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

Am J Physiol Renal Physiol. 2003 Jan;284(1):F82-94. doi: 10.1152/ajprenal.00200.2002.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Line
  • DNA-Binding Proteins / metabolism*
  • Drosophila
  • Drosophila Proteins
  • Fibroblasts / cytology
  • Fibroblasts / physiology
  • GC Rich Sequence / physiology
  • Gene Expression / physiology
  • Glomerular Mesangium / cytology
  • Glomerular Mesangium / physiology
  • Humans
  • In Vitro Techniques
  • Kidney / cytology*
  • Kidney / physiology*
  • Kidney Tubules, Collecting / cytology
  • Kidney Tubules, Collecting / physiology
  • Kidney Tubules, Proximal / cytology
  • Kidney Tubules, Proximal / physiology
  • Male
  • Mice
  • Mice, Inbred Strains
  • Oligonucleotides / pharmacology
  • Phosphorylation
  • Promoter Regions, Genetic / physiology
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-met / genetics*
  • Proto-Oncogene Proteins c-met / metabolism
  • Rats
  • Sp1 Transcription Factor / metabolism*
  • Sp3 Transcription Factor
  • Transcription Factors / metabolism*
  • Transcription, Genetic / physiology

Substances

  • DNA-Binding Proteins
  • Drosophila Proteins
  • Oligonucleotides
  • Proto-Oncogene Proteins
  • SP3 protein, human
  • Sp1 Transcription Factor
  • Sp3 protein, mouse
  • Sp3 protein, rat
  • Transcription Factors
  • Sp3 Transcription Factor
  • Proto-Oncogene Proteins c-met
  • AKT1 protein, human
  • Akt1 protein, Drosophila
  • Akt1 protein, rat
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt