Regulation of a senescence checkpoint response by the E2F1 transcription factor and p14ARF tumor suppressor
- LBNL Library
Normal cells do not divide indefinitely due to a process known as replicative senescence. Human cells arrest growth with a senescent phenotype when they acquire one or more critically short telomere as a consequence of cell division. Recent evidence suggests that certain types of DNA damage, chromatin remodeling, or oncogenic forms of Rasor Raf can also elicit a senescence response. We show here that E2F1, a multifunctional transcription factor that binds the retinoblastoma (pRb) tumor suppressor and can either promote or suppress tumorigenesis, induces a senescent phenotype when overexpressed in normal human fibroblasts. Normal human cells stably arrested proliferation and expressed several markers of replicative senescence in response to E2F1. This activity of E2F1 was independent of its pRb binding activity, but dependent on its ability to stimulate gene expression. The E2F1 target gene critical for the senescence response appeared to be the p14ARF tumor suppressor. Replicatively senescent human fibroblasts overexpressed p14ARF, and ectopic expression of p14ARF in presenescent cells induced a phenotype similar to that induced by E2F1. Consistent with a critical role for p14ARF, cells with compromised p53 function were immune to senescence induction by E2F1, as were cells deficient in p14ARF. Our findings support the idea that the senescence response is a critical tumor suppressive mechanism, provide an explanation for the apparently paradoxical roles of E2F1 in oncogenesis, and identify p14ARF as a potentially important mediator of the senescent phenotype.
- Research Organization:
- Lawrence Berkeley National Lab., CA (US)
- Sponsoring Organization:
- National Institutes of Health (US)
- DOE Contract Number:
- AC03-76SF00098
- OSTI ID:
- 771752
- Report Number(s):
- LBNL--44492
- Journal Information:
- Molecular and Cellular Biology, Journal Name: Molecular and Cellular Biology Journal Issue: 1 Vol. 20; ISSN 0270-7306; ISSN MCEBD4
- Country of Publication:
- United States
- Language:
- English
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