THE ALPHA(1)-FETOPROTEIN LOCUS IS ACTIVATED BY A NUCLEAR RECEPTOR OF THE DROSOPHILA FTZ-F1 FAMILY

The alpha(1)-fetoprotein (AFP) gene is located between the albumin and alpha-albumin genes and is activated by transcription factor FTF (fet oprotein transcription factor), presumed to transduce early developmen tal signals to the albumin gene cluster. We have identified FTF as an orphan nuclear receptor of the Drosophila FTZ-F1 family. FTF recognize s the DNA sequence 5'-TCAAGGTCA-3', the canonical recognition motif fo r FTZ-F1, receptors. cDNA sequence homologies indicate that rat FTF is the ortholog of mouse LRH-1 and Xenopus xFF1rA. Rodent FTF is encoded by a single-copy gene, related to the gene encoding steroidogenic fac tor 1 (SF-1). The 5.2-kb FTF transcript is translated from. several in -frame initiator codons into FTF isoforms (54 to 64 kDa) which appear to bind DNA as monomers, with no need for a specific ligand, similar K (d)s (similar or equal to 3 x 10(-10) M), and similar transcriptional effects. FTF activates the AFP promoter without the use of an amino-te rminal activation domain; carboxy; terminus-truncated FTF exerts stron g dominant negative effects. In the AFP promoter, FTF recruits an acce ssory trans-activator which imparts glucocorticoid reactivity upon the AFP gene. FTF binding sites are found in the promoters of other liver -expressed genes, some encoding liver transcription factors; FTF, live r alpha 1-antitrypsin promoter factor LFB2, and HNF-3 beta promoter fa ctor UF2-H3 beta are probably the same factor. FTF is also abundantly expressed in the pancreas and may exert differentiation functions in; endodermal sublineages, similar to SF-1 in steroidogenic tissues. HepG 2 hepatoma cells seem to express a mutated form of FTF.