Par-4 inhibits Akt and suppresses Ras-induced lung tumorigenesis.
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.
Joshi
Jayashree
J
Department of Cancer and Cell Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
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
D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000201:enzymology; D004789:Enzyme Activation; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008168:Lung / Q000201:enzymology / Q000473:pathology; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D010766:Phosphorylation; D011485:Protein Binding; D011493:Protein Kinase C / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D018179:Receptors, Thrombin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000378:metabolism; D051636:X-Linked Inhibitor of Apoptosis Protein; D000099221:Protein Kinase C zeta
D011493:Protein Kinase C; D051057:Proto-Oncogene Proteins c-akt; D016283:Proto-Oncogene Proteins p21(ras); D018179:Receptors, Thrombin; D051996:Transcription Factor RelA; D051636:X-Linked Inhibitor of Apoptosis Protein; D000099221:Protein Kinase C zeta; C495971:Hras protein, mouse; C112908:protease-activated receptor 4