Ring Finger Protein 14 (RNF14, ARA54, Triad2) belongs to the ring between ring fingers (RBR) family []. It is an E3 ubiquitin ligase that acts on unknown substrates and has autoubiquitination activity []. It is an enhancer of the Wnt-dependent transcriptional outputs acting at the level of the TCF/LEF-beta-catenin complex [, ]. It may function as an AR (androgen receptor) coactivators to induce AR target gene expression []. RNF14 may play a regulatory role in mitochondrial and immune gene expression [].
This entry includes animal ARIP4 and its homologues from fungi and plants. ARIP4 contains a SNF2 ATPase domain and is an active DNA-dependent ATPase that activate AR (androgen receptor) function []. The Drosophila homologue, XNP, interacts with DLP (DAXX-like protein) and is involved in heterochromatin assembly and maintenance [].
BAP18 is a component of chromatin complexes such as the MLL1/MLL []and NURF. It has been shown to facilitate the recruitment of MLL1 subcomplex and androgen receptor (AR) to androgen-response element (ARE) of AR target genes []. BAP18 contains a SANT domain.
AT-rich interactive domain-containing protein 4B (ARID4B) acts as a transcriptional repressor. It may function in the assembly and/or enzymatic activity of the Sin3A corepressor complex or in mediating interactions between the complex and other regulatory complexes []. It may play an integral part in the AR (androgen receptor) and RB (retinoblastoma) regulatory pathways involved in the regulation of Sertoli cell function and male fertility []. It is linked to tumor growth and metastasis [].
Nuclear receptor coactivator 4, also known as ARA70, is a coactivator for the androgen receptor (AR) []and can function as a ligand-enhanced coactivator of PPARgamma. AR can suppress PPARgamma-ARA70 transactivation, suggesting cross-talk between PPARgamma- and AR-mediated responses in adipocytes []. NCOA4 has been identified as a selective cargo receptor for the autophagic turnover of ferritinin, a critical process for regulation of iron homeostasis [, ].
MYSM1 (MEROPS identifier M67.005) is a deubiquitinase specific for monoubiquitinated histone H2A (uH2A). It is a positive regulator of androgen receptor (AR) activity on an AR responsive element (ARE)-containing reporter gene []. It plays important regulator roles in hematopoietic stem cell function, blood cell production and immune response []. It has been shown to represses innate immunity and autoimmunity through suppressing the cGAS-STING Pathway [].
Ubiquitously expressed transcript protein UXT is involved in gene transcription regulation. It acts in concert with the corepressor URI1 to regulate androgen receptor transcription (AR). It is an AR N terminus-associated coactivator which may play a role in facilitating receptor-induced transcriptional activation []. It is a protein which interacts with the N terminus of the Down's syndrome candidate region 1 (DSCR1) protein, encoded by a gene located in the human chromosome 21. DSCR1 interacts with calcineurin and is overexpressed in Down's syndrome patients. UXT, which is encoded in human Xp11, is a 157-amino acid protein present in both cytosol and nucleus of the cells []. The members of this family are related to prefoldin, which is part of a molecular chaperone system that promotes the correct folding of nascent polypeptide chains. Prefoldin interacts with the nascent chain to stabilise it prior to its folding within the central cavity of a chaperonin. Prefoldin is a hexamer consisting of two types of subunits, alpha and beta. Archaeal prefoldin contains one type of alpha and one type of beta subunit [], while eukaryotic prefoldin contains two different but related alpha subunits and four related beta subunits [].
Steroid or nuclear hormone receptors (NRs) constitute an important super-family of transcription regulators that are involved in diverse physiological functions, including control of embryonic development, cell differentiation and homeostasis. Members include the steroid hormone receptors and receptors for thyroid hormone, retinoids and 1,25-dihydroxy-vitamin D3. The proteins function as dimeric molecules in the nucleus to regulate the transcription of target genes in a ligand-responsive manner [, ]. NRs are extremely important in medical research, a large number of them being implicated in diseases such as cancer, diabetes and hormone resistance syndromes. Many do not yet have a defined ligand and are accordingly termed "orphan"receptors. More than 300 NRs have been described to date and a new system has recently been introduced in an attempt to rationalise the increasingly complex set of names used to describe superfamily members.The androgen receptor (AR) consists of 3 functional and structural domains: an N-terminal (modulatory) domain; a DNA binding domain () that mediates specific binding to target DNA sequences (ligand-responsive elements); and a hormone binding domain. The N-terminal domain (NTD) is unique to the androgen receptors and spans approximately the first 530 residues; the highly-conserved DNA-binding domain is smaller (around 65 residues) and occupies the central portion of the protein; and the hormone ligand binding domain (LBD) lies at the receptor C terminus. In the absence of ligand, steroid hormone receptors are thought to be weakly associated with nuclear components; hormone binding greatly increases receptor affinity. The LBDs of steroid hormone receptors fold into 12 helices that form a ligand-binding pocket. When an agonist is bound, helix 12 folds over the pocket to enclose the ligand []. When an antagonist is unbound, helix 12 is positioned away from the pocket in a way that interferes with the binding of coactivators to a groove in the hormone-binding domain formed after ligand binding. In AR, ligand binding that induces folding of helix 12 to overlie the pocket discloses a groove that binds a region of the NTD. Coactivator molecules can also bind to this groove, but the predominant site for coactivator binding to AR is in the NTD. AR ligand resides in a pocket and primarily contacts helices 4, 5, and 10. The DNA-binding region includes eight cysteine residues that form two coordination complexes, each composed of four cysteines and a Zn2+ion. These two zinc fingers form the structure that binds to the major groove of DNA. The second zinc finger stabilises the binding complex by hydrophobic interactions with the first finger and contributes to specificity of receptor DNA binding.It is also necessary for receptor dimerisation that occurs during DNA bindingDefects in the androgen receptor cause testicular feminisation syndrome,androgen insensibility syndrome (AIS) [, ]. AIS may be complete (CAIS), where external genitalia are phenotypically female; partial (PAIS), where genitalia are substantively ambiguous; or mild (MAIS), where external genitalia are normal male, or nearly so. Defects in the receptor also cause X-linked spinal and bulbar muscular atrophy (also known as Kennedy's disease).
