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1-induced HGF receptor expression in renal epithelial cells
1 Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA
* To whom correspondence should be addressed. E-mail: liuy{at}upmc.edu.
Hepatocyte growth factor (HGF) receptor is a transmembrane receptor tyrosine kinase encoded by c-met
proto-oncogene. In this study, we demonstrated that c-met expression was up-regulated in the kidney after obstructive injury in mice. Because the pattern of c-met induction was closely correlated with 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, 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. Over-expression 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 c-met promoter, in
which resided a putative Smad binding element (SBE) and an adjacent Sp1 site. TGF-1 not only induced
Smads binding to the SBE/Sp1 sites in c-met promoter, but also enhanced the binding of Sp proteins. Furthermore, Sp1 could form 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.
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