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    Biallelic mutations in p16(INK4a) confer resistance to Ras- and Ets-induced senescence in human diploid fibroblasts.

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    Authors
    Huot, Thomas J G
    Rowe, Janice
    Harland, Mark
    Drayton, Sarah
    Brookes, Sharon
    Gooptu, Chandra
    Purkis, Patricia
    Fried, Mike
    Bataille, Veronique
    Hara, Eiji
    Newton-Bishop, Julia
    Peters, Gordon
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    Affiliation
    Cancer Research UK London Research Institute, Lincoln's Inn Fields, London WC2A 3PX.
    Issue Date
    2002-12
    
    Metadata
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    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.
    Citation
    Biallelic mutations in p16(INK4a) confer resistance to Ras- and Ets-induced senescence in human diploid fibroblasts. 2002, 22 (23):8135-43 Mol. Cell. Biol.
    Journal
    Molecular and Cellular Biology
    URI
    http://hdl.handle.net/10541/82460
    DOI
    10.1128/MCB.22.23.8135-8143.2002
    PubMed ID
    12417717
    Type
    Article
    Language
    en
    ISSN
    0270-7306
    ae974a485f413a2113503eed53cd6c53
    10.1128/MCB.22.23.8135-8143.2002
    Scopus Count
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