SEARCH · PubMed Health

Results for “Receptors, Androgen”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources

PubMed2000

The role of estrogen receptor, androgen receptor and growth factors in diethylstilbestrol-induced programming of prostate differentiation.

Recently, others and we have demonstrated that prenatal exposure to an extremely low dose of diethylstilbestrol (DES) and other estrogenic compounds produces a significant effect on mouse prostate development in vivo and in vitro in the presence and absence of androgen. In this study, we investigated the mechanism by which DES produces this effect and determined the role of its estrogenic activity on the growth and branching, induced by DES in the 17-day-old fetal prostate in culture. Additionally, we investigated whether the androgen receptor (AR) plays a role and whether any of the growth factors, namely, EGF and IGF-1 which are known to modulate the estrogen receptor (ER) and androgen receptor (AR)-dependent process, mediate the DES-induced effects. Using the organ culture bioassay of prostate development, we demonstrate that DES enhanced the growth and branching of the prostate at both 0.1 and 0.5 pg/ml dosages, thus, confirming a previous report of ours. An anti-estrogen, ICI164,387 blocked both of the effect of DES, suggesting that both of these two effects are ER dependent. Anti-androgen, flutamide also blocked both branching and prostatic growth induced by DES, while cyproterone acetate blocked only the branching effect, suggesting a role for AR in the DES-induced effects. Depletion of EGF by anti-EGF antibody blocked the DES-induced effects and this was reversed following EGF replacement in the organ culture system. Anti-IGF-1 antibody, on the other hand, only blocked the branching effect, but produced no effect on the prostatic growth, induced by DES. Estrogenic chemicals, bisphenol A and DES enhanced EGF-mRNA level of the cultured prostates. Taken together, it appears that DES-induced prostatic enlargement involves enhancement of ER-dependent EGF and IGF-1 synthesis, mediating prostatic enlargement and androgen action.

Androgen Antagonists↗

PubMed2004

Genetic variations in the vitamin D receptor, androgen receptor and enzymes that regulate androgen metabolism.

PURPOSE: We review the current literature on genetic variations in the vitamin D receptor (VDR), androgen receptor (AR) and enzymes regulating androgen development. MATERIALS AND METHODS: A MEDLINE search was conducted to identify research investigating associations between polymorphisms in important regulatory genes that may indirectly affect cancer risk, with special regard to prostate cancer. RESULTS: Genes involved in androgen regulation, metabolism and their related pathways, and the vitamin D receptor are prime candidates for study of prostate cancer risk. Expression and nuclear activation of the VDR are necessary for the antiproliferative effects of 1alpha,25-dihydroxyvitamin D3 (calcitriol), which is involved in calcium and bone homeostasis. Several genetic variations have been identified in the VDR, and at least 1 VDR polymorphism appears to confer some predictability of prostate cancer risk in various ethnic cohorts. Interactions between the androgen receptor and circulating androgens have a major role in the development of normal and malignant prostate cells. CONCLUSIONS: Due to the relationship between the AR and prostatic growth, it has been proposed that polymorphisms within the AR may have a role in susceptibility to prostate cancer.

Calcitriol↗

PubMed1997

Spermatogenesis in the vitamin A-deficient rat: possible interplay between retinoic acid receptors, androgen receptor and inhibin alpha-subunit.

In order to understand the mechanisms of retinol action on the testis, testicular retinoic acid receptor alpha, beta(RAR alpha and beta), androgen receptor (AR) and inhibin alpha-subunit were studied in normal, vitamin A-deficient (VAD) and vitamin A-supplemented rats by immunohistochemistry and immunoblotting. Compared to the normal testis, expression of 110 K AR was up-regulated by vitamin A withdrawal, whereas 51 K RAR alpha remained unchanged. An additional 55 K RAR alpha signal was observed. Readministration of retinol caused a marked decrease of AR in the VAD testis. By 24 h, AR declined to below the normal level. Although the 51 K RAR alpha signal remained unchanged, the 55 K band was slightly up-regulated at 6 h after retinol administration. A 51 K RAR beta protein was seen in the VAD but in not the normal testis. The intensity of the 51 K RAR beta band remained constant before and after the administration of retinol, but it had a slight up-shift at 6 h after retinol injection, suggesting post-translational modification of the receptor. The inhibin alpha-subunit of 18 K protein was undetectable in the VAD testis and increased to above normal level at 24 h after retinol administration. Immunohistochemically, nuclear AR immunostaining was more intense in the VAD testis than in the normal testis. The intensity of immunostaining declined in all AR-positive cells after the injection of retinol, but the decrease was more evident in Sertoli than in other cells. At 24 h after retinol the immunostaining was undetectable in most Sertoli cells. The regulation of the inhibin alpha-subunit by retinol in the cytoplasm of Sertoli cells detected by immunohistochemistry was correlated to the results in immunoblotting. These results suggest a possible interplay between retinoids, androgen and inhibin signalling systems in Sertoli cells in the regulation of spermatogenesis during retinol action.

Animals↗

PubMed2006

Androgens in female pig reproduction: actions mediated by the androgen receptor.

Androgens have potential actions in almost all the organs of males and females. In females, most organs contain some tissues with cells that have androgen receptors. Androgens can regulate cellular functions by binding to androgen receptors or be converted to other hormones. For example, testosterone can bind to the androgen receptor or be aromatised to oestradiol. Treating animals with testosterone, therefore, might elicit some androgenic and oestrogenic effects. Alternatively, testosterone can be converted to other androgens, which in turn, have more or less affinity with the androgen receptor and these new metabolites may or may not be aromatised to oestrogens. This review will highlight the roles of androgens in female mammals other than those as a substrate for oestrogen, with particular emphasis on the actions of the androgen receptors in uteri and ovaries of pigs. Utilising small dosages of an androgen receptor agonist, DHT (5alpha-dihydrotestosterone) we have observed that some uterine functions were inhibited while ovarian follicular development was augmented. These inhibitory and stimulatory effects of androgen therapy on reproductive organs can potentially be balanced to enhance ovulation rate and litter size in gilts and sows. Perhaps after future experimentation, new uses of androgens or anti-androgens could improve additional aspects of sow performance not presently under consideration.

Androgens↗

PubMedDate not supplied

Lessons to be learned from the androgen receptor.

Androgen action is mediated by the androgen receptor, a ligand dependent transcription factor, belonging to the superfamily of nuclear receptors. The two most important androgens are testosterone and 5a-dihydrotestosterone and their tissue specific actions are mediated by the same androgen receptor protein. Binding of androgens by the androgen receptor results in two consecutive conformational changes, which are different from those induced by anti-androgens. The androgen receptor can use different transactivation domains (AF1 and AF5, respectively, in the NH2-terminal domain and AF2-AD in the COOH-terminal domain) depending on the "form" of the receptor protein. The AF2 function is strongly dependent on the presence of nuclear receptor coactivators. Two AF functions are ligand dependent (AF-1 and AF2), whereas AF5 operates in a ligand independent way. The ligand dependency of AF-1 in the full length androgen receptor and the switch to AF5 in the COOH-terminal truncated androgen receptor strongly suggests a functional inhibitory action of the ligand-binding domain on AF-1 in the absence of ligand and on AF5 in the presence of ligand. In vivo experiments favour a ligand dependent functional interaction between the AF-2 AD core region in the ligand-binding domain with the NH2-terminal domain. This interaction might be either direct or indirect, requiring additional factors, and results in androgen receptor driven transcription activation. The androgen receptor protein can undergo two post-translational modifications during receptor activation. Firstly, upon synthesis the protein is rapidly phosphorylated to acquire hormone binding capacities and secondly, upon hormone binding an additional phosphorylation occurs during transformation to the DNA-binding transcription activation form.

Humans↗

PubMed1988

[Androgen receptors in primary breast carcinoma. Relation to prognostic factors in comparison with estrogen and progesterone receptors].

Androgen receptor content was correlated with various prognostic factors in 274 patients with breast cancer. Receptor content was determined by the dextran-coated charcoal method (DCC). No direct relationship was found between androgen receptor content and age of patient, menstruation status, TN status and number of affected lymph nodes. But in 232 patients in whom tumour differentiation could be determined, there was a highly significant relationship between it and androgen receptor content (P less than 0.01). Similar correlations were found also between these prognostic factors and oestrogen or progesterone receptors. The percentage distribution of tumours of different degrees of differentiation was independent of the kind of demonstrable steroid-hormone receptor. However, the frequency of highly differentiated tumours rose with the number of different receptors that were determined. Thus steroid-hormone receptors can be considered as markers for differentiation. It seems possible that the additional determination of androgen receptors allows for a more exact selection of patients who should receive hormonal treatment.

Adult↗

PubMed1988

Transplantable human prostatic carcinoma (PC-82) in athymic nude mice. II. Tumor growth and androgen receptors.

Androgen receptor (AR) levels were measured in PC-82 tumor tissue grown in hormonally manipulated nude mice. In the nuclei of tumor tissue from intact male mice a relatively low concentration (mean 25 fmol/mg protein) of androgen receptors (ARn) was found, while no receptors for estrogens or progestins were detected. The total number of androgen receptors in the PC-82 tumor tissue (measured in the nuclei 1 h after injection of a single high dose of testosterone (T) was found to be 100 fmol/mg protein. The antiandrogen cyproterone acetate, administered in combination with the high dose of T, significantly lowered the amount of ARn in the tumor tissue. In the nuclei of tumor tissue from intact tumor-bearing male mice with T-containing Silastic implants, a 4-times higher amount of tightly associated AR was found. In addition, an increased growth rate of the tumor was observed following T implantation. This finding suggests that the increased growth rate of the PC-82 tumor is associated with a continuous occupancy of AR in the nuclei of the tumor tissue. Castration of tumor-bearing male mice, which arrests the growth of this tumor, did not affect the concentration of ARn in the tissue compared to that of tissue in the intact control situation. In addition, the total amount of AR measured after T injection was not affected by castration. Therefore, the availability of a sufficient and steady level of T in the plasma and consequently the duration of the presence of AR in the nucleus of the PC-82 tumor tissue, rather than the total concentration of AR, appear to be the limiting factors in the modulation of hormonal responses in this androgen target tissue.

Animals↗

PubMed1999

Two distinct isoforms of cDNA encoding rainbow trout androgen receptors.

Androgens play an important role in male sexual differentiation and development. The activity of androgens is mediated by an androgen receptor (AR), which binds to specific DNA recognition sites and regulates transcription. We describe here the isolation of two distinct rainbow trout cDNA clones, designated rtAR-alpha and rtAR-beta, which contain the entire androgen receptor coding region. Comparison of the predicted amino acid sequence of rtAR-alpha to that of rtAR-beta revealed 85% identity. Interestingly, despite this high homology, rtAR-alpha activated transcription of an androgen-responsive reporter gene in co-transfection assays, but rtAR-beta did not. These results suggest that rainbow trout contains two distinct isoforms of androgen receptors whose functions differ. The region of rtAR-beta responsible for its inactivity was mapped to its ligand binding domain by analyzing chimeras of the rtAR-alpha, rtAR-beta, and rtGR-I (glucocorticoid) receptors. Alteration of any one of three out of four segments within this domain restored activity. Extracts made from COS-1 cells transfected with an rtAR-alpha expression plasmid produced a high level of [3H]mibolerone binding, whereas no binding was observed by extracts of cells transfected with an rtAR-beta expression plasmid. These data demonstrate that the lack of transactivation activity of rtAR-beta is due to its inability to bind hormone.

Amino Acid Sequence↗

PubMed1987

Estrogen receptors and androgen receptors in the mammalian liver.

An estrogen receptor and an androgen receptor are present in the mammalian liver. In the liver of the rat, the estrogen receptor concentration increases markedly at puberty and this change correlates with enhanced estrogen stimulation of plasma renin substrate synthesis. High doses of estrogen are required for nuclear binding in liver when compared to doses for the uterus. The high dose requirement appears to be predominantly due to extensive metabolism in the hepatocyte of the estrogen to inactive derivatives. Furthermore, estradiol is much weaker than ethinyl estradiol for promoting nuclear binding in the liver. This is due to extremely rapid and extensive metabolism of estradiol. In human liver the concentration of estrogen receptor is low. An androgen receptor is present in high concentration in rabbit liver and is located predominantly in the nucleus after androgen administration. High concentrations of a putative androgen receptor are also present in human liver cytosol. Preliminary studies indicate that synthetic progestins can attach to the human liver androgen receptor. To date, a progesterone receptor has not been found in the mammalian liver. Thus, it appears that extensive steroid metabolism in liver preferentially diminishes sex steroid interaction with liver receptors and that androgen receptors may mediate progestin effects in liver. These observations provide a scientific basis for improved safety of oral contraceptives. Lowering the estrogen and progestin doses in oral contraceptives will decrease the major side-effects, which are liver mediated, and still maintain the desired effects at the hypothalamic-pituitary axis and uterus. Furthermore, it is likely that by selecting which estrogen, progestin or androgen is administered as well as by utilizing a parenteral route of administration that sex steroid effects on the liver could be minimized.

Animals↗

PubMed2001

Regulation of keratinocyte growth factor receptor and androgen receptor in epithelial cells of the human prostate.

PURPOSE: Stromal-epithelial interactions of growth factors and the androgen receptor may have implications for the pathophysiology of benign and neoplastic transformation of the human adult prostate. We investigated a possible interaction of keratinocyte growth factor with its receptor as well as with the androgen receptor signaling pathway in human prostatic epithelial cells. MATERIALS AND METHODS: Human prostatic epithelial cells were obtained from explant primary culture, established in DU145 cell conditioned medium and maintained in keratinocyte serum-free medium with supplements. Epithelial cells were characterized by light and electron microscopy, and immunocytochemical study using epithelial and mesenchymal markers. Androgen receptor, keratinocyte growth factor receptor and keratinocyte growth factor messenger RNA expression was measured by polymerase chain reaction (PCR). The response to 0.01 to 10 nM. dihydrotestosterone, 10 microM. flutamide and 1 to 1,000 ng./ml. keratinocyte growth factor was tested by [3H] thymidine assay. The difference in keratinocyte growth factor receptor and androgen receptor gene expression after treatment with and without keratinocyte growth factor and flutamide were determined by quantitative multiplex PCR and quantitated using densitometry analysis. RESULTS: Immunocytochemical and electron microscopy characterization revealed typical epithelial differentiation. PCR showed keratinocyte growth factor receptor and androgen receptor expression in epithelial cultured cells but no keratinocyte growth factor expression. Epithelial cells showed a significant time and dose dependent stimulation of cell proliferation with keratinocyte growth factor and dihydrotestosterone (p <0.05). When combined with the anti-androgen flutamide the effect of 100 ng./ml. keratinocyte growth factor was significantly decreased (p <0.05). At 100 ng./ml. keratinocyte growth factor quantitative multiplex PCR revealed stimulated keratinocyte growth factor receptor and androgen receptor messenger RNA expression. CONCLUSIONS: These results show that keratinocyte growth factor up-regulates the keratinocyte growth factor and androgen receptors in the absence of androgen. Thus, the androgen signaling pathway may be activated by growth factors such as keratinocyte growth factor in an androgen deficient environment.

Androgen Antagonists↗

PubMed1993

Single nucleotide substitution of the androgen receptor gene in a case with receptor-positive androgen insensitivity syndrome (complete form).

Complete androgen insensitivity syndrome is caused by X chromosome linked disorder resulting in a target organ insensitivity to androgen. Two variants have been described in this syndrome. In the first, the binding of [3H]dihydrotestosterone (17 beta-hydroxy-5 alpha-androstan-3-one) to the androgen receptor is undetectable (receptor-negative), whereas in the second variant normal levels of androgen receptor are detectable but the binding of [3H] dihydrotestosterone to the androgen receptor is significantly thermolabile under certain conditions (receptor-positive). In receptor-negative cases, genetic disorders of the androgen receptor gene have been demonstrated. On the other hand, the genetic disorder of androgen receptor in receptor-positive cases is little known. In this study, the gene structure of androgen receptor in a receptor-positive case using a polymerase chain reaction technique is studied in the fibroblasts cultured from genital skin. The results demonstrate that the substitution of nucleotide (guanine-->cytosine) in exon G of the androgen receptor causes the replacement of an amino acid in position 820 (glycine-->alanine) which occurs in the hormone-binding domain of the androgen receptor. The substitution of nucleotide may explain the thermolability of the androgen receptor in a case with receptor-positive androgen insensitivity syndrome.

Adult↗

PubMed1999

Cloning and characterization of human prostate coactivator ARA54, a novel protein that associates with the androgen receptor.

Androgen receptor (AR) is a member of the steroid receptor superfamily that may require coactivators for proper or maximal transactivation. Using a yeast two-hybrid screening followed by mammalian cell analyses, we identified a novel ligand-dependent AR-associated protein, ARA54, which consists of 474 amino acids with a molecular mass of 54 kDa. We demonstrated that ARA54 might function as a preferential coactivator for AR-mediated transactivation in human prostate cancer DU145 cells. Interestingly, our data also showed that ARA54 could significantly enhance the transcriptional activity of LNCaP mutant AR (ARt877a) but not wild type AR or another mutant AR (ARe708k) in the presence of 10 nM 17beta-estradiol or 1 microM hydroxyflutamide. These results imply that both ARA54 and the positions of the AR mutation (877 versus 708) might contribute to the specificity of AR-mediated transactivation. Our findings further demonstrated that the C-terminal domain of ARA54 can serve as a dominant negative inhibitor and exogenous full-length ARA54 can reverse this squelching effect on AR transcriptional activity. Co-expression of ARA54 with other AR coactivators, such as ARA70 or SRC-1, showed additive stimulation of AR-mediated transactivation, which indicates that these cofactors may function individually as AR coactivators to induce AR target gene expression. Through our findings, we have identified and characterized a novel AR coactivator, ARA54, which may play an important role in the AR signaling pathway in human prostate.

Amino Acid Sequence↗

PubMed2005

Androgen receptor expression in ductal carcinoma in situ of the breast: not a helpful marker for classification such as estrogen receptor alpha and progesterone receptor.

Androgen receptor (AR) is known to be expressed in approximately 70 to 90% of invasive breast cancers, but there are still conflicting data in terms of AR expression in ductal carcinoma in situ (DCIS). The aim of this study was to evaluate AR expression in DCIS and to compare these results with nuclear grading and with other common endocrine-related markers. On this basis the authors performed immunohistochemical staining for estrogen receptor (ER)-alpha and ER-beta, progesterone receptor (PR), pS2, her-2/neu, and AR in 59 cases of DCIS (24 low grade, 5 intermediate grade, 30 high grade). They found a strong correlation of expression of ER-alpha (P=0.003), PR (P<0.0001), and nuclear grading. For AR expression, 44.1% of all DCIS were positive, but there was no correlation between nuclear grading (P=0.535) and the expression of the other factors. The authors conclude that AR expression in DCIS is not correlated with nuclear grading and with the expression of other known endocrine-related markers such as ER-alpha and -beta, PR, pS2, and her-2/neu. The immunohistochemical assessment of AR status, therefore, may not help in providing a more objective way of classifying DCIS.

Adolescent↗

PubMed2004

Ectopic expression of the amino-terminal peptide of androgen receptor leads to androgen receptor dysfunction and inhibition of androgen receptor-mediated prostate cancer growth.

Androgen receptor (AR) is a ligand-activated transcription factor that requires androgen binding to initiate a series of molecular events leading to specific gene activation. AR has been suggested to form an antiparallel homodimer based on the characteristics of high affinity interaction between the amino (N) and carboxyl (C) termini of it. Recently, it is suggested that AR N-to-C interaction is critical for the ability of this receptor to up-regulate the transcription of androgen-responsive genes, and may be a new target for treatment of prostate cancer (PCa). In this study, we investigated the effect of N-terminal (1-34) peptide of AR (ARN34) on androgen-dependent function in PCa cell. Ectopic expression of ARN34 suppressed both androgen-dependent AR N-to-C interaction and prostate specific antigen transcription. Ectopic expression of ARN34 also caused delaying translocation to the nucleus and the decreasing stability of the AR. Stable expression of ARN34 suppressed androgen-dependent cell growth of LNCaP cells. Moreover, transactivation and cell growth of the AR variant in LNCaP cells by the AR antagonist, hydroxyflutamide, were also inhibited by ARN34. Although treatment of LNCaP cells with androgen drove transition of cells from G1 to S-phase, the cells expressing ARN34 were inhibited to enter into S phase in the presence of androgen. This cell cycle arrest was attended by decrease in cyclin E levels and cyclin-dependent-kinase 2 activity, and increase in p27 levels. Our results demonstrated that disruption of AR N-to-C interaction caused by ARN34 leads to AR dysfunction and inhibition of AR-mediated prostate cancer cell growth. This approach is thus considered to provide a useful therapeutic opinion for blocking AR-mediated PCa growth.

Active Transport, Cell Nucleus↗

PubMed1991

A mutation in the DNA-binding domain of the androgen receptor gene causes complete testicular feminization in a patient with receptor-positive androgen resistance.

Androgen resistance is associated with a wide range of quantitative and qualitative defects in the androgen receptor. However, fibroblast cultures from approximately 10% of patients with the clinical, endocrine, and genetic features characteristic of androgen resistance express normal quantities of apparently normal androgen receptor in cultured genital skin fibroblasts (receptor-positive androgen resistance). We have analyzed the androgen receptor gene of one patient (P321) with receptor-positive, complete testicular feminization and detected a single nucleotide substitution at nucleotide 2006 (G----C) within the second "zinc finger" of the DNA-binding domain that results in the conversion of the arginine residue at position 615 into a proline residue. Introduction of this mutation into the androgen receptor cDNA and transfection of the expression plasmid into eukaryotic cells lead to the synthesis of a receptor protein that displays normal binding kinetics but is inactive in functional assays of receptor activity. We conclude that substitution mutations in the DNA-binding domain of the androgen receptor are one cause of "receptor-positive" androgen resistance.

Androgen-Insensitivity Syndrome↗

PubMed1986

Androgen-induced biochemical responses in epithelium lacking androgen receptors: characterization of androgen receptors in the mesenchymal derivative of urogenital sinus.

Heterotypic tissue recombinants, composed of adult bladder epithelium obtained from testicular feminization syndrome mice (TfmBLE) and embryonic wild-type rat urogenital sinus mesenchyme (UGM) were grown as subcapsular renal grafts in male athymic nude mice for 30 days. The resultant prostatic tissue that developed was subjected to extensive biochemical analyses for androgen receptors. From previous autoradiographic studies it was shown that UGM possesses androgen receptors and induces the TfmBLE to form prostatic ductal-acinar epithelium that lacks androgen receptors. The purpose of the present study is to biochemically characterize the mesenchymal androgen receptors. According to results obtained by autoradiographic analyses, androgen receptors are expressed in the mesenchyme of tissue recombinants. Cytosolic androgen receptors analyzed by the Scatchard method utilizing R-1881 as a ligand showed that the dissociation constant (Kd) of androgen receptors localized within the mesenchyme of the tissue recombinants differs from that found in the mouse prostate gland, but resembles that found in the rat ventral prostate (VP). Sucrose density gradient analysis of the cytosol androgen receptors showed the presence of 8 S [3H]dihydrotestosterone (DHT) binding component under the low salt condition. The mesenchymal androgen receptors are capable of translocating efficiently from cytosol to nuclear compartment, seemingly unaffected by adjacent TfmBLE. The quantity of both cytosol and nuclear androgen receptors expressed in tissue recombinants is only about 1/3 of that found in the rat VP and is in agreement with the morphometric analysis of tissue recombinants, which indicated that about 1/3 of the cells in the tissue recombinants are stromal cells. These results extend previous autoradiographic results and further suggest that androgen receptors present in the mesenchymal compartment may be necessary for the expression of androgen-elicited responses in the TfmBLE that lacks androgen receptors. In addition, this study confirms a novel model system for the study of mesenchymal androgen receptors in tissues unmolested by mechanical or enzymatic dissociation.

Androgen-Insensitivity Syndrome↗

PubMed2004

The molecular mechanisms of coactivator utilization in ligand-dependent transactivation by the androgen receptor.

Androgens drive sex differentiation, bone and muscle development, and promote growth of hormone-dependent cancers by binding the nuclear androgen receptor (AR), which recruits coactivators to responsive genes. Most nuclear receptors recruit steroid receptor coactivators (SRCs) to their ligand binding domain (LBD) using a leucine-rich motif (LXXLL). AR is believed to recruit unique coactivators to its LBD using an aromatic-rich motif (FXXLF) while recruiting SRCs to its N-terminal domain (NTD) through an alternate mechanism. Here, we report that the AR-LBD interacts with both FXXLF motifs and a subset of LXXLL motifs and that contacts with these LXXLL motifs are both necessary and sufficient for SRC-mediated AR regulation of transcription. Crystal structures of the activated AR in complex with both recruitment motifs reveal that side chains unique to the AR-LBD rearrange to bind either the bulky FXXLF motifs or the more compact LXXLL motifs and that AR utilizes subsidiary contacts with LXXLL flanking sequences to discriminate between LXXLL motifs.

Amino Acid Motifs↗

PubMed2004

A novel genetic system for analysis of co-activators for the N-terminal transactivation function domain of the human androgen receptor.

Androgen receptor (hAR) regulates transcription of target genes in a ligand-dependent manner and recruits a number of co-activators for the ligand-induced transactivation via the N-terminal, activation function-1 (AF-1), and C-terminal, AF-2, transactivation domains. But the co-regulator functions on each of AR domains have not yet been fully understood. We have established a Drosophila transgenic system in which hAR and its deletion mutants are ectopically expressed in fly tissues together with an AR response element (ARE)-GFP reporter gene, and have confirmed that hAR was functional in ARE transactivation without affecting the expression of endogenous genes. We found that transcriptional activity of the hAR AF-1 domain was markedly reduced in Drosophila deficiency mutants of homologs for known mammalian co-activators of the AR ligand-dependent AF-2 domain. This suggests that hAR AF-1 recruits co-activators previously known only to interact with the AF-2 domain. Therefore, Drosophila with the hAR AF-1 transgene provides a relevant genetic system in which to uncover novel functions of vertebrate steroid hormone receptors and to screen for novel AF-1 co-regulators.

Animals↗