Article

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: 3.3). 02/2003; 284(1):F82-94. DOI: 10.1152/ajprenal.00200.2002
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ABSTRACT 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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    • "Sp family members, Sp1–4, have been shown to play important roles during differentiation and development of human cells, as well as in cell cycle regulation. Sp1, Sp3 and Sp4 interact with several proteins involved in cell cycle regulation, such as E2F family members and retinoblastoma-like proteins (Rb and P130), as well as interacting with each other (e.g, Sp1 binds to both Sp3 and Sp4) (Karlseder et al., 1996; Rotheneder et al., 1999; Chang et al., 2001; Zhang et al., 2003). Thus the possibility exists that part of the ability of these factors (specifically Sp3 and Sp4) to enhance IE62-mediated transactivation may be due to their ability to recruit additional cellular factors involved in transcriptional activation. "
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