Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Elevation of intracellular calcium levels in the presence of normal androgen levels has been implicated in apoptotic prostate cell death. Since the androgen receptor (AR) plays a critical role in the regulation of growth and differentiation of the prostate, it was of interest to determine whether Ca2+ would affect the expression of androgen receptor messenger RNA (mRNA) and protein, thus affecting the ability of androgens to control prostate function. AR-positive human prostate cancer cells, LNCaP, were incubated with either the calcium ionophore A23187 or the intracellular endoplasmic reticulum Ca(2+)-ATPase inhibitor thapsigargin. Subsequently, AR mRNA and protein levels were assessed by Northern and Western blot analysis. Both A23187 and thapsigargin were found to down-regulate steady state AR mRNA levels in a time- and dose-dependent manner. AR mRNA began to decrease after 6-8 h of incubation with 10(-6) M A23187 or 10(-7) M thapsigargin, reaching a nadir at 16 and 10 h of incubation, respectively. In contrast, control mRNA (glyceraldehyde 3-phosphate dehydrogenase) did not change significantly during the treatments with either A23187 or thapsigargin. AR protein levels were found to be decreased after 12 h of incubation with either 10(-6) M A23187 or 10(-7) M thapsigargin. The decrease in AR mRNA and protein seemed to precede apoptosis, since neither A23187 (24 h) nor thapsigargin (30 h) was found to alter cell morphology within the treatment time. Cycloheximide and actinomycin D were unable to change the calcium-mediated decrease in AR mRNA, ruling out the necessity for de novo protein synthesis or a change in mRNA stability. Moreover, the decrease in AR mRNA induced by calcium does not seem to involve protein kinase C- or calmodulin-dependent pathways, since inhibitors of these cellular components had no effect. Nuclear run-on assays demonstrated little or no effects of either A23187 or thapsigargin treatment on AR gene transcription (8 h and 10 h). In conclusion, these studies show that intracellular calcium seems to be a potent regulator of AR gene expression in LNCaP cells.
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PMID:Calcium regulation of androgen receptor expression in the human prostate cancer cell line LNCaP. 772 Jun 67

The present study was performed to further clarify the influences of vasectomy on functions of testis and to disclose the possible mechanisms of infertility after vasovasostomy (VV). Thirty-one rabbits were divided into sham-operated control group (C), vasectomy control group (V), VV fertility group (VaF) and VV infertility group (VaI). Serum testosterone (ST) level, testicular cAMP, androgen binding protein (ABP), nuclear androgen receptor (NAR) concentrations, testis cell membrane Na(+)-, K(+)-ATPase, Mg(2+)-ATPase activities, sperm density and testis weight were measured. Vasectomy resulted in significantly reduced cAMP, Na(+)-, K(+)-ATPase, Mg(2+)-ATPase, testis weight and increased ABP; VV completely restore testis weight in VaF and VaI, Na(+)-, K(+)-ATPase, Mg(2+)-ATPase in VaF, partly cAMP in VaF and VaI, Na(+)-, K(+)-ATPase, Mg(2+)-ATPase in VaI, but did not restore ABP. The NAR content in VaI was significantly lower than those in C, VaF and V. No statistical differences among 4 groups were seen in Kd values for [3H]-T. ST levels in VaF, VaI and V were insignificantly different compared with C, but the value in VaF was higher than that in VaI (p < 0.05). Sperm density after VV reached 122 +/- 62 x 10(6)/ml in VaF and 10 +/- 24 x 10(6)/ml in VaI, both in VaF and VaI were significantly low compared with C (p < 0.001), and the value in VaI was remarkedly lower than that in VaF (p < 0.001). It was shown that sperm density was positively correlated with cAMP content, Na(+)-, K(+)-ATPase, Mg(2+)-ATPase activities, but negatively with ABP. These results suggest that vasectomy gives rise to damage to the testis, and vasovasostomy does not appear completely effective in reversing testicular changes.
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PMID:The influence of vasectomy and vasovasostomy on testicular ATPases, cAMP, ABP and androgen receptor in rabbits. 785 57

When androgen receptor containing cells are cultured in the presence of the PKA stimulator forskolin, a rapid dephosphorylation of the androgen receptor occurs resulting in a decrease in the amount of 112 kDa androgen receptor isoform and an increase in 110 kDa androgen receptor isoform on SDS-PAGE. To establish which amino acid residues in the androgen receptor were phosphorylated in control and forskolin-treated cells, trypsin-digested androgen receptors were subjected to RP-HPLC analysis and subsequently to Edman degradation. It was observed that serine residues 506, 641, and 653 were potentially phosphorylated in control cells, while after forskolin treatment strong evidence was obtained that phosphorylation of serines 641 and 653 was significantly reduced. When the dephosphorylated androgen receptor was analyzed for its transcription activation capacity, it was observed that androgen-induced transcriptional regulation of two endogenous genes (PSA) and beta 1-subunit of Na,K-ATPase), in cells cultured in the presence of forskolin, was inhibited as compared to the control situation. The observation that the dephosphorylated androgen receptor was transcriptionally less active was further strengthened by the finding that the dephosphorylated androgen receptor was markedly impaired in ligand binding (Bmax was found to be reduced by approximately 40%). The current investigations show for the first time a clear function for the rapid phosphorylation which occurs directly after synthesis of the androgen receptor, namely, effective ligand binding.
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PMID:Forskolin-induced dephosphorylation of the androgen receptor impairs ligand binding. 952 5

An ATP-dependent chromatin remodeling factor, SNF/SWI complex, acts as a coactivator for numerous transcriptional factors. One of the best-documented examples is nuclear receptors, although the molecular mechanism for this coactivation has not been sufficiently elucidated. Here we show that hbrm/hSNF2 alpha and BRG-1/hSNF2 beta, the ATPase subunits of the human SNF/SWI complexes, specifically associate in vitro and in vivo with TATA element modulatory factor (TMF)/ARA160, which has been described as a binding protein to and coactivator for the androgen receptor. This interaction requires highly conserved N-terminal regions of hbrm/hSNF2 alpha and BRG-1/hSNF2 beta and a C-terminal region of TMF/ARA160. Immunofluorescence and Western blot studies revealed that the TMF isoforms differentially localize in the Golgi apparatus and the nucleus.
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PMID:A putative nuclear receptor coactivator (TMF/ARA160) associates with hbrm/hSNF2 alpha and BRG-1/hSNF2 beta and localizes in the Golgi apparatus. 1204 84

Nuclear receptors, including the androgen receptor (AR), regulate target cell transcription through interaction with auxiliary proteins to modify chromatin structure. We describe herein a novel AR-interacting protein, termed ARIP4, that has structural features typical of the SNF2-like protein family. With regard to the Snf2 domain, the closest homolog of ARIP4 is the ATRX protein. ARIP4 is a nuclear protein and comprises 1466 amino acids. It interacts with AR in vitro and in cultured yeast and mammalian cells. ARIP4 can be labeled with 8-azido-[gamma-32P]ATP and exhibits DNA-dependent ATPase activity. Like several ATP-dependent chromatin remodeling proteins, ARIP4 generates superhelical torsion within linear DNA fragments in an ATP-dependent manner. With a stably integrated target promoter, ARIP4 elicits a modest enhancement of AR-dependent transactivation. In transient cotransfection assays, ARIP4 modulates AR function in a promoter-dependent manner; it enhances receptor activity on minimal promoters, but does not activate more complex promoters. ARIP4 mutants devoid of ATPase activity fail to alter DNA topology and behave as trans-dominant negative regulators of AR function in transient assays.
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PMID:Novel ATPase of SNF2-like protein family interacts with androgen receptor and modulates androgen-dependent transcription. 1205 73

Vacuolar type H(+)-ATPase is involved in lumenal acidification of the epididymis. This protein is highly expressed in narrow and clear cells where it is located in the apical pole, and it contributes to proton secretion into the lumen. We have previously shown that in rats, epididymal cells rich in H(+)ATPase appear during postnatal development and reach maximal numbers at 3-4 wk of age. The factors that regulate the appearance of these cells have not been investigated, but androgens, estrogens, or both may be involved. This study examined whether neonatal administration of estrogens (diethylstilbestrol [DES] or ethinyl estradiol) or an antiandrogen (flutamide), or the suppression of androgen production via administration of a GnRH antagonist (GnRHa), was able to alter the appearance of cells rich in H(+)-ATPase in the rat epididymis when assessed at age 25 days. Surprisingly, all of these treatments were able to significantly reduce the number of H(+)-ATPase positive cells; this was determined by immunofluorescence and confirmed by Western blotting. In contrast, neonatal coadministration of DES and testosterone maintained the expression of H(+)-ATPase in the epididymis at Day 25 despite the high level of concomitant estrogen exposure. These findings indicate that androgens, acting via the androgen receptor, are essential for the normal development of epididymal cells rich in H(+)-ATPase, and that treatments that interfere directly or indirectly with androgen production (GnRHa, DES) or action (flutamide, DES) will result in reduced expression of H(+)-ATPase. Our findings do not exclude the possibility that estrogens can directly suppress the postnatal development of cells in the epididymis that are rich in H(+)-ATPase, but if this is the case, this suppression can be prevented by testosterone administration.
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PMID:Modulation of the onset of postnatal development of H(+)-ATPase-rich cells by steroid hormones in rat epididymis. 1229 25

Spinal and bulbar muscular atrophy (SBMA) is a neurodegenerative disorder caused by the expansion of a polyglutamine tract in the androgen receptor (AR). The N-terminal fragment of AR containing the expanded polyglutamine tract aggregates in cytoplasm and/or in nucleus and induces cell death. Some chaperones such as Hsp40 and Hsp70 have been identified as important regulators of polyglutamine aggregation and/or cell death in neuronal cells. Recently, Hsp105alpha, expressed at especially high levels in mammalian brain, has been shown to suppress apoptosis in neuronal cells and prevent the aggregation of protein caused by heat shock in vitro. However, its role in polyglutamine-mediated cell death and toxicity has not been studied. In the present study, we examined the effects of Hsp105alpha on the aggregation and cell toxicity caused by expansion of the polyglutamine tract using a cellular model of SBMA. The transient expression of truncated ARs (tARs) containing an expanded polyglutamine tract caused aggregates to form in COS-7 and SK-N-SH cells and concomitantly apoptosis in the cells with the nuclear aggregates. When Hsp105alpha was overexpressed with tAR97 in the cells, Hsp105alpha was colocalized to aggregates of tAR97, and the aggregation and cell toxicity caused by expansion of the polyglutamine tract were markedly reduced. Both beta-sheet and alpha-helix domains, but not the ATPase domain, of Hsp105alpha were necessary to suppress the formation of aggregates in vivo and in vitro. Furthermore, Hsp105alpha was found to localize in nuclear inclusions formed by ARs containing an expanded polyglutamine tract in tissues of patients and transgenic mice with SBMA. These findings suggest that overexpression of Hsp105alpha suppresses cell death caused by expansion of the polyglutamine tract without chaperone activity, and the enhanced expression of the essential domains of Hsp105alpha in brain may provide an effective therapeutic approach for CAG repeat diseases.
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PMID:Hsp105alpha suppresses the aggregation of truncated androgen receptor with expanded CAG repeats and cell toxicity. 1271 91

Gonadotropin-regulated testicular RNA helicase (GRTH) is a novel DEAD-box protein with ATPase and RNA helicase activities. GRTH gene transcription is stimulated by human chorionic gonadotropin (hCG) via cyclic AMP-induced androgen formation in testicular Leydig cells. In this study, immunocytochemical and Western analyses identified GRTH as a developmentally regulated protein in Leydig cells and in germ cells (pachytene spermatocytes and round spermatids) of the rat testis. Three ATGs with the potential for generation of multiple protein species were identified. Germ cells primarily utilized the 1st ATG codon (+1) and contained major proteins of 61/56 kDa, whereas Leydig cells utilized preferentially the 2nd ATG codon (+ 343) with expression of 48/43 kDa species. A 3rd ATG was weakly utilized and yielded a 33-kDa protein only in germ cells. The increase in GRTH 43-kDa protein in Leydig cells caused by hCG treatment was prevented by the androgen receptor antagonist, flutamide. In round spermatids, hCG caused a significant decrease of 61 kDa species and an induction 48/43 kDa species, whereas no changes were observed in pachytene spermatocytes. Reversal of this hormone-induced switch of expression by flutamide indicated a role of androgen in utilization of the 2nd ATG. These studies have demonstrated a cell-specific and hormone-dependent alternative usage of ATG codons in the testis. They have also revealed that the androgen-dependent transcription of GRTH expression in Leydig cells is accompanied by a marked increase of 43-kDa species. The findings indicate that expression of GRTH proteins is regulated by gonadotropin/androgen at the translational level.
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PMID:Cell-specific and hormone-regulated expression of gonadotropin-regulated testicular RNA helicase gene (GRTH/Ddx25) resulting from alternative utilization of translation initiation codons in the rat testis. 1273 86

Dehydroepiandrosterone (DHEA) has been reported to have diverse effects on overall physiology, although its mechanism of action and specific receptor are not yet known. We have used the immortalized, clonal GT1-7 hypothalamic neurons to study DHEA effects on gonadotropin-releasing hormone (GnRH) gene expression. DHEA (10(-4) M) downregulates GnRH transcription by 39, 70 and 83% at 24, 36, and 48 h, respectively, while DHEA-sulphate had no effect. Hydroxyflutamide a specific androgen receptor (AR) antagonist, and cyproterone acetate or trilostane, both inhibitors of 3 beta-hydroxysteroid dehydrogenase/delta 4,5 isomerase, the rate-limiting enzyme for the conversion of DHEA to sex steroids, did not affect the ability of DHEA to downregulate GnRH gene expression. We found that GT1-7 cells did not express aromatase, thereby precluding conversion to estrogen. Analysis of [(14)C] DHEA metabolism by thin layer chromatography indicates that the main metabolites produced are 7 alpha- and 7 beta-hydroxy DHEA, and 7-oxo DHEA, although these steroids were not able to repress GnRH gene expression alone. Cell viability studies indicated that the transcriptional repression observed is not due to GT1-7 cell death. Interestingly, SV40 T-antigen mRNA levels, under the control of 2.3 kb of the rat GnRH gene 5' regulatory region, are also repressed by DHEA. Our studies indicate that DHEA has direct effects on GnRH transcription that appear to be unique from those observed after conversion to other steroidogenic compounds.
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PMID:Evidence that dehydroepiandrosterone, DHEA, directly inhibits GnRH gene expression in GT1-7 hypothalamic neurons. 1278 99

Inhibition of sodium-potassium adenosine 5'-triphosphatase ((Na(+), K(+))-ATPase) activity causes edema and cell death in the central nervous system, and impairment of learning and memory. Several sex steroid hormones have a protective effect against neuronal cell damage and the hypofunction of learning and memory. To examine the possible roles and mechanism of action of steroid hormones against amnesia induced by ouabain, an inhibitor of (Na(+), K(+))-ATPase, gonadectomized male mice were administrated ouabain (0.1 microg per mouse) intracisternally (i.cist.), and the learning and memory abilities of the mice were assessed by a step-through passive avoidance task. Subcutaneous (s.c.) administration of 17beta-estradiol (betaE2; 10 microg kg(-1)) or testosterone (TES; 1 mg kg(-1)) improved the memory impairment induced by ouabain, while administration of dihydrotestosterone (1 mg kg(-1)) or corticosterone (COR) (1 mg kg(-1)) did not. Treatment with the estradiol receptor antagonists, tamoxifen (TAM) (10 mg kg(-1); s.c. or 0.1 microg; i.cist.) and 4-hydroxytamoxifen (10 mg kg(-1); s.c.), or the androgen receptor antagonist, cyproterone (10 mg kg(-1); s.c. or 1 microg; i.cist.), did not influence the protective effect of betaE2 or TES on ouabain-induced amnesia. Moreover, we studied the effects of several free radical scavengers-17alpha-estradiol (10 microg kg(-1); s.c.), alpha-tocopherol (VE: 200 mg kg(-1); per os (p.o.), ascorbic acid (VC: 200 mg kg(-1); p.o.), or VE+VC (200 mg kg(-1) each; p.o.)-on ouabain-induced amnesia, and compared those effects with that of betaE2. The administration of free radical scavengers had no significant effect on memory impairment. These results indicate that betaE2 and TES ameliorate the amnesia induced by inhibition of (Na(+), K(+))-ATPase activity, and that the protective effect of betaE2 is caused by a non-genomic, rather than a genomic effect or a radical scavenging action. Additionally, the ameliorative effect of TES does not appear to involve free radical scavenging, but its aromatization to estrogen could contribute to the non-genomic action of betaE2.
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PMID:Effects of steroid hormones on (Na+, K+)-ATPase activity inhibition-induced amnesia on the step-through passive avoidance task in gonadectomized mice. 1464 95


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