Chick Ovalbumin Upstream Promoter-Transcription Factors (COUP-TFs): Coming of Age*

THE steroid/thyroid hormone receptor (TR) superfamily of proteins consists of many ligand-activated transcriptional regulators and a rapidly growing number of orphan receptors (1–7). Among the orphan receptors, Chick Ovalbumin Upstream Promoter-Transcription Factor (COUP-TF) is one of the best characterized. COUP-TF was first identified as a homodimer that binds to a direct repeat regulatory element in the chicken ovalbumin promoter (8–10). This element contains an imperfect direct repeat of AGGTCA sequence, which has been shown to be essential for efficient in vitro transcription of the chicken ovalbumin promoter (8, 9, 11). In the late 1980s, our laboratory successfully purified COUP-TF from HeLa cell nuclear extracts using a combination of conventional and DNA affinity column chromatographic techniques (10, 12). A polyclonal antibody was then generated against the purified material and used to screen a HeLa cell cDNA library (10). A clone that cross-reacted with both the antibody and COUP-TF-binding site was obtained and designated as human COUP-TFI (hCOUP-TFI) (10). In 1988 hCOUP-TFI was also cloned independently by another group via homology to human erbA and named EAR-3 (13). Sequence analysis revealed that COUP-TFI is a member of the steroid/TR superfamily. Subsequently, hCOUP-TFII was cloned based on its high homology to hCOUP-TFI (14). hCOUP-TFII was also cloned independently by another group as an apolipoprotein AI-regulatory protein-1 (ARP-1) from a placental library (15). Through homology screening, homologs of COUP-TFs from many different species have been identified (16, 17), and their expression patterns have been analyzed.