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Par-4 inhibits Akt and suppresses Ras-induced lung tumorigenesis.

ABSTRACT: The atypical PKC-interacting protein, Par-4, inhibits cell survival and tumorigenesis in vitro, and its genetic inactivation in mice leads to reduced lifespan, enhanced benign tumour development and low-frequency carcinogenesis. Here, we demonstrate that Par-4 is highly expressed in normal lung but reduced in human lung cancer samples. We show, in a mouse model of lung tumours, that the lack of Par-4 dramatically enhances Ras-induced lung carcinoma formation in vivo, acting as a negative regulator of Akt activation. We also demonstrate in cell culture, in vivo, and in biochemical experiments that Akt regulation by Par-4 is mediated by PKCzeta, establishing a new paradigm for Akt regulation and, likely, for Ras-induced lung carcinogenesis, wherein Par-4 is a novel tumour suppressor.

SUBMITTER: Joshi J

PROVIDER: S-EPMC2519103 | biostudies-literature | 2008 Aug

REPOSITORIES: biostudies-literature

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Par-4 inhibits Akt and suppresses Ras-induced lung tumorigenesis.

Joshi Jayashree J Fernandez-Marcos Pablo J PJ Galvez Anita A Amanchy Ramars R Linares Juan F JF Duran Angeles A Pathrose Peterson P Leitges Michael M Cañamero Marta M Collado Manuel M Salas Clara C Serrano Manuel M Moscat Jorge J Diaz-Meco Maria T MT

The EMBO journal 20080724 16

The atypical PKC-interacting protein, Par-4, inhibits cell survival and tumorigenesis in vitro, and its genetic inactivation in mice leads to reduced lifespan, enhanced benign tumour development and low-frequency carcinogenesis. Here, we demonstrate that Par-4 is highly expressed in normal lung but reduced in human lung cancer samples. We show, in a mouse model of lung tumours, that the lack of Par-4 dramatically enhances Ras-induced lung carcinoma formation in vivo, acting as a negative regulat ...[more]

PMID: 18650932

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