The hepatocyte nuclear factor-3/forkhead transcription regulatory family in development, inflammation, and neoplasia

Abstract

HNF-3/FKH genes are a large family of transcriptional activators. They are expressed in specific developmental and tissue patterns. Indeed, several of them are known to be essential for normal development (e.g. Dfkh and slp-1,2). Mutation within one of these genes produces mutant fruitfly embryos that are unable to survive. This family shares conserved DNA binding and transcriptional activation domains. The DNA binding domain has been crystallized, and its structure determined. Although it has resemblance to helices of homeodomains and H5 histones, it represents a new DNA binding motif, which has been called the 'winged helix,' because it contains additional interactive peptide regions called termed wings. Subtle amino acid variations in a region adjacent to the DNA recognition helix influence the recognition specificity of each HNF-3/FKH protein and therefore confer selectivity in promoter regulation. Members of this family are important in regulating the inflammatory response of the liver (the three HNF-3 genes). In addition, several members may be important in blood cell development (H3 and 5-3). Finally, two of these genes have been found to produce neoplasia (qin and FKHR). As investigation progresses, the mechanism by which these genes regulate development, inflammation and neoplasia will become more clear.