title: Biallelic mutations in p16(INK4a) confer resistance to Ras- and Ets-induced senescence in human diploid fibroblasts.
abstract: The INK4a/ARF tumor suppressor locus is implicated in the senescence-like growth arrest provoked by oncogenic Ras in primary cells. INK4a and ARF are distinct proteins encoded by transcripts in which a shared exon is decoded in alternative reading frames. Here we analyze dermal fibroblasts (designated Q34) from an individual carrying independent missense mutations in each copy of the common exon. Both mutations alter the amino acid sequence of INK4a and functionally impair the protein, although they do so to different degrees. Only one of the mutations affects the sequence of ARF, causing an apparently innocuous change near its carboxy terminus. Unlike normal human fibroblasts, Q34 cells are not permanently arrested by Ras or its downstream effectors Ets1 and Ets2. Moreover, ectopic Ras enables the cells to grow as anchorage-independent colonies, and in relatively young Q34 cells anchorage independence can be achieved without addition of telomerase or perturbation of the p53 pathway. Whereas ARF plays the principal role in Ras-induced arrest of mouse fibroblasts, our data imply that INK4a assumes this role in human fibroblasts.
authors.affiliation: Cancer Research UK London Research Institute, Lincoln's Inn Fields, London WC2A 3PX.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Huot
authors.forename: Janice
authors.initials: J
authors.lastname: Rowe
authors.forename: Mark
authors.initials: M
authors.lastname: Harland
authors.forename: Sarah
authors.initials: S
authors.lastname: Drayton
authors.forename: Sharon
authors.initials: S
authors.lastname: Brookes
authors.forename: Chandra
authors.initials: C
authors.lastname: Gooptu
authors.forename: Patricia
authors.initials: P
authors.lastname: Purkis
authors.forename: Mike
authors.initials: M
authors.lastname: Fried
authors.forename: Veronique
authors.initials: V
authors.lastname: Bataille
authors.forename: Eiji
authors.initials: E
authors.lastname: Hara
authors.forename: Julia
authors.initials: J
authors.lastname: Newton-Bishop
authors.forename: Gordon
authors.initials: G
authors.lastname: Peters
mesh_terms: D000328:Adult; D000483:Alleles; D000818:Animals; D002460:Cell Line; D016922:Cellular Senescence / Q000502:physiology*; D051358:Cyclin-Dependent Kinase 4; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism; D020405:Dermis / Q000166:cytology / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D008545:Melanoma; D009154:Mutation; D050784:Proto-Oncogene Protein c-ets-1; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D050783:Proto-Oncogene Proteins c-ets; D014157:Transcription Factors / Q000378:metabolism*; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; C494041:ETS1 protein, human; C494042:Ets1 protein, mouse; D050784:Proto-Oncogene Protein c-ets-1; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D014157:Transcription Factors; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; D018631:ras Proteins