Opposing effects of Ets and Id proteins on p16INK4a expression during cellular senescence.

2.50
Hdl Handle:
http://hdl.handle.net/10541/85725
Title:
Opposing effects of Ets and Id proteins on p16INK4a expression during cellular senescence.
Authors:
Ohtani, Naoko; Zebedee, Zoe; Huot, Thomas J G; Stinson, Julie A; Sugimoto, Masataka; Ohashi, Yasuhiro; Sharrocks, Andrew D; Peters, Gordon; Hara, Eiji
Abstract:
The p16INK4a cyclin-dependent kinase inhibitor is implicated in replicative senescence, the state of permanent growth arrest provoked by cumulative cell divisions or as a response to constitutive Ras-Raf-MEK signalling in somatic cells. Some contribution to senescence presumably underlies the importance of p16INK4a as a tumour suppressor but the mechanisms regulating its expression in these different contexts remain unknown. Here we demonstrate a role for the Ets1 and Ets2 transcription factors based on their ability to activate the p16INK4a promoter through an ETS-binding site and their patterns of expression during the lifespan of human diploid fibroblasts. The induction of p16INK4a by Ets2, which is abundant in young human diploid fibroblasts, is potentiated by signalling through the Ras-Raf-MEK kinase cascade and inhibited by a direct interaction with the helix-loop-helix protein Id1 (ref. 11). In senescent cells, where the Ets2 levels and MEK signalling decline, the marked increase in p16INK4a expression is consistent with the reciprocal reduction of Id1 and accumulation of Ets1.
Affiliation:
Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, UK.
Citation:
Opposing effects of Ets and Id proteins on p16INK4a expression during cellular senescence. 2001, 409 (6823):1067-70 Nature
Journal:
Nature
Issue Date:
22-Feb-2001
URI:
http://hdl.handle.net/10541/85725
DOI:
10.1038/35059131
PubMed ID:
11234019
Type:
Article
Language:
en
ISSN:
0028-0836
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorOhtani, Naokoen
dc.contributor.authorZebedee, Zoeen
dc.contributor.authorHuot, Thomas J Gen
dc.contributor.authorStinson, Julie Aen
dc.contributor.authorSugimoto, Masatakaen
dc.contributor.authorOhashi, Yasuhiroen
dc.contributor.authorSharrocks, Andrew Den
dc.contributor.authorPeters, Gordonen
dc.contributor.authorHara, Eijien
dc.date.accessioned2009-11-10T09:55:13Z-
dc.date.available2009-11-10T09:55:13Z-
dc.date.issued2001-02-22-
dc.identifier.citationOpposing effects of Ets and Id proteins on p16INK4a expression during cellular senescence. 2001, 409 (6823):1067-70 Natureen
dc.identifier.issn0028-0836-
dc.identifier.pmid11234019-
dc.identifier.doi10.1038/35059131-
dc.identifier.urihttp://hdl.handle.net/10541/85725-
dc.description.abstractThe p16INK4a cyclin-dependent kinase inhibitor is implicated in replicative senescence, the state of permanent growth arrest provoked by cumulative cell divisions or as a response to constitutive Ras-Raf-MEK signalling in somatic cells. Some contribution to senescence presumably underlies the importance of p16INK4a as a tumour suppressor but the mechanisms regulating its expression in these different contexts remain unknown. Here we demonstrate a role for the Ets1 and Ets2 transcription factors based on their ability to activate the p16INK4a promoter through an ETS-binding site and their patterns of expression during the lifespan of human diploid fibroblasts. The induction of p16INK4a by Ets2, which is abundant in young human diploid fibroblasts, is potentiated by signalling through the Ras-Raf-MEK kinase cascade and inhibited by a direct interaction with the helix-loop-helix protein Id1 (ref. 11). In senescent cells, where the Ets2 levels and MEK signalling decline, the marked increase in p16INK4a expression is consistent with the reciprocal reduction of Id1 and accumulation of Ets1.en
dc.language.isoenen
dc.subject.meshAnimals-
dc.subject.meshCell Aging-
dc.subject.meshCell Line-
dc.subject.meshCyclin-Dependent Kinase Inhibitor p16-
dc.subject.meshDNA-Binding Proteins-
dc.subject.meshFibroblasts-
dc.subject.meshGene Expression Regulation-
dc.subject.meshHumans-
dc.subject.meshInhibitor of Differentiation Protein 1-
dc.subject.meshMAP Kinase Kinase Kinase 1-
dc.subject.meshMAP Kinase Signaling System-
dc.subject.meshMice-
dc.subject.meshPromoter Regions, Genetic-
dc.subject.meshProtein Binding-
dc.subject.meshProtein-Serine-Threonine Kinases-
dc.subject.meshProto-Oncogene Protein c-ets-1-
dc.subject.meshProto-Oncogene Protein c-ets-2-
dc.subject.meshProto-Oncogene Proteins-
dc.subject.meshProto-Oncogene Proteins c-ets-
dc.subject.meshProto-Oncogene Proteins c-raf-
dc.subject.meshRepressor Proteins-
dc.subject.meshTrans-Activators-
dc.subject.meshTranscription Factors-
dc.subject.meshras Proteins-
dc.titleOpposing effects of Ets and Id proteins on p16INK4a expression during cellular senescence.en
dc.typeArticleen
dc.contributor.departmentPaterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, UK.en
dc.identifier.journalNatureen

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