Article
- The EMBO Journal (2008) 27, 2181 - 2193
- doi:10.1038/emboj.2008.149
Published online: 24 July 2008
Subject Categories:
Par-4 inhibits Akt and suppresses Ras-induced lung tumorigenesis
Jayashree Joshi1,a, Pablo J Fernandez-Marcos2,a, Anita Galvez1, Ramars Amanchy1, Juan F Linares1, Angeles Duran1, Peterson Pathrose1, Michael Leitges3, Marta Cañamero2, Manuel Collado2, Clara Salas4, Manuel Serrano2, Jorge Moscat1 and Maria T Diaz-Meco1
- Department of Cancer and Cell Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, Madrid, Spain
- The Biotechnology Centre of Oslo, University of Oslo, Oslo, Norway
- Department of Pathology, Hospital Universitario Puerta de Hierro, Madrid, Spain
Correspondence to:
Jorge Moscat, Department of Cancer and Cell Biology, University of Cincinnati College of Medicine, 3125 Eden Ave., Cincinnati, OH 45267, USA. Tel.: +1 513 558 8419; Fax: +1 513 558 5061; E-mail: jorge.moscat@uc.edu
Maria T Diaz-Meco, Department of Cancer and Cell Biology, University of Cincinnati College of Medicine, 3125 Eden Ave., Cincinnati, OH 45267, USA. Tel.: +1 513 558 8419; Fax: +1 513 558 5061; E-mail: maria.diazmeco@uc.edu
aThese authors contributed equally to this work
Received 14 April 2008; Accepted 7 July 2008
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 PKC
, establishing a new paradigm for Akt regulation and, likely, for Ras-induced lung carcinogenesis, wherein Par-4 is a novel tumour suppressor.
Keywords:
- Akt,
- lung cancer,
- NF-
B, - Par-4,
- PKC,
- Ras
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