SEVERAL TRANSCRIPTION FACTORS PARTICIPATE IN THE FUNCTIONING OF THE ALPHA-FETOPROTEIN PROMOTER

The oncodevelopmentally regulated alpha-fetoprotein (AFP) gene offers a very good model system to better understand the molecular mechanisms which dictate the specificity of gene expression in liver and control its light modulation in the course of development and carcinogenesis. Transcription factors of the CCAAT/enhancer-binding protein (C/EBP), hepatocyte nuclear factor-1 (HNF-1), and nuclear factor-1 (NF-1) famil ies can bind in vitro to the promoter of the rat AFP gene, which makes the expression of the AFP gene specific to the liver. We have evaluat ed the influence of some of these factors on the activity of the AFP p romoter by transfection of HepG2 hepatoma cells with the appropriate e xpression vector plus a CAT plasmid under the control of the AFP promo ter. A similar plasmid bearing the rat albumin promoter was used as a control. C/EBP alpha, and C/EBP beta acted as transactivators on the A FP promoter, while LIP, a truncated form of C/EBP beta, was a potent n egative regulator of the promoter. Interestingly, HNF-1 beta was found to be more potent than HNF-1 alpha in activating the AFP promoter in the HepG2 cells. This effect was highly promoter and cell specific sin ce it did not occur with the rat albumin promoter or in Chinese hamste r ovary cells. HNF-1 beta, which is produced earlier than HNF-1 alpha during liver development, would thus have the greater influence on the AFP promoter in early development. Our results pointed to a key role that NF1 might play in the functioning of the AFP promoter. Indeed, ov erexpression of NF1 induced a specific decrease in the activity of the AFP promoter. Competition between NF1 and HNF-1 for binding to their overlapping binding sites on the AFP promoter would be critical for mo dulating its activity.