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1 Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261; and 2 Department of Cell Biology, Peking Union Medical College, Beijing 100005, China
Hepatocyte
growth factor (HGF) receptor, the product of the 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 mouse renal inner medullary collecting
duct epithelial 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
directly bind to its cis-acting element in the
c-met gene. Induction of Egr-1 by oxidative stress
attenuated the binding of Sp1 to its cognate sites, but it did not
affect Sp1 abundance in renal epithelial cells. Immunoprecipitation
uncovered that Egr-1 physically interacted with Sp1 by forming the
Sp1/Egr-1 complex, which presumably resulted in a decreased
availability of unbound Sp1 as a transcriptional activator for the
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.
hepatocyte growth factor; c-met receptor; gene transcription; tubular epithelial cells; H2O2
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