Journal
EMBO JOURNAL
Volume 27, Issue 16, Pages 2181-2193Publisher
WILEY
DOI: 10.1038/emboj.2008.149
Keywords
Akt; lung cancer; NF-kappa B; Par-4; PKC zeta; Ras
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Funding
- University of Cincinnati-Consejo Superior de Investigaciones Cientificas Research Collaborative Agreement
- NIH [R01-AI072581]
- CNIO
- Spanish Ministry of Education
- European Union (INTACT and PROTEOMAGE)
- 'Marcelino Botin' Foundation
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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 zeta, establishing a new paradigm for Akt regulation and, likely, for Ras-induced lung carcinogenesis, wherein Par-4 is a novel tumour suppressor.
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