title: Increased susceptibility to tumorigenesis of ski-deficient heterozygous mice.
abstract: The c-ski proto-oncogene product (c-Ski) acts as a co-repressor and binds to other co-repressors N-CoR/SMRT and mSin3A which form a complex with histone deacetylase (HDAC). c-Ski mediates the transcriptional repression by a number of repressors, including nuclear hormone receptors and Mad. c-Ski also directly binds to, and recruits the HDAC complex to Smads, leading to inhibition of tumor growth factor-beta (TGF-beta) signaling. This is consistent with the function of ski as an oncogene. Here we show that loss of one copy of c-ski increases susceptibility to tumorigenesis in mice. When challenged with a chemical carcinogen, c-ski heterozygous mice showed an increased level of tumor formation relative to wild-type mice. In addition, c-ski-deficient mouse embryonic fibroblasts (MEFs) had increased proliferative capacity, whereas overexpression of c-Ski suppressed the proliferation. Furthermore, the introduction of activated Ki-ras into c-ski-deficient MEFs resulted in neoplastic transformation. These findings demonstrate that c-ski acts as a tumor suppressor in some types of cells. The level of cdc25A mRNA, which is down regulated by two tumor suppressor gene products, Rb and Mad, was upregulated in c-ski-deficient MEFs, whereas it decreased by overexpressing c-Ski in MEFs. This is consistent with the fact that c-Ski acts as a co-repressor of Mad and Rb. These results support the view that the decreased activities of Mad and Rb in ski-deficient cells at least partly contribute to enhanced proliferation and susceptibility to tumorigenesis. Human c-ski gene was mapped to a region close to the p73 tumor suppressor gene at the 1p36.3 locus, which is already known to contain multiple uncharacterized tumor suppressor genes.
authors.affiliation: Laboratory of Molecular Genetics, RIKEN Tsukuba Institute, and CREST (Core Research for Evolutionary Science and Technology) Research Project of JST (Japan Science & Technology Corporation), 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Shinagawa
authors.forename: T
authors.initials: T
authors.lastname: Nomura
authors.forename: C
authors.initials: C
authors.lastname: Colmenares
authors.forename: M
authors.initials: M
authors.lastname: Ohira
authors.forename: A
authors.initials: A
authors.lastname: Nakagawara
authors.forename: S
authors.initials: S
authors.lastname: Ishii
mesh_terms: D000818:Animals; D002455:Cell Division; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology*; D004198:Disease Susceptibility; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D017353:Gene Deletion; D016147:Genes, Tumor Suppressor; D006579:Heterozygote; D007700:Kinetics; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000209:etiology* / Q000473:pathology; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D021101:Radiation Hybrid Mapping; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*; D020687:cdc25 Phosphatases / Q000096:biosynthesis / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C512653:Ski protein, mouse; D025521:Tumor Suppressor Proteins; C517004:CDC25A protein, human; C517005:Cdc25a protein, mouse; D020687:cdc25 Phosphatases