Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Currently, our understanding of the mechanism(s) of radiation-induced death of prostate cancer is limited. In-depth analysis of these processes would facilitate the design of more effective treatment strategies utilizing radiation therapy. An increasingly recognized form of radiation-induced death is postmitotic apoptosis. In this process, radiation damages the tumor cell s DNA. The cell then divides prior to completing DNA repair, an event that is lethal. In order to avoid this fate, the cancer cell may attempt to halt its cell-cycle machinery temporarily to repair its DNA prior to dividing. In the treatment of prostate cancer, radiation therapy currently is being evaluated in combination with androgen deprivation (AD). However, because AD can induce growth arrest, it may reduce the effectiveness of radiation through a reduction in postmitotic apoptosis. To study this effect, we examined the effect of AD on prostate cancer radiosensitivity as it is related to cell-cycle progression. Androgen-sensitive prostate cancer cells demonstrated increased resistance to radiation when deprived of androgenic stimuli. Thus, paradoxically, AD may reduce the radiosensitivity of prostate cancer by means of cell-cycle delay, which results in a reduction in postmitotic apoptosis.
Mol Urol 2000
PMID:Combined androgen deprivation with radiotherapy for prostate cancer: does it make sense? 1106 76

Androgen-independent prostate cancer cells are remarkably resistant to therapeutic agents that work by triggering apoptosis via the caspase cascade. The recent sequencing of the entire genome of one of the most radiation-resistant organisms known, Deinococcus radiodurans, yields some insight into how prostate cancer cells might mount such resistance to apoptosis. Rather than being attributable to any one mechanism, the extreme radiation resistance of D. radiodurans appears to reflect the expression of a large number of different systems capable of preventing, repairing, or tolerating DNA damage and a very high degree of redundancy in these systems. Many molecular alterations that may influence the threshold for apoptosis have already been described in advanced prostate cancer; changes in bcl-2, p53, and the androgen receptor have been the most extensively studied. Current information is consistent with the concept that individual prostate cancer cells express multiple antiapoptotic mechanisms. This conclusion implies that it will not be possible to enhance cellular sensitivity to therapeutics that activate apoptosis by disabling just one target in a pathway, because other proteins are likely to be available to assume its function. Likewise, even elimination of a whole pathway may have little effect on sensitivity because cellular viability is protected by so many different mechanisms. However, where molecular changes have a phenotypic consequence, they offer a window of opportunity for the development of novel therapeutic strategies. One such example is a recently identified small organic compound that can inhibit p53 function and thus protect normal tissues against radiation-induced apoptosis without impairing killing of p53-deficient tumor cells.
Mol Urol 2000
PMID:Resistance to apoptosis in prostate cancer cells. 1106 78

Androgen receptors (AR) have been identified in the human endometrium, but their role in endometrial function and development towards endometrial receptivity remains poorly understood. In an effort to study the regulation and possible function in endometrial epithelium, we utilized the well-differentiated endometrial adenocarcinoma cell line, Ishikawa, as a model system. This cell line has proven to be stable, hormonally responsive, contains both estrogen and progesterone receptors, and has been shown to express endometrial proteins in a hormone responsive manner. In the present study, we demonstrate that Ishikawa cells also express AR, based on immunohistochemical staining, radioactive binding studies, RT-PCR and Northern blot analysis. The expression of AR is induced in Ishikawa cells by estrogens, similar to that reported for normal endometrium. Further, using an estrogen-responsive gene that has been characterized in this cell line, alkaline phosphatase, we show that androgens act as antiestrogens in diethylstilbestrol (DES) treated cells, inhibiting enzymatic activity in a dose-dependent manner. These data support a physiologic role for AR in the endometrium. Elevations in endometrial AR in certain clinical situations such as polycystic ovarian syndrome (PCOS) may amplify the effects of androgens on the endometrium leading to suspected defects in uterine receptivity, higher than expected infertility and high miscarriage rates observed in patients with this disorder.
J Steroid Biochem Mol Biol 2000 Nov 15
PMID:Characterization of androgen receptors in a well-differentiated endometrial adenocarcinoma cell line (Ishikawa). 1116 29

One of the dramatic changes in the prostate during androgen manipulation is the alteration in cellular content of total RNA - the amount of total RNA in each cell. The abundance of cellular total RNA correlates with the RNA polymerase (RNAP) activity in the prostate. One possible mechanism of androgen regulation of RNAP activity involves the regulation of RNAP expression. Western blot analysis showed that the largest subunit of the RNAP II, an essential component of the transcriptional machinery for mRNA, is indeed regulated by androgens. Castration down-regulates the protein level of RNAP II, whereas androgen replacement up-regulates the protein. However, androgen manipulation does not have consistent effects on the phosphorylation of the C-terminal domain (CTD) of the RNAP II. Androgen regulation of the RNAP II protein expression was also observed in the seminal vesicles but not in the thymus and liver, indicating that androgen regulation of RNAP II protein expression appears to be limited to the male sex accessory organs. These observations suggest that RNAP II plays an essential role in androgen action in male sex accessory organs.
J Steroid Biochem Mol Biol 2000 Dec 01
PMID:Androgen regulation of the largest subunit of RNA polymerase II in the rat ventral prostate. 1117 7

Cultured human dermal papilla cells are useful for studying the androgen-dependent growth of hair follicles. We cloned the human homolog of FAR-17a, a gene identified from the hamster flank organ as one of the androgen inducible genes, by degenerative PCR and human dermal papilla cDNA library screening. We isolated a novel cDNA clone, designated as AIG1 (Androgen-inducible Gene 1), whose expression was found to be inducible by androgen. AIG1 cDNA consists of 1,398 nucleotides in length, which encodes a protein of 238 amino acids (27 kDa). The deduced protein sequence showed 35% overall homology with FAR-17a. RT-PCR of human dermal papilla cDNA revealed two mRNA transcripts, which differed by 156 nucleotides. This results in an in-frame deletion of 52 amino acids. A computer analysis of hydropathy indicated five hydrophobic domains are present in the large protein sequence, while four hydrophobic portions are in the smaller protein sequence. In a Northern blot analysis, the major 1.5 kb and minor 1.2 kb bands of AIG1 mRNA were detected. AIG1 mRNA was expressed at a relatively high level in the heart, ovary, testis, liver, and kidney. However, they were expressed at a low level in the spleen, prostate, brain, skeletal muscle, pancreas, small intestine, and colon. When dermal sheath cells were stimulated with DHT, the level of AIG1 mRNA expression was increased at 30 ng/ml. The level of expression was higher in males than females. In this study, we cloned and initially characterized AIG1. Further study will be needed to understand the functions of AIG1 in the androgen-regulated hair cycle.
Mol Cells 2001 Feb 28
PMID:Cloning of androgen-inducible gene 1 (AIG1) from human dermal papilla cells. 1126 18

Luteinizing hormone (LH) supports steroidogenesis and maintains testicular and ovarian function. Mediators of LH action exert homologous regulation of membrane receptors, steroidogenic enzymes and other regulatable genes of the Leydig cell (LC). Androgen and estrogen induced by LH could act through its cognate receptors in the LC to regulate gene expression. Although androgens are unquestionable essential for spermatogenesis and presumably exert their heterologous action through androgen receptors present in the Sertoli its regulatory mechanism in germinal cell maturation is far from clear. In contrast to physiological concentrations of gonadotropins which maintain the steroidogenic functions and LH and prolactin receptors in the gonads, high concentrations of gonadotropin (hCG) cause receptor down-regulation and desensitization of steroidogenic enzymes of the LCs in vivo (3beta-hydroxysteroid dehydrogenase types I and II, 17alpha-hydroxylase/17,20 lyase, and 17beta-hydroxysteroid dehydrogenase type III [17beta-HSD]). In addition, 17beta-HSD is regulated by compartmentalized endogenous glucose/ATP. The attenuation of steroidogenesis which results from receptor mediated activation by cognate hormone, but is independent of the subsequent phase of receptor down-regulation, is due to changes at the transcriptional level. Among the candidates affecting this regulation are active steroid metabolites (direct or indirect of steroids and other mediator(s) i.e. cAMP, putative transcription factors induced by LH action). Differential display assay revealed another gene which is transcriptionally regulated by gonadotropin termed GRTH (Gonadotropin Regulated Testicular Helicase). GRTH is a novel member of the DEAD-box family of RNA helicases, and is specifically expressed in LCs and meiotic LC of the testis. It is markedly up-regulated by hCG via cAMP-induced androgen formation in LCs at doses that cause down-regulation of receptors and steroidogenic enzymes. GRTH functions as a translational activator. Androgen produced by gonadotropin stimulation exerts intracrine/autocrine actions on GRTH, and also could influence transcription within the seminiferous tubule. GRTH may contribute to the control of steroidogenesis, including the restoration of down regulated cellular functions, and in the paracrine regulation of androgen dependent gene(s) involved in the meiotic process, and could thus have a crucial role in spermatogenesis.
J Steroid Biochem Mol Biol
PMID:Regulation of steroidogenic enzymes and a novel testicular RNA helicase. 1138 77

Genes that are regulated by androgens in the human prostate are believed to play an essential role in prostate physiology and they may also be involved in the proliferative response of prostate cancer cells to androgens. We used a cDNA subtraction approach to identify novel androgen-regulated transcripts in LNCaP cells that were exposed to 0.1 nM R1881 for 24 h. We report here that SPAK, a recently identified STE20/SPS1-related kinase that modulates p38 MAP kinase activity, exhibited increased expression in androgen-treated LNCaP cells. Androgen regulation of SPAK was both dose- and time-dependent. R1881-induced SPAK expression was completely abrogated by the antiandrogen casodex and by actinomycin D indicating that androgen induction of SPAK requires the androgen receptor and transcription. Cycloheximide caused a partial inhibition of R1881-induced SPAK expression which suggests that androgen induction of SPAK expression may require synthesis of additional proteins. Northern blot and ribonuclease protection assays demonstrated that SPAK is expressed at high levels in normal human testes and prostate, as well as in a number of breast and prostate cancer cell lines. These results identify SPAK, a member of a key cell signalling pathway, as an androgen-responsive gene in LNCaP cells. We hypothesize that SPAK may mediate androgen action in the normal and cancerous prostate gland.
Mol Cell Endocrinol 2001 Sep
PMID:Androgens induce expression of SPAK, a STE20/SPS1-related kinase, in LNCaP human prostate cancer cells. 1151 53

Metabolic stability is a key issue in the development of orally active androgens for Partial Androgen Deficiency in Aging Males (PADAM) and male contraception. Rates of metabolism in human hepatocyte suspensions provide useful information on the stability of compounds that undergo a first pass metabolism. We have derived a structure-pharmacokinetic relationship for a data set of 32 in-house steroidal androgens by means of the decision-trees technique. Volume, shape, number of rotatable bonds, and surface turned out to be the most important descriptors for classification. Only 2 of the 32 compounds were misclassified. The most stable compounds were classified in three leaf nodes on different branches of the tree, suggesting that higher metabolic stability can be achieved for the same substrate by different steric modifications. Further, it is generally assumed that the first step in cytochrome P450s oxidation reactions takes place by hydrogen abstraction to form a radical intermediate. An electronic model for hydrogen abstraction in steroidal androgens was, therefore, developed by means of ab initio calculations. Activation energies of steroid radical systems calculated as energy differences between the reactants equilibrium geometry energies and their corresponding transition states energies could be used to predict relative rates of metabolism to guide the design and redesign process of metabolically more stable steroidal androgens.
J Mol Graph Model 2001
PMID:(Q) SAR study on the metabolic stability of steroidal androgens. 1155 83

Steroids may regulate LH subunit gene transcription by modulating hypothalamic GnRH pulse patterns or by acting at the pituitary gonadotrope to alter promoter activity. We tested direct pituitary effects of the androgen dihydrotestosterone (DHT) to modulate the rat LHbeta promoter in transfected LbetaT2 clonal gonadotrope cells and in pituitaries of transgenic mice expressing LHbeta-luciferase. The LHbeta promoter (-617 to +44 bp)-luciferase construct was stimulated in LbetaT2 cells 7- to 10-fold by GnRH. Androgen treatment had little effect on basal promoter activity but suppressed GnRH stimulation by approximately 75%. GnRH stimulation of LHbeta was also suppressed by DHT in isolated pituitary cells from male or female mice with functional nuclear ARs, but not in male littermates with mutant AR. GnRH stimulation of the LHbeta promoter requires interactions between a complex distal response element containing two specificity protein-1 (Sp1) binding sites and a CArG box, and a proximal element with two bipartite binding sites for steroidogenic factor-1 and early growth response protein-1 (Egr-1). DHT effectively suppressed promoter constructs with an intact distal response element. The distal response element does not bind AR, but AR reduces Sp1 binding to this region. Glutathione-S-transferase pull-down studies demonstrated direct interactions of AR with Sp1, which requires the DNA-binding domain of AR, and weaker interactions with Egr-1. We conclude that androgen suppression of the rat LHbeta promoter occurs primarily through direct interaction of AR with Sp1, with some possible role through binding to Egr-1. These interactions result in interference with GnRH-stimulated gene transcription by reducing cooperation between the distal and proximal GnRH response elements.
Mol Endocrinol 2001 Nov
PMID:Androgen suppression of GnRH-stimulated rat LHbeta gene transcription occurs through Sp1 sites in the distal GnRH-responsive promoter region. 1168 22

The human immortalized prostatic cell line PNT1A has been proved to be a good model for analysis of cellular processes such as the prostatic epithelium proliferation in response to androgens and growth factors. Here we used this cell line for studying the transcriptional activity and trafficking of the androgen receptor (AR) by analyzing several actions of antiandrogens. Transient transfection experiments with PNT1A cells were performed with wild type human AR and an androgen-responsive gene reporter. We demonstrated that the transcription of reporter gene could be triggered by natural androgens (testosterone and dihydrotestosterone) in PNT1A cells as well as in the prostatic carcinoma cell line DU-145. With competitive experiments in the two cell lines, we observed no difference between the antagonistic capacity of cyproterone acetate (CPA) and hydroxyflutamide at 10(-7) M. At this concentration, bicalutamide antagonist activity was lower. In parallel, we compared the subcellular localization of the modified green fluorescent protein (EGFP)-AR in COS-7, PNT1A and DU-145 cell lines under fluorescence microscopy: we found different distributions between nucleus and cytoplasm, depending on the cell line and the culture medium. Androgen induced cluster formation within the nucleus of the PNT1A and DU-145 cells. However, the cytonuclear trafficking of androgen bound EGFP-AR in the same living cell and nuclear foci were easier to examine in the PNT1A cells. The antiandrogen capacity of bicalutamide was manifested by a slower androgen-dependent nuclear transfer of EGFP-AR and a homogeneous nuclear localization. A delayed advent of nuclear clusters was observed in presence of CPA. We conclude that the PNT1A cell line is a better model than the DU-145 cell line to analyze the trafficking of AR and the association of AR on the nuclear matrix, as well as to observe the action of antiandrogens on these critical steps in prostate cells.
Mol Cell Endocrinol 2001 Nov 26
PMID:Human prostatic cell line PNT1A, a useful tool for studying androgen receptor transcriptional activity and its differential subnuclear localization in the presence of androgens and antiandrogens. 1169 37


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