Sp1 and Sp3 transcription factors synergistically regulate HGF receptor gene expression in kidney

University of Pittsburgh, Pittsburgh, Pennsylvania, United States
American journal of physiology. Renal physiology (Impact Factor: 3.25). 02/2003; 284(1):F82-94. DOI: 10.1152/ajprenal.00200.2002
Source: PubMed


We investigated the expression pattern and underlying mechanism that controls hepatocyte growth factor (HGF) receptor (c-met) expression in normal kidney and a variety of kidney cells. Immunohistochemical staining showed widespread expression of c-met in mouse kidney, a pattern closely correlated with renal expression of Sp1 and Sp3 transcription factors. In vitro, all types of kidney cells tested expressed different levels of c-met, which was tightly proportional to the cellular abundances of Sp1 and Sp3. Both Sp1 and Sp3 bound to the multiple GC boxes in the promoter region of the c-met gene. Coimmunoprecipitation suggested a physical interaction between Sp1 and Sp3. Functionally, Sp1 markedly stimulated c-met promoter activity. Although Sp3 only weakly activated the c-met promoter, its combination with Sp1 synergistically stimulated c-met transcription. Conversely, deprivation of Sp proteins by transfection of decoy Sp1 oligonucleotide or blockade of Sp1 binding with mithramycin A inhibited c-met expression. The c-met receptor in all types of kidney cells was functional and induced protein kinase B/Akt phosphorylation in a distinctly dynamic pattern after HGF stimulation. These results indicate that members of the Sp family of transcription factors play an important role in regulating constitutive expression of the c-met gene in all types of renal cells. Our findings suggest that HGF may have a broader spectrum of target cells and possess wider implications in kidney structure and function than originally thought.

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    • "Abbreviations used: ER␣, estrogen receptor ␣; FU, 5Ј-fluorouridine; HDAC, histone deacetylase. the nucleus of various cell types (Birnbaum et al., 1995; Pombo et al., 1998; Ross et al., 2002; Sapetschnig et al., 2002, 2004; Spann et al., 2002; Zhang et al., 2003; Spengler et al., 2005). However, no colocalization study of Sp1 and Sp3 in the same image has yet been performed. "
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