Suppression of HGF receptor gene expression by oxidative stress is mediated through the interplay between Sp1 and Egr-1.
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 H(2)O(2) 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 H(2)O(2)-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.
Mesh Terms:
Animals, Blotting, Northern, Cell Line, Cells, Cultured, DNA, DNA-Binding Proteins, Early Growth Response Protein 1, Electrophoretic Mobility Shift Assay, Gene Expression Regulation, Immediate-Early Proteins, Kidney, Luciferases, Mice, Nuclear Proteins, Oxidative Stress, Plasmids, Precipitin Tests, Proto-Oncogene Proteins c-met, RNA, RNA, Messenger, Transcription Factors, Transfection
Animals, Blotting, Northern, Cell Line, Cells, Cultured, DNA, DNA-Binding Proteins, Early Growth Response Protein 1, Electrophoretic Mobility Shift Assay, Gene Expression Regulation, Immediate-Early Proteins, Kidney, Luciferases, Mice, Nuclear Proteins, Oxidative Stress, Plasmids, Precipitin Tests, Proto-Oncogene Proteins c-met, RNA, RNA, Messenger, Transcription Factors, Transfection
Am. J. Physiol. Renal Physiol.
Date: Jun. 01, 2003
PubMed ID: 12569082
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