title: Par-4 inhibits Akt and suppresses Ras-induced lung tumorigenesis.
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.
authors.affiliation: Department of Cancer and Cell Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
authors.forename: Jayashree
authors.initials: J
authors.lastname: Joshi
authors.forename: Pablo J
authors.initials: PJ
authors.lastname: Fernandez-Marcos
authors.forename: Anita
authors.initials: A
authors.lastname: Galvez
authors.forename: Ramars
authors.initials: R
authors.lastname: Amanchy
authors.forename: Juan F
authors.initials: JF
authors.lastname: Linares
authors.forename: Angeles
authors.initials: A
authors.lastname: Duran
authors.forename: Peterson
authors.initials: P
authors.lastname: Pathrose
authors.forename: Michael
authors.initials: M
authors.lastname: Leitges
authors.forename: Marta
authors.initials: M
authors.lastname: Cañamero
authors.forename: Manuel
authors.initials: M
authors.lastname: Collado
authors.forename: Clara
authors.initials: C
authors.lastname: Salas
authors.forename: Manuel
authors.initials: M
authors.lastname: Serrano
authors.forename: Jorge
authors.initials: J
authors.lastname: Moscat
authors.forename: Maria T
authors.initials: MT
authors.lastname: Diaz-Meco
mesh_terms: 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
chemical_list: 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