TRANSCRIPTIONAL CONTROL BY NUCLEAR RECEPTORS

Gene regulation by steroid hormones is accomplished by a variety of different mechanisms leading to induction or repression of particular genes. These mechanisms are all mediated by a single class of intracellular hormone receptors, which in the unliganded state are maintained in an inactive form by association with other cellular proteins, including hsp90. Induction of the mouse mammary tumor virus (MMTV) requires binding of the hormone receptor to a hormone-responsive element (HRE) that is precisely organized in a phased nucleosome. After receptor binding, changes in chromatin structure are detected that correlate with binding of transcription factors, including nuclear factor I, to the MMTV promoter. However, although nuclear factor I acts as a basal transcription factor on the MMTV promoter it does not cooperate with the hormone receptors in terms of binding to free DNA, and mutation of the nuclear factor I binding site does not eliminate hormonal stimulation. This residual induction is mediated by octamer motifs upstream of the TATA box that bind the ubiquitous transcription factor OTF-1. Mutation of these octamer motifs does not influence basal transcription in vitro, but completely abolishes the stimulatory effect of progesterone receptor. Glucocorticoids also inhibit expression of many genes. The effect on the gene for the alpha-subunit of chorionic gonadotropin is due to DNA binding competition between the receptor and the protein mediating cAMP induction, whereas repression of the collagenase gene involves an interaction of the receptor with components of the AP1 complex, Jun and Fos. - Beato, M. Transcriptional control by nuclear receptors.