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1 Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Cell Biology, Peking Union Medical College, Beijing, China
2 Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
* To whom correspondence should be addressed. E-mail: liuy{at}msx.upmc.edu.
Hepatocyte growth factor (HGF) receptor, the product of c-met protooncogene, is transcriptionally regulated by a wide variety of cytokines as well as extracellular environmental cues. In this report, we demonstrate that c-met expression was significantly suppressed by oxidative stress. Treatment of renal epithelial mIMCD-3 cells with 0.5 mM H2O2 inhibited c-met mRNA and protein expression, which was concomitant with induction of Egr-1 transcription factor. Ectopic expression of Egr-1 in renal epithelial cells markedly inhibited endogenous c-met expression in a dose-dependent fashion, suggesting a causative effect of Egr-1 in mediating c-met suppression. The cis-acting element responsible for H2O2-induced c-met inhibition was localized at nucleotide position -223 to -68 of c-met promoter, in which reside an imperfect Egr-1 and three Sp1 binding sites. Egr-1 markedly suppressed c-met promoter activity but did not bind to its cis-acting element in c-met gene. Induction of Egr-1 by oxidative stress attenuated the binding of Sp1 to its cognate sites, but did not affect its abundance in renal epithelial cells. Immunoprecipitation uncovered that Egr-1 physically interacted with Sp1 by forming Sp1/Egr-1 complex, which presumably resulted in a decreased availability of unbound Sp1 as a transcriptional activator for c-met gene. Thus, it appears that inhibition of c-met expression by oxidative stress is mediated by the interplay between Sp1 and Egr-1 transcription factors. Our findings reveal a novel transcriptional regulatory mechanism by which Egr-1 sequesters Sp1 as a transcriptional activator of c-met via physical interaction.
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