Opposing effects of Ets and Id proteins on p16INK4a expression during cellular senescence.
Huot, Thomas J G
Stinson, Julie A
Sharrocks, Andrew D
AffiliationPaterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, UK.
MetadataShow full item record
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.
CitationOpposing effects of Ets and Id proteins on p16INK4a expression during cellular senescence. 2001, 409 (6823):1067-70 Nature
- ETS1 and ETS2 in p53 regulation: spatial separation of ETS binding sites (EBS) modulate protein: DNA interaction.
- Authors: Venanzoni MC, Robinson LR, Hodge DR, Kola I, Seth A
- Issue date: 1996 Mar 21
- Regulation of the human stress response gene GADD153 expression: role of ETS1 and FLI-1 gene products.
- Authors: Seth A, Giunta S, Franceschil C, Kola I, Venanzoni MC
- Issue date: 1999 Sep
- Altered Ets transcription factor activity in prostate tumor cells inhibits anchorage-independent growth, survival, and invasiveness.
- Authors: Foos G, Hauser CA
- Issue date: 2000 Nov 16
- Ets transcription factors and targets in osteogenesis.
- Authors: Raouf A, Seth A
- Issue date: 2000 Dec 18
- Id1 is down-regulated by hepatocyte growth factor via ERK-dependent and ERK-independent signaling pathways, leading to increased expression of p16INK4a in hepatoma cells.
- Authors: Ushio K, Hashimoto T, Kitamura N, Tanaka T
- Issue date: 2009 Jul