Identification of a tumour suppressor network opposing nuclear Akt function Journal Article

   

Authors:	Trotman, L. C.; Alimonti, A.; Scaglioni, P. P.; Koutcher, J. A.; Cordon-Cardo, C.; Pandolfi, P. P.
Article Title:	Identification of a tumour suppressor network opposing nuclear Akt function
Abstract:	The proto-oncogene AKT (also known as PKB) is activated in many human cancers, mostly owing to loss of the PTEN tumour suppressor. In such tumours, AKT becomes enriched at cell membranes where it is activated by phosphorylation. Yet many targets inhibited by phosphorylated AKT (for example, the FOXO transcription factors) are nuclear; it has remained unclear how relevant nuclear phosphorylated AKT (pAKT) function is for tumorigenesis. Here we show that the PMLtumour suppressor prevents cancer by inactivating pAKT inside the nucleus. We find in a mouse model that Pml loss markedly accelerates tumour onset, incidence and progression in Pten-heterozygous mutants, and leads to female sterility with features that recapitulate the phenotype of Foxo3a knockout mice. We show that Pml deficiency on its own leads to tumorigenesis in the prostate, a tissue that is exquisitely sensitive to pAkt levels, and demonstrate that Pml specifically recruits the Akt phosphatase PP2a as well as pAkt into Pml nuclear bodies. Notably, we find that Pml-null cells are impaired in PP2a phosphatase activity towards Akt, and thus accumulate nuclear pAkt. As a consequence, the progressive reduction in Pml dose leads to inactivation of Foxo3a-mediated transcription of proapoptotic Bim and the cell cycle inhibitor p27 kip1. Our results demonstrate that Pml orchestrates a nuclear tumour suppressor network for inactivation of nuclear pAkt, and thus highlight the importance of AKT compartmentalization in human cancer pathogenesis and treatment. © 2006 Nature Publishing Group.
Keywords:	protein kinase b; controlled study; genetics; cancer growth; nonhuman; cancer incidence; protein function; protein analysis; animal cell; mouse; phenotype; animal; metabolism; animals; mice; cells, cultured; cancer prevention; genes; nuclear protein; phosphatase; neoplasm proteins; animal experiment; animal model; bim protein; transcription factor; enzymology; enzyme activity; phosphorylation; heterozygote; carcinogenesis; transcription factors; nuclear proteins; prostate cancer; tumor suppressor gene; drug antagonism; transcription regulation; cell culture; tumors; cyclin dependent kinase inhibitor 1b; enzyme inactivation; tumor suppressor proteins; tumor protein; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; protein transport; proto-oncogene proteins c-akt; pten phosphohydrolase; tumour suppressor; gene inactivation; rodent; cell nucleus; tumor; tumor suppressor protein; enzyme localization; tissue; disease treatment; phosphoprotein phosphatase; experimental study; promyelocytic leukemia protein; cells; transcription factor foxo; compartmentalization; biological membranes; female sterility; human cancer pathogenesis; nuclear tumours; pml protein, mouse
Journal Title:	Nature
Volume:	441
Issue:	7092
ISSN:	0028-0836
Publisher:	Nature Publishing Group
Date Published:	2006-05-25
Start Page:	523
End Page:	527
Language:	English
DOI:	10.1038/nature04809
PUBMED:	16680151
PROVIDER:	scopus
PMCID:	PMC1976603
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-33745316089&partnerID=40&md5=9f2eb8bbe840491176c862643a74924a
Notes:	--- - "Cited By (since 1996): 180" - "Export Date: 4 June 2012" - "CODEN: NATUA" - "Source: Scopus"

https://synapse.mskcc.org/synapse/works/has_related_data_chk/28183