Steroid Hormone Regulation of Nuclear Proto-oncogenes*

The role of the nuclear proto-oncogenes as rapidly responding nuclear regulators in the cascade model for steroid hormone action is proposed. In this model, the nuclear proto-oncogenes respond within minutes to steroids and would code for regulatory proteins that in turn enter the nucleus to positively or negatively regulate "late" structural gene transcription and mRNA processing. The potential involvement of the nuclear matrix and one of its components, a receptor binding factor (RBF-1) for steroid receptors of these genes, is discussed. The nuclear proto-oncogenes, thus, may serve as important "early" regulatory genes and as excellent universal markers in all tissues in steroid hormone action. Proto-oncogenes are known to be regulatory genes since genetic alterations of amplification, mutations, chromosome translocation, and other rearrangements which result in overexpression, inactivation, and/or loss of regulatory control result in malignant transformation of the cell. It is now known that as many as six different proto-oncogenes must undergo alteration to induce the loss of cellular control of replication and/or for transformation to occur. The nuclear oncogenes, representing only one class of several of the known proto-oncogenes, code for transcription factors and enzymes involved in regulating these factors and other features of gene transcription. Possibly RNA processing is another function. Many of these genes and their responses to steroids are described in this chapter. The steroid receptors belong to a family which themselves represent transcription factors in that they reside in the nucleus and bind to specific DNA elements or other transcription factors to alter gene transcription and/or mRNA processing. The receptors for the various steroids are described as having a common structural motif and function using the above mentioned pathways. In the majority of cases cited, the steroid receptors mediate the rapid regulation of the nuclear proto-oncogene transcription. The role of palindromic SRE in or near these genes is to bind steroid hormone receptor dimers to regulate transcription. More powerful steroid response units (SRU), composed of two or more response elements for steroids or transcription factors, can act at great distances from the gene as enhancers for steroid- regulated transcription. What has become obvious from the studies of steroid effects on nuclear proto-oncogenes, is that, despite the tremendous scientific strides that have been made toward understanding gene regulation by steroids, we are still relatively naive.(ABSTRACT TRUNCATED AT 400 WORDS)