A NOVEL TRANSCRIPTIONAL REGULATORY REGION WITHIN THE CORE PROMOTER OFTHE HEPATOCYTE GROWTH-FACTOR GENE IS RESPONSIBLE FOR ITS INDUCIBILITYBY CYTOKINES VIA THE C EBP FAMILY OF TRANSCRIPTION FACTORS/

Hepatocyte growth factor (HGF) is an inducible cytokine that is essent ial for the normal growth and development of various tissues, such as the liver, To decipher the molecular mechanisms that regulate HGF gene induction at the transcriptional level, we carried out in vitro and i n vivo studies on the mouse HGF gene promoter. We have identified a no vel regulatory element, located between -6 and +7 bp (from the transcr iption start site) in the HGF basal promoter region, which binds to in ducible transcription factors and dictates responsiveness to extracell ular stimuli that activate this gene. The core binding sequence for th e inducible cis-acting factors was determined to be TTTGCAA (-4 to +3 bp) within the HGF promoter. Competition and gel mobility supershift a ssays showed that these binding complexes are composed of C/EBP beta ( CCAAT/enhancer binding protein beta) and C/EBP delta, DNA binding anal ysis also revealed that the binding site for the C/EBP family of trans cription factors in the HGF promoter region overlaps that of another b inding protein (complex C1), which binds specifically to a novel seque nce with a core binding site of ACCGGT located adjacent to the C/EBP s ite (-9 to -4 bp). C1 binds to this region of the promoter and repress es the inducible upregulation by C/EBP through direct competition for their individual binding sites, Partial hepatectomy which is known to activate HGF gene expression in the liver, increased C/EBP (especially C/EDP beta) binding activity to this region of the HGF promoter, Thus , our present results provide a mechanistic explanation for the transc riptional induction of the HGF gene by extracellular signals (i.e., cy tokines) that induce tissue growth and regeneration.