Identification of a tumour suppressor network opposing nuclear Akt function

Trotman, L. C., Alimonti, A., Scaglioni, P. P., Koutcher, J. A., Cordon-Cardo, C., Pandolfi, P. P. (May 2006) Identification of a tumour suppressor network opposing nuclear Akt function. Nature, 441 (7092). pp. 523-527. ISSN 00280836 (ISSN)

URL: http://www.ncbi.nlm.nih.gov/pubmed/16680151
DOI: 10.1038/nature04809

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.

Item Type: Paper
Uncontrolled Keywords: Biological membranes Cells Genes Tissue Compartmentalization Human cancer pathogenesis Nuclear tumours Tumour suppressor Tumors BIM protein cyclin dependent kinase inhibitor 1B phosphatase promyelocytic leukemia protein protein kinase B transcription factor FOXO nuclear protein phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase phosphoprotein phosphatase Pml protein, mouse transcription factor tumor protein tumor suppressor protein cancer disease treatment experimental study rodent tumor animal cell animal experiment animal model article cancer growth cancer incidence cancer prevention carcinogenesis cell nucleus controlled study enzyme activity enzyme inactivation enzyme localization female sterility gene inactivation heterozygote mouse nonhuman phenotype priority journal prostate cancer protein analysis protein function transcription regulation tumor suppressor gene animal cell culture drug antagonism enzymology female genetics metabolism phosphorylation protein transport Animals Cells, Cultured Mice Neoplasm Proteins Nuclear Proteins Proto-Oncogene Proteins c-akt PTEN Phosphohydrolase Transcription Factors Tumor Suppressor Proteins
Subjects: diseases & disorders > cancer > cancer types > prostate cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein expression
CSHL Authors:
Communities: CSHL labs > Trotman lab
Depositing User: Brian Soldo
Date: 25 May 2006
Date Deposited: 23 Mar 2012 16:08
Last Modified: 08 May 2013 16:39
PMCID: PMC1976603
Related URLs:
URI: http://repository.cshl.edu/id/eprint/25529

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