Title | Par-4 inhibits Akt and suppresses Ras-induced lung tumorigenesis. |
Publication Type | Journal Article |
Year of Publication | 2008 |
Authors | Joshi J, Fernandez-Marcos PJ, Galvez A, Amanchy R, Linares JF, Duran A, Pathrose P, Leitges M, CaƱamero M, Collado M, Salas C, Serrano M, Moscat J, Diaz-Meco MT |
Journal | EMBO J |
Volume | 27 |
Issue | 16 |
Pagination | 2181-93 |
Date Published | 2008 Aug 20 |
ISSN | 1460-2075 |
Keywords | Animals, Cell Line, Cell Nucleus, Enzyme Activation, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Lung, Lung Neoplasms, Mice, Phosphorylation, Protein Binding, Protein Kinase C, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins p21(ras), Receptors, Thrombin, Signal Transduction, Transcription Factor RelA, X-Linked Inhibitor of Apoptosis Protein |
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. |
DOI | 10.1038/emboj.2008.149 |
Alternate Journal | EMBO J |
PubMed ID | 18650932 |
Grant List | R01-AI072581 / AI / NIAID NIH HHS / United States |
Related Faculty:
Jorge Moscat, Ph.D. Juan Francisco Linares Rodriguez, Ph.D. Maria Diaz-Meco Conde, Ph.D.