title: The stress kinase MKK7 couples oncogenic stress to p53 stability and tumor suppression.
abstract: Most preneoplastic lesions are quiescent and do not progress to form overt tumors. It has been proposed that oncogenic stress activates the DNA damage response and the key tumor suppressor p53, which prohibits tumor growth. However, the molecular pathways by which cells sense a premalignant state in vivo are largely unknown. Here we report that tissue-specific inactivation of the stress signaling kinase MKK7 in KRas(G12D)-driven lung carcinomas and NeuT-driven mammary tumors markedly accelerates tumor onset and reduces overall survival. Mechanistically, MKK7 acts through the kinases JNK1 and JNK2, and this signaling pathway directly couples oncogenic and genotoxic stress to the stability of p53, which is required for cell cycle arrest and suppression of epithelial cancers. These results show that MKK7 functions as a major tumor suppressor in lung and mammary cancer in mouse and identify MKK7 as a vital molecular sensor to set a cellular anti-cancer barrier.
authors.affiliation: Institute of Molecular Biotechnology of Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Daniel
authors.initials: D
authors.lastname: Schramek
authors.forename: Athanassios
authors.initials: A
authors.lastname: Kotsinas
authors.forename: Arabella
authors.initials: A
authors.lastname: Meixner
authors.forename: Teiji
authors.initials: T
authors.lastname: Wada
authors.forename: Ulrich
authors.initials: U
authors.lastname: Elling
authors.forename: J Andrew
authors.initials: JA
authors.lastname: Pospisilik
authors.forename: G Gregory
authors.initials: GG
authors.lastname: Neely
authors.forename: Ralf-Harun
authors.initials: RH
authors.lastname: Zwick
authors.forename: Verena
authors.initials: V
authors.lastname: Sigl
authors.forename: Guido
authors.initials: G
authors.lastname: Forni
authors.forename: Manuel
authors.initials: M
authors.lastname: Serrano
authors.forename: Vassilis G
authors.initials: VG
authors.lastname: Gorgoulis
authors.forename: Josef M
authors.initials: JM
authors.lastname: Penninger
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D016922:Cellular Senescence; D004249:DNA Damage; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D016158:Genes, p53; D011905:Genes, ras; D008175:Lung Neoplasms / Q000235:genetics / Q000401:mortality; D048688:MAP Kinase Kinase 7 / Q000235:genetics*; D020935:MAP Kinase Signaling System; D008325:Mammary Neoplasms, Experimental / Q000235:genetics; D051379:Mice; D055550:Protein Stability
chemical_list: D048688:MAP Kinase Kinase 7; C482570:Map2k7 protein, mouse