eroid hormones, androgens are derived from cholesterol; their biosynthesis is tightly regulated by the hypothalamus-pituitary-gonadal axis. Testosterone or DHT bind to the androgen receptor to initiate the androgen signaling pathway. The receptor is a member of the nuclear receptor superfamily of ligand activated transcription factors. It is composed of several functional domains: the N-terminal regulatory domain (NTD) containing glutamine (CAG) and glycine repeats, the DNA binding domain (DBD), a hinge region and the ligand binding domain (LBD). In the absence of the ligand the receptor is localized in the cytoplasm and complexed with heat shock proteins. The interactions appear to involve the LBD domain of the receptor and the role of the chaperones is to maintain the receptor into a partially unfolded but ligand primed state. Several such chaperones are believed to constitute a minimal heterocomplex for all steroid hormone receptors, known as the 'foldosome'. The formation of the foldosome is thought to proceed in an assembly-line fashion. Upon ligand binding, the complex translocates to the nucleus where the receptor dissociates from the chaperones. The DBD contains two zinc-fingers of which one appears to mediate recognition of androgen-response elements (ARE) while the second stabilizes the DNA-bound receptor and facilitates dimerization. The receptor binds to the direct-repeat response elements as head-to-head dimer. A wide array of coregulators interacts with the receptor to modulate its transcriptional activity; the NTD domain is a major site of interaction. There are over 130 potential coregulators acting as coactivators or corepressors that belong to several distinct functional classes - chromatin remodeling, histone and various protein modification types, cell cycle and DNA repair, general and specific transcription factors, structural proteins and others. Various methods have led to their identification but for many further experiments are necessary to ascertain a bona fide androgen receptor coregulator function. Important issues to elucidate are: how the receptor accommodates such an array of interactions, how these interactions integrate into the tapestry of androgen signaling pathway. Up-regulation of the pathway has been observed in prostate cancer; it is mostly due to amplification of the receptor or acquired mutations that render the receptor promiscuous and responsive to a variety of molecules.  In addition, changes in testosterone, DHT and/or coactivators levels have also been proposed to play a role in the enhanced androgen signaling activity associated with the disease. To see the ontology report for annotations, GViewer and downloads, click here
[click to see the ontology report for related GO term - GO:0030521]

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