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Identification of PHLPP1 as a Tumor Suppressor Reveals the Role of Feedback Activation in PTEN-Mutant Prostate Cancer Progression
Ist Teil von
Cancer cell, 2011-08, Vol.20 (2), p.173-186
Ort / Verlag
United States: Elsevier Inc
Erscheinungsjahr
2011
Quelle
MEDLINE
Beschreibungen/Notizen
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.
►
PHLPP1 is a prostate tumor suppressor that cooperates with
PTEN ►
Phlpp1/Pten codeletion requires p53 inactivation for senescence bypass ► Codeletion is associated with metastatic disease ► Codeletion triggers rapamycin-sensitive p53 and Phlpp2 activation