title: Depletion of CSN5 inhibits Ras-mediated tumorigenesis by inducing premature senescence in p53-null cells.
abstract: The mammalian COP9 signalosome (CSN) complex is involved in cell transformation, but its molecular mechanism remains undetermined. Here we show that disruption of the fifth component (CSN5) prevented the formation of tumors by p53-null cells transformed with an active form of Ras in subcutaneously injected mice. Depletion of CSN5 suppressed cell proliferation, and induced premature senescence characterized by upregulation of senescence-associated-β-galactosidase activity and increased expression of CDK inhibitors. CSN5-depleted cells exhibited enhanced activation of the PI3 kinase-Akt pathway, and chemical inhibition of this pathway reduced the level of senescence. Thus, CSN5 is suggested to be a novel target in cancer therapy and for drugs against tumor cells harboring mutated p53.
authors.affiliation: Graduate School of Biological Sciences, Nara Institute of Science and Technology, Nara, Japan.
authors.forename: Ikuko
authors.initials: I
authors.lastname: Tsujimoto
authors.forename: Akihiro
authors.initials: A
authors.lastname: Yoshida
authors.forename: Noriko
authors.initials: N
authors.lastname: Yoneda-Kato
authors.forename: Jun-ya
authors.initials: JY
authors.lastname: Kato
mesh_terms: D000818:Animals; D000075686:COP9 Signalosome Complex; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D016922:Cellular Senescence; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000096:biosynthesis; D055785:Gene Knockdown Techniques; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010447:Peptide Hydrolases / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D001616:beta-Galactosidase / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016159:Tumor Suppressor Protein p53; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D001616:beta-Galactosidase; D010447:Peptide Hydrolases; C501490:Cops5 protein, mouse; D000075686:COP9 Signalosome Complex; D018631:ras Proteins