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

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 prog...

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Vydané v:	The Journal of clinical investigation Ročník 122; číslo 5; s. 1920 - 1932
Hlavní autori:	Nacerddine, Karim, 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
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States American Society for Clinical Investigation 01.05.2012
Predmet:	Adenocarcinoma - enzymology Adenocarcinoma - metabolism Adenocarcinoma - pathology Androgens Animals Biomedical research Cell cycle Cell Line, Tumor Cell Transformation, Neoplastic Cooperation Cytokeratin Development and progression DNA Breaks, Double-Stranded DNA damage DNA methylation DNA Repair Enzyme Activation Epigenetics Genetic aspects Genomic Instability Haploinsufficiency Histones - metabolism Humans Ligases Male Mice Mice, Inbred BALB C Mice, Nude Mice, Transgenic Mutation Neoplasm Grading Neoplasm Transplantation Nuclear Proteins - genetics Nuclear Proteins - metabolism Oncogenes Phosphorylation Polycomb Repressive Complex 1 Prostate - metabolism Prostate - pathology Prostate cancer Prostatic Intraepithelial Neoplasia - enzymology Prostatic Intraepithelial Neoplasia - metabolism Prostatic Intraepithelial Neoplasia - pathology Prostatic Neoplasms - enzymology Prostatic Neoplasms - metabolism Prostatic Neoplasms - pathology Protein Processing, Post-Translational Proto-Oncogene Proteins - genetics Proto-Oncogene Proteins - metabolism Proto-Oncogene Proteins c-akt - metabolism PTEN Phosphohydrolase - genetics PTEN Phosphohydrolase - metabolism Repressor Proteins - genetics Repressor Proteins - metabolism Signal Transduction Tumorigenesis Ubiquitin-Protein Ligases - metabolism Ubiquitination
ISSN:	0021-9738, 1558-8238, 1558-8238
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Shrnutí:	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.
Bibliografia:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 14 ObjectType-Article-1 ObjectType-Feature-2 content type line 23 Authorship note: Karim Nacerddine and Jean-Bernard Beaudry contributed equally to this work.
ISSN:	0021-9738 1558-8238 1558-8238
DOI:	10.1172/JCI57477