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Both Sp1 and Smad participate in mediating TGF-1-induced HGF receptor expression in renal epithelial cells

Division of Cellular and Molecular Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

Submitted 4 September 2003 ; accepted in final form 25 August 2004

Hepatocyte growth factor (HGF) receptor is a transmembrane receptor tyrosine kinase encoded by the c-met protooncogene. In this study, we demonstrated that c-met expression was upregulated in the kidney after obstructive injury in mice. Because the pattern of c-met induction was closely correlated with transforming growth factor-1 (TGF-1) expression in vivo, we further investigated the regulation of c-met expression in renal tubular epithelial (HKC) cells by TGF-1 in vitro. Real-time RT-PCR and Northern and Western blot analyses revealed that TGF-1 significantly induced c-met expression in HKC cells, which primarily took place at the gene transcriptional level. Overexpression of inhibitory Smad7 completely abolished c-met induction, indicating its dependence on Smad signaling. Interestingly, TGF-1-induced c-met expression was also contingent on a functional Sp1, as ablation of Sp1 binding with mithramycin A abrogated c-met induction in HKC cells. Transfection and sequence analysis identified a cis-acting TGF-1-responsive region in the c-met promoter, in which resided a putative Smad-binding element (SBE) and an adjacent Sp1 site. TGF-1 not only induced Smad binding to the SBE/Sp1 sites in the c-met promoter, but also enhanced the binding of Sp proteins. Furthermore, Sp1 could form a complex with Smads in a TGF-1-dependent fashion. These results suggest a novel regulatory mechanism controlling c-met expression by TGF-1 in renal epithelial cells, in which both Smad and Sp proteins participate and cooperate in activating c-met gene transcription.

transforming growth factor-1; hepatocyte growth factor; gene transcription; unilateral ureteral obstruction; tubular epithelial cells

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