Orphan receptors, proto-oncogenes and other nuclear factors regulate P450C17 gene transcription

Concerted, regulated expression of the rat P450c17 gene relies on the combined participation of multiple DNA regions and factors that bind to these sequences. SF-1 binds to at least two different regions, and has activities dependent 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 transcription. SET mRNA is highly expressed early during development, and its expression decreases thereafter. P450c17 expression is not restricted to steroidogenic tissues, but rather is highly expressed in specific locations in the central (CNS) and peripheral nervous systems (PNS) during development, where its steroidal products may regulate neuronal maturation. We have shown that physiologic concentrations of steroids derived from P450c17 activity, DHEA and DHEAS, have direct and distinct effects on neocortical axonal and dendritic growth and differentiation. In the CNS and PNS, SET mRNA is expressed in regions where we previously reported P450c17 expression. The ontogeny of SET expression in CNS and PNS tissues as well as in steroidogenic tissues precedes P450c17 expression, suggesting that in addition to regulating 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.