Sp1 and Sp3 transcription factors synergistically regulate HGF receptor gene expression in kidney.
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.
Zhang
Xianghong
X
Department of Pathology, University of Pittsburgh School of Medicine, Pennsylvania 15261, USA.
Li
Yingjian
Y
Dai
Chunsun
C
Yang
Junwei
J
Mundel
Peter
P
Liu
Youhua
Y
D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004330:Drosophila; D029721:Drosophila Proteins; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D020862:GC Rich Sequence / Q000502:physiology; D015870:Gene Expression / Q000502:physiology; D005920:Glomerular Mesangium / Q000166:cytology / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D007668:Kidney / Q000166:cytology* / Q000502:physiology*; D007685:Kidney Tubules, Collecting / Q000166:cytology / Q000502:physiology; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000502:physiology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009841:Oligonucleotides / Q000494:pharmacology; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000502:physiology; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D051705:Sp3 Transcription Factor; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology
D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D009841:Oligonucleotides; D011518:Proto-Oncogene Proteins; C497121:SP3 protein, human; D016329:Sp1 Transcription Factor; C497122:Sp3 protein, mouse; C497123:Sp3 protein, rat; D014157:Transcription Factors; D051705:Sp3 Transcription Factor; D019859:Proto-Oncogene Proteins c-met; C494918:AKT1 protein, human; C494917:Akt1 protein, Drosophila; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt