Identification of PHLPP1 as a Tumor Suppressor Reveals the Role of Feedback Activation in PTEN-Mutant Prostate Cancer Progression

Chen, M. H., Pratt, C. P., Zeeman, M. E., Schultz, N., Taylor, B. S., O'Neill, A., Castillo-Martin, M., Nowak, D. G., Naguib, A., Grace, D. M., Murn, J., Navin, N., Atwal, G. S., Sander, C., Gerald, W. L., Cordon-Cardo, C., Newton, A. C., Carver, B. S., Trotman, L. C. (August 2011) Identification of PHLPP1 as a Tumor Suppressor Reveals the Role of Feedback Activation in PTEN-Mutant Prostate Cancer Progression. Cancer Cell, 20 (2). pp. 173-186. ISSN 1535-6108

URL: http://www.ncbi.nlm.nih.gov/pubmed/21840483
DOI: 10.1016/j.ccr.2011.07.013

Abstract

Hyperactivation of the PI 3-kinase/AKT pathway is a driving force of many cancers. Here we identify the AKT-inactivating phosphatase PHLPP1 as a prostate tumor suppressor. We show that Phlpp1-loss causes neoplasia and, on partial Pten-loss, carcinoma in mouse prostate. This genetic setting initially triggers a growth suppressive response via p53 and the Phlpp2 ortholog, and reveals spontaneous Trp53 inactivation as a condition for full-blown disease. Surprisingly, the codeletion of PTEN and PHLPP1 in patient samples is highly restricted to metastatic disease and tightly correlated to deletion of TP53 and PHLPP2. These data establish a conceptual framework for progression of PTEN mutant prostate cancer to life-threatening disease.

Item Type: Paper
Uncontrolled Keywords: mtor complex mice akt phosphatase senescence pathway protein growth dephosphorylates tumorigenesis
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > PTEN
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > kinase
diseases & disorders > cancer > cancer types > prostate cancer
CSHL Authors:
Communities: CSHL Cancer Center Program > Cancer Genetics
CSHL Cancer Center Shared Resources > Animal Services
CSHL Cancer Center Shared Resources > Antibody and Phage Display Service
CSHL Cancer Center Shared Resources > Bioinformatics Service
CSHL Cancer Center Shared Resources > DNA Sequencing Service
CSHL Cancer Center Shared Resources > Flow Cytometry Service
CSHL Cancer Center Shared Resources > Microarray Service
CSHL Cancer Center Shared Resources > Microscopy Service
CSHL Post Doctoral Fellows
CSHL labs > Atwal lab
CSHL labs > Trotman lab
CSHL Cancer Center Program > Signal Transduction
Depositing User: CSHL Librarian
Date: August 2011
Date Deposited: 07 Nov 2011 21:36
Last Modified: 15 Oct 2015 20:04
PMCID: PMC3176728
Related URLs:
URI: http://repository.cshl.edu/id/eprint/15615

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