New concepts in steroid hormone action: transcription factors, proto-oncogenes, and the cascade model for steroid regulation of gene expression.

The past 6 years have seen a significant increase in our understanding of steroid receptor-mediated regulation of gene transcription. As a means to understanding receptors as transcriptional activators, several steroid receptor genes have been identified, cloned, and are now known to belong to a receptor superfamily. All steroid receptors possess conserved domains which confer various aspects of receptor function such as those that regulate DNA and steroid binding. In addition to the distinct intrinsic functions of these domains, nonreceptor proteins associated with the unactivated forms of the receptor appear to play a crucial role in receptor function. One such protein, hsp90, is speculated to stabilize the unactivated form of the receptor in the absence of hormone. Posttranslational modification also appears to be important in regulating the transcriptional activity of steroid receptors. Steroid receptors may exist in several phosphorylation states, each intimately linked to steps involved in the conversion of the newly synthesized protein to the steroid-bound form capable of transcriptional activation. The activated steroid-receptor complexes bind to chromatin "acceptor sites", the composition of which is presently under investigation. Steroid response elements, DNA-binding "acceptor" proteins in the nuclear matrix, and transcription factors and their elements appear to play a role in this binding and in the transcriptional control of genes exerted by steroid receptors. Different genes utilize different elements and factors for each particular steroid receptor species, reflecting the steroid- and gene-specific patterns of regulation of gene expression. In this review, a cascade model is used to explain how the receptor interaction with specific sites upstream of "regulatory (early) genes" may regulate a variety of steps in gene expression from transcription and mRNA half-life to protein processing. This model not only accounts for the paradoxical "lag phase" observed between steroid treatment and structural gene transcription, but also shows how steroid-regulated gene expression may occur an posttranscriptional steps. The rapid regulation of the nuclear proto-oncogenes, e.g., c-myc, c-fos, and c-jun, are used as examples of these early regulatory genes in steroid-regulated, receptor-mediated gene transcription.