Synergy of SF1 and RAR in activation of Oct-3/4 promoter

The Oct-3/4 transcription factor is expressed in the earliest stages of emb ryogenesis, and is thus likely to play an important role in regulation of i nitial decisions in development For the first time, We have shown that SF1 and Oct-3/4 are co-expressed in embryonal carcinoma (EC) P19 cells, and the ir expression is down-regulated with very similar kinetics following retino ic acid (RA) induced differentiation of these cells, suggesting a functiona l relationship between the two. Previously, Re have shown that the Oct-3/4 promoter harbors an RA-responsive element, RAREoct, which functions in EC c ells as a binding site for positive regulators of transcription, such as RA R and RXR. In this study we have identified in the Oct-3/4 promoter two nov el SF1-binding sites: SF1(a) and SF1(b). The proximal site, SF1(a), is loca ted within the RAREoct, and the distal site, SF1(b), is located between nuc leotide -193 and -209 of the Oct-3/4 promoter. Both sites contribute to act ivation of Oct-3/4 promoter in EC cells, with SF1(a) playing a more crucial role. SF1, and its isoforms ELP2 and ELP3 bind to both SF1 sites and activ ate the Oct-3/4 promoter. This activation depends on the presence of SF1 DN A-binding domain. Thus, Oct-3/4 is the first EC-specific gene reported that is regulated by SF1. Interestingly, SF1 and RAR form a novel complex on th e RAREoct sequence that synergistically activate the Oct-3/4 promoter. Both RARE and SF1 cis regulatory elements, as well as the SF1 DNA-binding domai n, are needed for this synergism, SF1 and Oct-3/4 transcription factors pla y a role in the same developmental regulatory cascade.