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

2.50
Hdl Handle:
http://hdl.handle.net/10541/82460
Title:
Biallelic mutations in p16(INK4a) confer resistance to Ras- and Ets-induced senescence in human diploid fibroblasts.
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
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.
Affiliation:
Cancer Research UK London Research Institute, Lincoln's Inn Fields, London WC2A 3PX.
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
Issue Date:
Dec-2002
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
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorHuot, Thomas J G-
dc.contributor.authorRowe, Janice-
dc.contributor.authorHarland, Mark-
dc.contributor.authorDrayton, Sarah-
dc.contributor.authorBrookes, Sharon-
dc.contributor.authorGooptu, Chandra-
dc.contributor.authorPurkis, Patricia-
dc.contributor.authorFried, Mike-
dc.contributor.authorBataille, Veronique-
dc.contributor.authorHara, Eiji-
dc.contributor.authorNewton-Bishop, Julia-
dc.contributor.authorPeters, Gordon-
dc.date.accessioned2009-09-24T10:08:08Z-
dc.date.available2009-09-24T10:08:08Z-
dc.date.issued2002-12-
dc.identifier.citationBiallelic mutations in p16(INK4a) confer resistance to Ras- and Ets-induced senescence in human diploid fibroblasts. 2002, 22 (23):8135-43 Mol. Cell. Biol.en
dc.identifier.issn0270-7306-
dc.identifier.pmid12417717-
dc.identifier.doi10.1128/MCB.22.23.8135-8143.2002-
dc.identifier.urihttp://hdl.handle.net/10541/82460-
dc.description.abstractThe 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.en
dc.language.isoenen
dc.subjectTumour Suppressor Protein p14ARFen
dc.subjectTumour Suppressor Protein p53en
dc.subject.meshAdult-
dc.subject.meshAlleles-
dc.subject.meshAnimals-
dc.subject.meshCell Aging-
dc.subject.meshCell Line-
dc.subject.meshCyclin-Dependent Kinase 4-
dc.subject.meshCyclin-Dependent Kinase Inhibitor p16-
dc.subject.meshCyclin-Dependent Kinases-
dc.subject.meshDermis-
dc.subject.meshFemale-
dc.subject.meshFibroblasts-
dc.subject.meshGene Expression Regulation-
dc.subject.meshHumans-
dc.subject.meshMale-
dc.subject.meshMelanoma-
dc.subject.meshMutation-
dc.subject.meshProto-Oncogene Protein c-ets-1-
dc.subject.meshProto-Oncogene Proteins-
dc.subject.meshProto-Oncogene Proteins c-ets-
dc.subject.meshTranscription Factors-
dc.subject.meshTumor Suppressor Protein p14ARF-
dc.subject.meshTumor Suppressor Protein p53-
dc.subject.meshras Proteins-
dc.titleBiallelic mutations in p16(INK4a) confer resistance to Ras- and Ets-induced senescence in human diploid fibroblasts.en
dc.typeArticleen
dc.contributor.departmentCancer Research UK London Research Institute, Lincoln's Inn Fields, London WC2A 3PX.en
dc.identifier.journalMolecular and Cellular Biologyen

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