Positive and negative elements modulate the promoter of the human liver-specific alpha 2-HS-glycoprotein gene

The human alpha 2-HS-glycoprotein (AHSG) and the 63-kDa rat phosphoprotein (pp63) are homologous plasma proteins that belong to the fetuin family. AHS G and pp63 are involved in important functions such as inhibition of insuli n receptor tyrosine kinase activity, inhibition of protease activities, and regulation of calcium metabolism and osteogenesis. Studies of the AHSG pro ximal promoter performed in vitro, in rat and human cells indicate that sev eral NF-1 and C/EBP binding sites exert a positive effect on its transcript ional activity. However, until now, no distal elements have been examined i n this gene, in either species. We report that the human AHSG gene promoter acts in a liver-specific manner and is further controlled by three distal, 5'-flanking elements. The negative elements III and I are, respectively, l ocated 5' and 3' of the positive element II. All three elements require the natural context of the human AHSG gene to fully exert their negative or po sitive effect. Element I harbours a single binding site for NF-1. This nucl ear factor thus appears to be able to up- or downregulate the AHSG gene dep ending on the site it binds to. Elements I, II and possibly III are absent in the rodent Ahsg gene encoding pp63.