Early growth response 1 protein, an upstream gatekeeper of the p53 tumor suppressor, controls replicative senescence
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- Anja Krones-Herzig
- Sidney Kimmel Cancer Center, San Diego, CA 92121; The Burnham Institute, La Jolla, CA 92037; and Cancer Center, University of California at San Diego, La Jolla, CA 92093
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- Eileen Adamson
- Sidney Kimmel Cancer Center, San Diego, CA 92121; The Burnham Institute, La Jolla, CA 92037; and Cancer Center, University of California at San Diego, La Jolla, CA 92093
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- Dan Mercola
- Sidney Kimmel Cancer Center, San Diego, CA 92121; The Burnham Institute, La Jolla, CA 92037; and Cancer Center, University of California at San Diego, La Jolla, CA 92093
書誌事項
- 公開日
- 2003-03-10
- DOI
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- 10.1073/pnas.2628034100
- 公開者
- National Academy of Sciences
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説明
<jats:p> 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 <jats:sup>Cip1/Waf1</jats:sup> , 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. </jats:p>
収録刊行物
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- Proceedings of the National Academy of Sciences
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Proceedings of the National Academy of Sciences 100 (6), 3233-3238, 2003-03-10
National Academy of Sciences
