Early growth response 1 protein, an upstream gatekeeper of the p53 tumor suppressor, controls replicative senescence.
The proliferation of most primary cells in culture is limited by replicative senescence and crisis, p53-dependent events. However, the regulation of p53 itself has not been defined. We find that deletion of the early growth response 1 (EGR1) transcription factor leads to a striking phenotype, including complete bypass of senescence and apparent immortal growth consistent with loss of a suppressor gene. EGR1-null mouse embryo fibroblasts (MEFs) exhibit decreased expression of p53, p21(Cip1/Waf1), and other p53 "marker" proteins. Precrisis WT but not EGR1-null cells exhibit irradiation-induced arrest. WT MEFs that emerge from crisis exhibit a mutated p53 (sequence confirmed), colony formation, and tumorigenicity. In contrast, high-passage EGR1-null MEFs retain the WT p53 sequence but with much reduced expression, remain untransformed, and grow continuously. An EGR1- expressing retrovirus restores p53 expression and sencescence to EGR1-null but not p53-null MEFs or postcrisis WT cells. Taken together, the results establish EGR1 as a major regulator of cell senescence and previously undescribed upstream "gatekeeper" of the p53 tumor suppressor pathway.[1]References
- Early growth response 1 protein, an upstream gatekeeper of the p53 tumor suppressor, controls replicative senescence. Krones-Herzig, A., Adamson, E., Mercola, D. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
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