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PMID: 18650932 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

The EMBO journal ·Vol. 27 ·No. 16 ·2008-08-20 ·Pages 2181-93

Joshi J, Fernandez-Marcos PJ, Galvez A, Amanchy R, Linares JF, Duran A, Pathrose P, Leitges M, Cañamero M, Collado M, Salas C, Serrano M, Moscat J, Diaz-Meco MT

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.

MeSH Terms
Animals Cell Line Cell Nucleus/enzymology Enzyme Activation Gene Expression Profiling Gene Expression Regulation, Neoplastic Humans Lung/enzymology,pathology Lung Neoplasms/enzymology,genetics,pathology Mice Phosphorylation Protein Binding Protein Kinase C/metabolism Proto-Oncogene Proteins c-akt/antagonists & inhibitors Proto-Oncogene Proteins p21(ras)/metabolism Receptors, Thrombin/deficiency,genetics,metabolism Signal Transduction Transcription Factor RelA/metabolism X-Linked Inhibitor of Apoptosis Protein
Chemicals
Receptors, Thrombin Transcription Factor RelA X-Linked Inhibitor of Apoptosis Protein Proto-Oncogene Proteins c-akt protein kinase C zeta Protein Kinase C Hras protein, mouse Proto-Oncogene Proteins p21(ras) protease-activated receptor 4
Authors & Affiliations
14 authors, click to expand affiliations / ORCID
Joshi Jayashree
Department of Cancer and Cell Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
Fernandez-Marcos Pablo J
Galvez Anita
Amanchy Ramars
Linares Juan F
Duran Angeles
Pathrose Peterson
Leitges Michael
Cañamero Marta
Collado Manuel
Salas Clara
Serrano Manuel
Moscat Jorge
Diaz-Meco Maria T
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
1460-2075
DOI
10.1038/emboj.2008.149
Published
2008-08-20
Epub
2008-00-24
Pages
2181-93
Language
English
Region
England
NLM ID
8208664
PMCID
PMC2519103
Subset
IM
Grants
NIAID NIH HHS · R01 AI072581 · United States
NIAID NIH HHS · R01-AI072581 · United States
External Links
PubMed source DOI: 10.1038/emboj.2008.149 PMC Full Text View journal details
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