Transcriptional Induction of the agp/ebp ( c/ebp β) Gene by Hepatocyte Growth Factor

Abstract

Hepatocyte growth factor (HGF) is a pleiotropic factor with mitogenic, morphogenic, motogenic, cytotoxic, or growth inhibitory activity. Although the signaling of HGF is mediated through the cell membrane receptor c-Met, the molecular mechanism of downstream signal transduction remains obscure. In this report, we present evidence that shows HGF can stimulate the expression of AGP/EBP (C/EBPβ) and NF-κB, which are both key transcription factors responsible for the regulation of many genes under stress conditions or during the acute-phase response. Biochemical and functional analysis indicates that the HGF-responsive element is located in the region -376 to -352 (URE1) of the 5′-upstream regulatory sequence of agp/ebp. Activation of NF-κB by HGF was observed to precede the induction of agp/ebp. Further studies indicate that NF-κB can cooperate with AGP/EBP or other members of the C/EBP family to activate the agp/ebp gene in both URE1 and URE2-dependent manner. These results suggest that the induction of the agp/ebp gene by HGF is mediated at least in part by its activation of NF-κB. The activated NF-κB then interacts with AGP/EBP, resulting in the induction of agp/ebp.