The concerted regulatory functions of the transcription factors nuclear factor-1 and upstream stimulatory factor on a composite element in the promoter of the hepatocyte growth factor gene

Hepatocyte growth factor (HGF) is an important multifunctional cytokine who se gene expression is regulated mainly at the transcriptional level, Previo us studies using transgenic mice as well as in vitro analyses showed that a potential regulatory element(s) exists between -260 to -230 bp in the upst ream region of the HGF gene promoter. In the present study, me have discove red that this region is a composite site through which members of the nucle ar factor 1 (NF1) and upstream stimulatory factor (USF) families bind to an d regulate HGF gene transcription. Gel mobility shift and supershift assays revealed that USF and NF1 have high binding affinity for this region and t hat the binding sites of the two different transcription factor families ov erlap. Functional studies showed that NF1 suppresses HGF gene promoter acti vity and that USF has an activating function, We found that the NF1/X and N F1/Red1 isoforms strongly suppressed HGF promoter activity while the NF1/L variant had no obvious effects. USF1, but not USF2, of the USF family stimu lated HGF gene promoter activity, More interestingly, during liver regenera tion after partial hepatectomy, a process which activates the HGF gene, we noted that the binding activity of USF to the HGF promoter element increase d while that of NF1 decreased. These data provide insight into the molecula r mechanisms that govern HGF gene transcription.