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Early Growth Response 1 Acts as a Tumor Suppressor In vivo and In vitro via Regulation of p53

¹ Sidney Kimmel Cancer Center, San Diego, California and ² The Burnham Institute; ³ Cancer Center, University of California at San Diego, La Jolla, California

Requests for reprints: Dan Mercola, Sidney Kimmel Cancer Center, 10835 Altman Row, San Diego, CA 92121. Phone: 858-450-5990, ext. 370; Fax: 858-450-3251; E-mail: danmercola{at}skcc.org.

The early growth response 1 (Egr1) gene is a transcription factor that acts as both a tumor suppressor and a tumor promoter. Egr1-null mouse embryo fibroblasts bypass replicative senescence and exhibit a loss of DNA damage response and an apparent immortal growth, suggesting loss of p53 functions. Stringent expression analysis revealed 266 transcripts with >2-fold differential expression in Egr1-null mouse embryo fibroblasts, including 143 known genes. Of the 143 genes, program-assisted searching revealed 66 informative genes linked to Egr1. All 66 genes could be placed on a single regulatory network consisting of three branch points of known Egr1 target genes: TGFß1, IL6, and IGFI. Moreover, 19 additional genes that are known targets of p53 were identified, indicating that p53 is a fourth branch point. Electrophoretic mobility shift assay as well as chromatin immunoprecipitation confirmed that p53 is a direct target of Egr1. Because deficient p53 expression causes tumors in mice, we tested the role of Egr1 in a two-step skin carcinogenesis study (144 mice) that revealed a uniformly accelerated development of skin tumors in Egr1-null mice (P < 0.005). These studies reveal a new role for Egr1 as an in vivo tumor suppressor.

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