Beaudry Jean-Bernard
Ginjala Vasudeva
Westerman Bart
Mattiroli Francesca
Song Ji-Ying
van der Poel Henk
Ponz Olga Balagué
Pritchard Colin
Cornelissen-Steijger Paulien
Zevenhoven John
Tanger Ellen
Sixma Titia K
Ganesan Shridar
van Lohuizen Maarten
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
1558-8238
DOI
10.1172/JCI57477
Published
2012-05-00
Epub
2012-00-16
Pages
1920-32
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC3336972
Subset
IM
Corrections
CommentIn
PMID: 23312204
External Links
PubMed source DOI: 10.1172/JCI57477 PMC Full Text View journal details
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