A critical function of USF in HGF gene regulation mediated by a multiconsensus region.
Hepatocyte growth factor (HGF) is a multifunctional growth factor implicated in a variety of tissue restructuring processes. Since HGF acts as a highly potent mitogen, HGF expression is suggested to be under a well-defined transcriptional control. The 5' sequence of the HGF gene clusters a set of several binding sites for transcription factors in a so-called multiconsensus region (MCR) located between -230 and 260. Our studies demonstrate that a NF1-like element and the E(1)-box of the MCR form the main complexes with nuclear proteins and that both are involved in transcriptional silencing of the HGF gene in non-HGF expressing cell types. The E(1)-box of two tandemly arranged E-boxes was shown to be a binding site of high affinity interacting with the upstream stimulatory factor (USF). While recombinant expression of a wild-type USF did not affect gene expression, a USF variant lacking the DNA binding domain restored the MCR mediated transcriptional repression. In conclusion, our data provide evidence that USF is a central factor of cell-type specific HGF regulation, acting in cooperation with additional regulatory proteins as a bivalent mediator of transcriptional activation or repression.
Odenthal
M
M
Institute for Pathology, University Clinic of Cologne, Joseph Stelzmann Str. 9, Koeln, Germany. m.odenthal@uni-koeln.de
Spindler
M P
MP
Kerres
K
K
Dienes
H P
HP
Schirmacher
P
P
D000818:Animals; D002460:Cell Line; D016384:Consensus Sequence / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D017228:Hepatocyte Growth Factor / Q000235:genetics* / Q000378:metabolism; D016350:Leucine Zippers; D051379:Mice; D008954:Models, Biological; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D051381:Rats; D014157:Transcription Factors / Q000378:metabolism*; D051720:Upstream Stimulatory Factors
D004268:DNA-Binding Proteins; D014157:Transcription Factors; D051720:Upstream Stimulatory Factors; C497183:Usf1 protein, mouse; C497182:Usf1 protein, rat; D017228:Hepatocyte Growth Factor