Repression Steroid hormone receptor

Enzymes that are involved in steroid hormone biosynthesis or in steroid metabolism are also targets of anti-hormonal therapy. Recently, it was discovered that certain co-factors modulate the signalling of steroid hormone receptors in a tissue-selective fashion. By binding the receptor ligand complex, these co-activators and co-repressors are capable of either activating or repressing transcription, respectively [5j. 

The steroid hormone receptors can not only activate transcription, but can also repress transcription (review Beato, 1995). This function is mechanistically poorly understood. Repression by nuclear receptors has been observed for genes whose control regions have, apart from the HREs, binding sites for other transcription factors, e.g. AP-1 and NFxB. In AP-1 and NFxB controlled genes it has been observed that the steroid hormone receptors have an inhibitory effect on the transcription activation of both transcription factors. The mechanism of this mutual interaction remains unclear. 

The observation that steroid hormone receptors act as activators as well as repressors of gene activity suggests that receptors can assume an activating and a repressing conformation. In the latter state, the transcriptional activating domain of the receptors is masked. 

Secretion of ecdysone starts the many biochemical processes that are necessary for the molting. The cells in the epidermis are stimulated to produce a new cuticle, and when ready, the insect will creep out of its old skin. The molecular mechanism of ecdysone has been studied in some detail. The molecular target of ecdysone and other ecdysteroids consists of at least two proteins, the ecdysteroid receptor (EcR) and ultraspiracle (USP). Both EcR and USP are members of the steroid hormone receptor superfamily with characteristic ligand-binding domains. An EcR-USP-ecdysteroid complex is formed, which activates several genes that code for transcription factors, i.e., proteins that activate or repress the activity of other genes, and the appropriate amounts of proteases and other enzymes necessary to degrade old structures and rebuild new ones are formed in a time-controlled sequence. 

The vitamin D receptor (VDR/NR1I1) is a member of the superfamily of steroid hormone receptors. It regulates calcium homeostasis, cell proliferation, and differentiation, and exerts immunomodulatory and antimicrobial functions [119]. VDR binds to and mediates the calcemic effects of calcitriol (la,25-dihydroxy vitamin D3) after forming an heterodimer with RXR. la,25-dihydroxyvitamin D3 negatively regulates its own synthesis by repressing the 25-hydroxyvitamin D3 la-hydroxylase (CYP27B1) in a cell-type selective event that involves different combinations of multiple VDR response elements [120, 121]. 

Steroid hormones penetrate the cell and bind to receptors in the nucleus, and activate (or sometimes repress) transcription of specific genes. Thyroid hormones act similarly. 

Steroid hormones both increase and decrease the levels of gene expression to give induction and repression, respectively. However, it is not yet clear whether all HRE-bound receptor-agonist complexes are transcriptionally active (77). A major unanswered question is how superficially similar steps can cause opposite responses. As described, the HREs for gene induction and repression are different. Repression is often achieved via receptors that are tethered to a different DNA-bound protein (97, 98) but see (99) as opposed to the... 

---