Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Whereas the androgen receptor (AR) protein shares similarities in the structure of its DNA- and hormone-binding domains with other members of the steroid nuclear receptor family, the molecule in its unliganded form has a seemingly unordered amino-terminal transactivation domain unique to the AR. A comprehensive understanding of the specific sub-structures and protein-protein interactions inherent to this domain in both its inactive and activated states remains un-achieved. Therefore, the malleability of this peptide region in accommodating the diverse repertoire of transcription-modulating AR cofactors creates a great challenge for those intent on generating relevant three-dimensional molecular models. The AR transactivation domain achieves this flexibility through a series of conformational steps dependent on the presence of cofactors that induce allosteric changes, and thus has evolved several conserved peptide motifs representing key protein-protein interaction surfaces. Elucidation of these signaling regions, including their involvement in inducing AR transactivation domain structural changes, is of foremost interest in understanding how the AR achieves its pivotal role in regulating the androgen signaling axis particularly during the progression of prostate cancer.
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PMID:The androgen receptor: unlocking the secrets of its unique transactivation domain. 1611 72

The development of reproductive organ tumors such as breast and prostate cancer often depends on the action of sex hormones. Nuclear sex hormone receptors are members of the nuclear hormone receptor superfamily and act as ligand-inducible transcription factors, controlling the expression of target genes. Nuclear receptors are considered to directly and indirectly interact with a number of nuclear co-regulatory complexes involved in chromatin remodeling and histone modification. Moreover, many intracellular signalings via cell membrane receptors are shown to modulate nuclear receptor-regulated transcription. We have shown that estrogen receptors (ER) associate with a number of nuclear complexes, one of which is a spliceosome complex. We recently found that this spliceosome complex interacts with phosphorylated ER by MAP kinase, generating a novel cross-talk of estrogen and growth factor signalings. We also observed that a dioxin receptor (AhR) is capable of associating with ER, resulting in modulation of ER transactivation function. From our findings we believe that development of estrogen-dependent breast cancer may be mediated through the other signaling pathways. To address the function of the androgen receptor (AR) in androgen-dependent prostate cancer, we established a transgenic mouse line expressing a human AR mutant that is found in androgen-independent prostate cancer patients. The hAR mutant mice, generated through a Cre-loxP system, developed hyperplasia in the prostates. Hypersensitivity of AR mutants to antagonists and endogenous steroid hormones may potentiate hormone-dependency in prostate cancer development.
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PMID:Function of nuclear sex hormone receptors in gene regulation. 1627 65

We have investigated the role of corepressors SMRT (silencing mediator of retinoid and thyroid hormone receptor) and N-CoR (nuclear receptor corepressor) in transcriptional regulation by androgen receptor (AR) in the LNCaP prostate cancer cell line. Using specific small interference RNAs to knock down SMRT and/or N-CoR in LNCaP cells, we found that SMRT and N-CoR not only mediate antagonist-dependent inhibition of AR activation but also have a widespread role in suppressing agonist-dependent activation of several AR target genes we have tested, including PSA (prostate-specific antigen), TSC22 (TSC22 domain family member 1), NKX3-1 (NK3 transcription factor locus 1), and B2M(beta-2-microglobulin). By sequencing analysis followed by analysis of physical association by chromatin immunoprecipitation assay, we mapped the putative androgen response elements in the NKX3-1 and B2M. Consistent with a role in both antagonist- and agonist-regulated transcription by AR, chromatin immunoprecipitation analysis revealed that both SMRT and N-CoR were recruited by AR to these genes in the presence of either flutamide or R1881. Knocking down SMRT and N-CoR enhanced the recruitment of the coactivators steroid receptor coactivator 1 and p300 by agonist-bound AR and led to increased hyperacetylation of histone H3 and H4, suggesting that the corepressors actively compete with coactivators for binding to agonist-bound AR. Taken together, our data indicate that SMRT and N-CoR corepressors are involved in transcriptional regulation by both agonist- and antagonist-bound AR and regulate the magnitude of hormone response, at least in part, by competing with coactivators.
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PMID:The corepressors silencing mediator of retinoid and thyroid hormone receptor and nuclear receptor corepressor are involved in agonist- and antagonist-regulated transcription by androgen receptor. 1637 95

Prostate cancer (PC) is one of the main causes of disease and death and represents the second cause of death among men in Brazil. Benign prostate hyperplasia is a progressive and prevalent disease. It is estimated that men present around 50% and 90% of histological evidences of prostate hyperplasia at 50 and 80 years, respectively. While the pathogenesis of prostate neoplasias has been closely related to androgen and their specific nuclear receptor, the molecular mechanisms of cell growth, differentiation and apoptosis processes are still not clearly established. Co-activators and co-repressors could also contribute to prostate carcinogenesis by their binding to nuclear receptors or by interacting with the transcriptional machinery in order to increase the transcription of target genes. AR and type 2 5alpha reductase polymorphisms seem to be associated to the risk for PC. In addition, apoptosis and cellular cycle regulator genes, as well as growth factors, have been reported to be associated with the prostate tumorigenesis. Therefore, changes on the gene expression of normal tissue may be associated to the development of malign phenotype and these genes could be regarded as candidates of prognosis markers. The number of these genes increases every day but the present data needs further studies and correlation with the disease progression.
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PMID:[Molecular biology in the prostate neoplasia]. 1644 63

Defining the precise molecular strategies that coordinate patterns of transcriptional responses to specific signals is central for understanding normal development and homeostasis as well as the pathogenesis of hormone-dependent cancers. Here we report specific prostate cancer cell/macrophage interactions that mediate a switch in function of selective androgen receptor antagonists/modulators (SARMs) from repression to activation in vivo. This is based on an evolutionarily conserved receptor N-terminal L/HX7LL motif, selectively present in sex steroid receptors, that causes recruitment of TAB2 as a component of an N-CoR corepressor complex. TAB2 acts as a sensor for inflammatory signals by serving as a molecular beacon for recruitment of MEKK1, which in turn mediates dismissal of the N-CoR/HDAC complex and permits derepression of androgen and estrogen receptor target genes. Surprisingly, this conserved sensor strategy may have arisen to mediate reversal of sex steroid-dependent repression of a limited cohort of target genes in response to inflammatory signals, linking inflammatory and nuclear receptor ligand responses to essential reproductive functions.
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PMID:Macrophage/cancer cell interactions mediate hormone resistance by a nuclear receptor derepression pathway. 1646 93

The androgen receptor not only mediates prostate development but also serves as a key regulator of primary prostatic cancer growth. Although initially responsive to selective androgen receptor modulators (SARMs), which cause recruitment of the nuclear receptor-corepressor (N-CoR) complex, resistance invariably occurs, perhaps in response to inflammatory signals. Here we report that dismissal of nuclear receptor-corepressor complexes by specific signals or androgen receptor overexpression results in recruitment of many of the cohorts of coactivator complexes that permits SARMs and natural ligands to function as agonists. SARM-bound androgen receptors appear to exhibit failure to recruit specific components of the coactivators generally bound by liganded nuclear receptors, including cAMP response element-binding protein (CBP)/p300 or coactivator-associated arginine methyltransferase 1 (CARM1) to the SARM-bound androgen receptor, although still causing transcriptional activation of androgen receptor target genes. SARM-bound androgen receptors use distinct LXXLL (L, leucine; X, any amino acid) helices in the p160 nuclear receptor interaction domains that may impose selective allosteric effects, providing a component of the molecular basis of differential responses to different classes of ligands by androgen receptor.
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PMID:Ligand-specific allosteric regulation of coactivator functions of androgen receptor in prostate cancer cells. 1649 76

Androgens are critical regulators of prostate differentiation and function, as well as prostate cancer growth and survival. Therefore, androgen ablation is the preferred systemic treatment for disseminated prostate cancer. Androgen action is exerted in target tissues via binding the androgen receptor (AR), a nuclear receptor transcription factor. Historically, the gene expression program mediated by the AR has been poorly understood. However, recent gene expression profiling and more traditional single-gene characterization studies have revealed many androgen-regulated genes that are important mediators of androgen action in both normal and malignant prostate tissue. This review will focus on the androgen-regulated gene expression program, and examine how recently identified androgen-regulated genes are likely to contribute to the development and progression of prostate cancer. We will also summarize several recent studies that have attempted to unravel how these genes are deregulated in androgen depletion independent prostate cancer.
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PMID:Molecular regulation of androgen action in prostate cancer. 1651 32

The NAD-dependent histone deacetylase Sir2 plays a key role in connecting cellular metabolism with gene silencing and aging. The androgen receptor (AR) is a ligand-regulated modular nuclear receptor governing prostate cancer cellular proliferation, differentiation, and apoptosis in response to androgens, including dihydrotestosterone (DHT). Here, SIRT1 antagonists induce endogenous AR expression and enhance DHT-mediated AR expression. SIRT1 binds and deacetylates the AR at a conserved lysine motif. Human SIRT1 (hSIRT1) repression of DHT-induced AR signaling requires the NAD-dependent catalytic function of hSIRT1 and the AR lysine residues deacetylated by SIRT1. SIRT1 inhibited coactivator-induced interactions between the AR amino and carboxyl termini. DHT-induced prostate cancer cellular contact-independent growth is also blocked by SIRT1, providing a direct functional link between the AR, which is a critical determinant of progression of human prostate cancer, and the sirtuins.
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PMID:Hormonal control of androgen receptor function through SIRT1. 1692 62

Although the antineoplastic activity of calcitriol in prostate cancer has been known for many years, the agent's use in oncology has been prevented because of the occurrence of hypercalcemia with daily administration. High-dose pulse administration of calcitriol has the potential to improve the therapeutic index of calcitriol. Results of a phase II study of calcitriol and docetaxel (Taxotere(R)) suggest that this combination may have utility in androgen-independent prostate cancer (AIPC). DN-101, a high-dose (15 mug) formulation of calcitriol suitable for use in oncology, is now being tested in a randomized trial (AIPC Study of Calcitriol Enhancing Taxotere). This formulation of calcitriol could become an important new tool for improving the efficacy of docetaxel in the treatment of AIPC and would join the ranks of other nuclear receptor ligands in cancer treatment. Investigations of DN-101 in the treatment of a broad range of tumor types and in combination with a variety of agents are an exciting new area of research.
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PMID:A New Formulation of Calcitriol (DN-101) for High-Dose Pulse Administration in Prostate Cancer Therapy. 1698 49

The AR (androgen receptor) is a hormone-dependent transcription factor that translates circulating androgen hormone levels into a physiological cellular response by directly regulating the expression of its target genes. It is the key molecule in e.g. the development and maintenance of the male sexual characteristics, spermatocyte production and prostate gland development and growth. It is also a major factor in the onset and maintenance of prostate cancer and a first target for pharmaceutical action against the further proliferation of prostate cancer cells. The AR is a member of the steroid hormone receptors, a group of steroid-inducible transcription factors sharing an identical consensus DNA-binding motif. The problem of how specificity in gene activation is achieved among the different members of this nuclear receptor subfamily is still unclear. In this report, we describe our investigations on how the AR can specifically activate its target genes, while the other steroid hormone receptors do not, despite having the same consensus monomeric DNA-binding motif. In this respect, we describe how the AR interacts with a newly identified class of steroid-response elements to which only the AR and not, for example, the glucocorticoid receptor can bind.
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PMID:The androgen receptor DNA-binding domain determines androgen selectivity of transcriptional response. 1707 57


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