Nuclear Receptors--Orphan Receptors

10 July, 1998

Nuclear Receptors--Orphan Receptors

Lipophilic ligands (steroid hormones, thyroid hormones, vitamin D3) bind to nuclear receptors to exert transcriptional stimulation. Since glucocorticoid receptor gene was cloned in 1985, 47 nuclear receptor genes have been identified so far (6 steroid receptor genes, 17 RAR/RXR dimerization partner genes, 10 dimeric orphans, 14 monomeric orphans) and form a nuclear receptor family. However, only a few of the ligands for these nuclear receptors are known thus those without cogante ligands identified are termed as "orphan receptors. It is quite likely that some of these orphan receptors are putative coactivators and/or corepressors that interact with hormone receptor complex. In fact, it was reported recently that a receptor-interacting factor, SMRT, is a silencing mediator (co-repressor) for retinoid and thyroid-hormone receptors and that the ligand hormone destabilizes the association of the receptor with SMRT (Chen JD et al. 1996: uid=96353857). The hypothetical notion here is that nuclear hormone receptors repress transcription in the absence of ligand in associations with nuclear hormone receptor corepressors and that ligand binding by the hormone receptor dissociates these corepressors and recruit coactivators to promote transcription from target promoters.
The transcriptional activation is not necessarily meant for cell growth. In human bronchial epithelial (HBE) cells, for instance, all trans-retinoic acid increases the levels of nuclear E2F-4, p107, and p130 and enhances the binding of E2F-4 to p107 that are associated with the conversion of E2F into a transcriptional suppressor (Lee HY et al. 1998: uid=98153227). The E2F transcription factor thus plays a role in G0 entry through transcriptional suppression of genes that induce cell cycle progression. Incidentally, retinoid-induced growth arrest found in normal HBE is thought to have implications for the use of retinoids in clinical trials on the prevention of lung cancer.

The research on nuclear and orphan receptors is extremely active at this moment that a comprehensive project: the Nuclear Receptor Resource (NRR) has been formed to offer and integrate information on glucocorticoid, androgen, mineralocorticoid, thyroid hormone, Vitamin D and more recently-discovered peroxisome-proliferator activated receptors. This project should help accelerate the progress in this area. In drug development, biological specificity is one of the most essential nature for a successful drug to possess. As the hormone is a most specific biological molecule, chances are that still unidentified ligands for orphan receptors are involved in essential physiological processes, aberration of which would lead to specific diseases. Transcriptional profiles of these orphan receptors could offer causative clues to human diseases.

Please send your comments and ideas through e-mail form at this website.

(go back to top)

Home | Site Map | Contact Us | About iHumans | Alliance and R&D Collaboration | Seach Executives and Scientists | Job Openings and Opportunities | Health Care | News and Commentaries | ニホン語のページ (Japanese Pages) |