Nuclear Hormone Receptors
Nuclear hormone receptors are a super-family of evolutionarily conserved ligandregulated transcription factors that collectively direct genomic programs for a wide array of biological processes including reproduction, development, metabolism, circadian rhythm and immune response. Nuclear receptors contain six modular regions, A-F. There are 48 genes that encode nuclear receptors in humans, and these receptors can be subdivided into three main groups based on the nature of their cognate ligand, which they bind with high affinity and specificity.
Steroid hormone receptors
The members of the steroid binding receptors are Glucocorticoid Receptor (GR), Estrogen Receptor (ER) α and β, Progesterone Receptor (PR), Mineralocorticoid Receptor (MR), and the Androgen Receptor (AR). These receptors bind DNA as homodimers in order to regulate transcription.
Non-steroid hormone receptors
Non-steroid binding receptors include Thyroid hormone receptors (TRs), Peroxisome proliferator-activated receptors (PPARs), the vitamin D3 receptor (VDR), Retinoic acid receptors (RARs), Farnesoid X Receptor (FXR) and Retinoid X receptor (RXR), etc. Other members of this group include Liver X Receptors (LXRs), which use oxysterols and glucose as ligands, steroidogenic factor 1 (SF-1) and Liver receptor homolog 1 (LRH-1), which use phospholipids as ligands, and Rev-Erbs, which were recently shown to use heme as a ligand.
This group of receptors contains DNA-binding transcription factors such as the Nerve
growth factor IB-like receptors Nur77/NR4A1 and Nurr1/NR4A2, which exhibit the
general domain organization of nuclear receptors but whose natural ligands are not yet
The Androgen Receptor (AR)
Androgens are steroid hormones that stimulate the development and maintenance of male sex characteristics. Examples of androgens include Testosterone (T), Dihydrotestosterone (DHT)-a key metabolite of T, and the predominant androgen found in the prostate in vivo, Dehydroepiandrosterone (DHEA)-a T precursor secreted by the adrenal gland, and synthetic compounds such as methyltrienolone (R1881).
The physiological effects of androgens are mediated by the androgen receptor (AR), which functions as an androgen-regulated transcription factor. In humans, the AR (NR3C4) gene is located on the X chromosome. Inactivating AR gene mutations in humans, and AR gene deletion in mice result in complete androgen-insensitivity/
testicular feminization syndrome (i.e. XY females) and infertility, and late onset obesity in mice. AR mRNA expression in a variety of mouse tissues has been determined and shows the highest levels in tissues from the male reproductive tract (rank order of expression: epididymus > vas deferens > prostate > testes). High expression was also observed in non-reproductive tissues including kidney, adrenal gland and muscle. AR expression in humans is likely similar to that observed in mice.
AR Function in Prostate Epithelial Cells and Cancer
Prostate cancer is described as an adenocarcinoma, because it most likely arises from the epithelial compartment. In mammals, castration results in severe atrophy of the prostate, suggesting that androgens sustain cell survival in the prostate. Immuno-staining of human prostate tissues showed that AR protein is predominantly expressed in the nucleus of differentiated prostate luminal epithelial cells that surround the lumen within the gland. In other studies using polyclonal or monoclonal antibodies against the AR N-terminus, the basal epithelial cells (proliferating cells located adjacent to the basal lamina) showed little to no AR immunoreactivity in the human or rat prostate. In situ hybridization studies on human prostate tissues detected AR mRNA in basal cells, and RT-PCR studies detected AR mRNA in cultured proliferating human prostate epithelial cells. Therefore, while the AR gene is expressed in both basal and luminal epithelial cells, it is possible that translation of AR mRNA is more efficient, or that AR protein is more stable in luminal compared to basal cells.
In normal prostate epithelial cells, AR is thought to drive luminal cell differentiation. Prostate epithelia-specific “knock-out” of AR reduced expression of luminal cell markers such as Nkx3.1 and probasin, and increased epithelial cell proliferation detected by BrdU-incorporation, leading to hyperplasia; and these effects were reversed by re-introduction of AR. Androgen stimulation of proliferating human prostate epithelial cells transduced with AR in culture, reduces expression of c-Myc and Bcl-2 (which drive cell proliferation and survival, respectively), and leads to terminal differentiation and expression of keratins 8 and 18, and prostate specific antigen (PSA), indicative of a luminal phenotype.
In contrast, androgen stimulation results in increased proliferation of AR-positive prostate cancer cells such as LNCaP. Prostate cancer is primarily an androgen-dependent disease that is thought to stem from prostatic intraepithelial neoplasia (PIN), a precursor condition indicating proliferation of luminal epithelial cells. Aggressive prostate cancer exhibits loss of the basal lamina and invasion of surrounding tissues by proliferating malignant cells.
JEROME C. NWACHUKWU. FUNCTION OF ANDROGEN RECEPTOR TRAPPED CLONE-27 IN PROSTATE CANCER CELLS