Orphan receptors, proto-oncogenes and other nuclear factors regulate P450c17 gene transcription

Concerted, regulated expression of the rat P450c17 gene relies on the combi ned participation of multiple DNA regions and factors that bind to these se quences. SF-1 binds to at least two different regions, and has activities d ependent upon the DNA context. COUP-TF, NGF-IB, together with SF-1, bind to overlapping regions, and the interaction among these factors increases or decreases transcription. A newly identified factor, the proto-oncogene SET, binds to a portion of the COUP-TF site, and strongly activates P450c17 tra nscription. SET mRNA is highly expressed early during development, and its expression decreases thereafter. P450c17 expression is not restricted to st eroidogenic tissues, but rather is highly expressed in specific locations i n the central (CNS) and peripheral nervous systems (PNS) during development , where its steroidal products may regulate neuronal maturation. We have sh own that physiologic concentrations of steroids derived from P450c17 activi ty, DHEA and DHEAS, have direct and distinct effects on neocortical axonal and dendritic growth and differentiation. In the CNS and PNS, SET mRNA is e xpressed in regions where we previously reported P450c17 expression. The on togeny of SET expression in CNS and PNS tissues as well as in steroidogenic tissues precedes P450c17 expression, suggesting that in addition to regula ting P450c17 gene transcription in adrenals and gonads, SET may be crucial for the regulation of P450c17 gene transcription in the CNS and PNS as well .