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:3.1.3.1 (alkaline phosphatase)
47,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the mechanism of ligand-independent activation of the estrogen receptor (ER) by 3,3'-diindolylmethane (DIM), a promising anticancer agent derived from vegetables of the Brassica genus, in Ishikawa and HEC-1B human endometrial cancer cells. DIM stimulated the activity of an ER-responsive reporter by over 40-fold, equivalent to the maximum induction produced by estradiol (E2), whereas cotreatment of cells with the ER antagonist, ICI-182,780 (ICI), abolished the stimulatory effect of DIM. DIM also induced the expressions of the endogenous genes, TGF-alpha, alkaline phosphatase, and progesterone receptor similar to levels induced by E2. Induction of gene expression by DIM was inhibited by the protein synthesis inhibitor, cycloheximide. In addition, cotreatment of cells with the protein kinase A (PKA) inhibitor, H89, or the MAPK inhibitor, PD98059, reduced DIM activation of the ER by 75% and 50%, respectively. Simultaneous treatment of cells with both inhibitors completely abolished the effect of DIM. DIM stimulated MAPK activity and induced phosphorylation of the endogenous PKA target, cAMP response element binding protein (CREB), in a PKA-dependent manner. Expression of MCREB, a nonphosphorylatable CREB mutant, partially abolished activation of the ER by DIM. These results demonstrate that DIM is a mechanistically novel activator of the ER that requires PKA-dependent phosphorylation of CREB.
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PMID:Potent ligand-independent estrogen receptor activation by 3,3'-diindolylmethane is mediated by cross talk between the protein kinase A and mitogen-activated protein kinase signaling pathways. 1464 98

The specific pharmacological profile of the 19-norprogestin nomegestrol acetate (NOMAC) is, at least in part, defined by its pattern of binding affinities to the different steroid hormone receptors. In the present study, its affinity to the progesterone receptor (PgR), the androgen receptor (AR) and the estrogen receptor (ER) was re-evaluated and compared to those obtained for progesterone (P) and several progestins. The characteristics of binding to the PgR in rat uterus were determined and Ki were found to be roughly similar with 22.8 and 34.3 nM for NOMAC and P, respectively. The binding characteristics of 3H-NOMAC were also determined and compared to that of 3H-ORG2058 with Kd of 5 and 0.6 nM, respectively for rat uterus and 4 and 3 nM, respectively for human T47-D cells. Structure-affinity and -activity relationships were studied on a variety of compounds related to NOMAC in order to assess its specificity as a progestin. The effects of NOMAC on the binding of androgen to the AR were investigated, using rat ventral prostate as target model. Contrary to what was observed for MPA, the RBA of NOMAC was found to decline with time, showing anti-androgenic rather than androgenic potential, a result that was confirmed in vivo. Regarding the ER, since none of the progestins were able to compete with estrogen for binding in rat uterus as well as in Ishikawa cells, the induction of alkaline phosphatase activity (APase) was used as an estrogen-specific response. It confirmed the intrinsic estrogenicity of progestins derived from 19-nor-testosterone (19NT), norethisterone acetate (NETA), levonorgestrel (LNG) or norgestimate (NGM) and others. In contrast, all P and 19-norP derivatives remained inactive. Finally, to complete this overview of NOMAC at the sex steroid receptor levels, the lack of estrogenic or estrogenic-like activity was checked out in different in vitro models. Data from this study have demonstrated that NOMAC is a progestin that has greater steroid receptor selectivity compared to MPA or some other synthetic progestins. It may provide a better pharmacological profile than those progestins currently in use in HRT and OC.
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PMID:An overview of nomegestrol acetate selective receptor binding and lack of estrogenic action on hormone-dependent cancer cells. 1467 31

TAK-778, a derivative of ipriflavone, has been shown to induce bone growth in in vitro and in vivo models. However, there are no studies evaluating by which mechanism TAK-778 exerts its effect. Considering the evidences that its precursors act via classical estrogen-receptor (ER)-mediated signaling, in the present study, we tested the hypothesis that TAK-778 induces osteogenesis in human bone marrow cell culture via an ER-dependent pathway. Cells were cultured in 24-well culture plates at a cell density of 2 x 10(4) cells/well in culture medium containing: TAK-778 (10(-5) M), Tamoxifen (10(-5) M), TAK-778 (10(-5) M) + Tamoxifen (10(-5) M), and vehicle. During the culture period, cells were incubated at 37 degrees C in a humidified atmosphere of 5% CO(2) and 95% air. At 7, 14, and 21 days, cell proliferation, cell viability, total protein content, alkaline phosphatase (ALP) activity, and bone-like formation were evaluated. Data were compared by two-way ANOVA and Duncan's multiple range test. TAK-778 did not affect cell viability. Cell number was reduced by TAK-778. Total protein content, ALP activity, and bone-like formation were increased by TAK-778. In general, Tamoxifen did not have any effect on cell behavior. However, when cells were cultured in medium containing both TAK-778 and Tamoxifen, the effect of TAK-778 on osteoblast differentiation was inhibited. The present results show that TAK-778 enhances osteoblast differentiation in human bone marrow cell culture, at least in part, via an ER-dependent pathway, since its effect was inhibited by Tamoxifen, a well-known estrogen receptor antagonist.
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PMID:TAK-778 enhances osteoblast differentiation of human bone marrow cells via an estrogen-receptor-dependent pathway. 1499 66

Many plant-derived substances have estrogenic activities. Due to their ability to bind the estrogen receptor (ER), these compounds have the potential to counteract the deleterious effects of estrogen deficiency on bone. In this study, we investigated the in vitro effect of two widespread flavonols, quercetin and kaempferol, on alkaline phosphatase (ALP) activity in MG-63 cultured human osteoblasts. We found that both flavonols significantly increased ALP activity. This effect was markedly reduced by PD 98059, an inhibitor of the extracellular regulated kinase (ERK) pathway, and by ICI 182780, an antagonist of ERs. Western blot studies confirmed that ERK is rapidly activated in cells treated by both flavonols. Finally, ICI 182780 markedly inhibits the flavonol-induced ERK activation. The data presented in this study support the conclusion that, in MG-63 osteoblasts (i) the increase in ALP activity by flavonols involves a rapid stimulation of ERK activation but also involves the ER, and that (ii) the activation of ERK by flavonols occurs most likely downstream of the ERs activation. Taken together, these results suggest that flavonols derivatives as quercetin and kaempferol can stimulate osteoblastic activity. Such compounds may represent new pharmacological tools for the treatment of osteoporosis.
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PMID:Stimulatory effect of naturally occurring flavonols quercetin and kaempferol on alkaline phosphatase activity in MG-63 human osteoblasts through ERK and estrogen receptor pathway. 1501 46

Overexpression of the lipogenic enzyme fatty acid synthase (FAS) is a common molecular feature in subsets of sex-steroid-related tumors including endometrium and breast carcinomas that are associated with poor prognosis. Pharmacological inhibition of tumor-associated FAS hyperactivity is under investigation as a chemotherapeutic target. We examined the effects of the mycotoxin cerulenin (a covalent FAS inactivator), and the novel small compound C75 (a slow-binding FAS inhibitor) on estradiol (E2)- and tamoxifen (TAM)-stimulated ER-driven molecular responses in Ishikawa cells, an in vitro model of well-differentiated human endometrial carcinoma. We evaluated the effects of FAS inhibition on E2- and TAM-induced estrogen receptor (ER) transcriptional activity by using transient cotransfection assays with an estrogen-response element reporter construct (ERE-Luciferase). Antiestrogenic effects of cerulenin and C75 were observed by dose-dependent inhibition of E2-stimulated ERE-dependent transcription, whereas FAS inhibitors did not significantly increase the levels of ERE transcriptional activity in the absence of E2. Moreover, pharmacological blockade of FAS activity completely abolished TAM-stimulated ERE activity. To address the reliability of transient transfection assays, the effects of FAS inhibitors on E2-inducible gene products were evaluated. FAS blockade induced a dose-dependent decrease in E2-inducible alkaline phosphatase activity. E2-stimulated accumulation of progesterone receptor (PR) and HER-2/neu oncogene was abolished in the presence of FAS blockers. FAS inhibition also resulted in a marked downregulation of E2-stimulated ERalpha expression, and noticeably impaired E2-induced ERalpha nuclear accumulation. A dose-dependent decrease in cell proliferation and cell viability was observed after FAS blockade. A Cell Death ELISA, detecting DNA fragmentation, demonstrated that FAS inhibitors stimulated apoptosis of Ishikawa cells. The analysis of critical E2- and TAM-related cell cycle proteins revealed an increase of both the expression and the nuclear accumulation of cyclin-dependent kinase inhibitors p21WAF1/CIP1 and p27Kip1 following FAS inhibition. To rule out non-FAS cerulenin- and C75-related effects, we finally monitored ER signaling after silencing of FAS gene expression using the highly sequence-specific mechanism of RNA interference (RNAi). The concentrations of E2 and TAM inducing half-maximal ERE activity (EC50) dramatically increased (>100 times) in FAS RNAi-transfected Ishikawa cells. Moreover, depletion of FAS by RNAi also caused loss of ERalpha expression, downregulation of PR, and accumulation of p21WAF1/CIP1 and p27Kip1 in E2-stimulated Ishikawa cells. If chemically stable FAS inhibitors or cell-selective vector systems able to deliver RNAi targeting FAS gene demonstrate systemic anticancer effects in vivo, our results render FAS as a novel target for the prevention and treatment of endometrial carcinoma.
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PMID:Inhibition of tumor-associated fatty acid synthase activity antagonizes estradiol- and tamoxifen-induced agonist transactivation of estrogen receptor (ER) in human endometrial adenocarcinoma cells. 1509 77

PD98059 and U0126 are considered as specific inhibitors of the p42/44 mitogen-activated protein kinases (MAPK) pathway, which affects osteogenesis and adipogenesis. Here, we show unexpected differential effects of PD98059 and U0126 on osteogenesis and adipogenesis as well as on estrogen (E2)-induced actions in osteoprogenitor KS483 cells. PD98059 dose-dependently inhibited osteogenesis indicated by cellular alkaline phosphatase (ALP) activity and nodule formation, but stimulated adipogenesis shown by the number of adipocytes. In contrast, U0126 slightly decreased osteogenesis but had no effects on adipogenesis, although it inhibited p42/44 MAPK more potently than PD98059. Furthermore, PD98059, but not U0126, counteracted E2-induced osteogenesis and adipogenesis. Transfection experiments showed that PD98059, but not U0126, had estrogenic transcriptional activity. Interestingly, both PD98059 and U0126 potentiated E2-induced estrogenic transcriptional activity in KS483 cells, which is opposite to the response in MCF7 breast cancer cells. Our data indicate that the cross-talk between growth factors and estrogen receptor (ER)-mediated pathways in KS483 cells is different from that in MCF7 cells. In summary, the differential effects of PD98059 and U0126 indicate their actions are not exclusively due to an inhibition of MAPK pathway. Caution should be taken in the interpretation of the results obtained using these inhibitors.
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PMID:Differential effects of PD98059 and U0126 on osteogenesis and adipogenesis. 1515 64

Perivascular epithelioid cells (PEC) in angiomyolipoma (AML) were recently proposed to be its most common progenitor cells. Histologically, triphasic components were present in various proportions, but were overwhelmingly myogenic in epithelioid variants of AML. Despite histological discrimination, the immunophenotypic profiles between triphasic and epithelioid AML have never been compared. The aim of the present study was to clarify the identity of PEC by using immunoreactivity to estrogen receptor (ER), progesterone receptor (PR), bcl-2 and placenta alkaline phosphatase (PLAP), and to use this information to compare triphasic and epithelioid AML. A total of 33 out of 67 cases of renal angiomyolipoma that underwent surgery were reviewed over the period 1998-2003. Two cases were associated with tuberous sclerosis. Ten patients had other malignant tumors, and three patients had a nodal extension. Immunohistochemistry showed that bcl-2 (59.4%), PLAP (46.9%), HMB-45 (100%) was predominantly localized around vessels. The stem cell markers were absolutely negative in all AML types. The estrogen receptors were positive in 14 cases (42.4%) and the progesterone receptors were positive in five cases. Bcl-2 and both female sex hormone receptors were significantly more frequent in the epithelioid variant of AML than in the triphasic type. Perivascular epithelioid cells express bcl-2, ER, PR and PLAP, and ER could be partly associated with myogenic proliferation.
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PMID:Estrogen receptor is significantly associated with the epithelioid variants of renal angiomyolipoma: a clinicopathological and immunohistochemical study of 67 cases. 1518 5

Ospemifene is a novel selective estrogen receptor modulator (SERM). Here we studied the effects of ospemifene on bone turnover in postmenopausal women. This was a randomized, double-blind study in which 159 healthy postmenopausal women received 30 (n = 40), 60 (n = 40) or 90 mg (n = 40) of ospemifene or placebo (n = 39) for 3 months. Bone resorption was assessed by measuring the urinary outputs of N- and C-terminal crosslinking telopeptides of type I collagen (NTX and CTX, respectively). Bone formation was assessed by measuring the levels of procollagen type I N propeptide (PINP), procollagen type I C propeptide (PICP), and bone-specific alkaline phosphatase (bone ALP) in serum. All markers were studied at baseline, 3 months, and 2-4 weeks after cessation of the medication. Ospemifene decreased bone resorption dose-dependently, as seen from falls in NTX by 6.1, 9.4 and 12.9% in the 30, 60 and 90 mg ospemifene groups, respectively (p < 0.05 for all dose levels when compared to placebo). CTX values decreased in the 90 mg ospemifene group by 4.8% (p < 0.05). A dose-dependent decrease was also observed in the bone formation markers: PINP values decreased by 9.8 (p < 0.05) and 15.3% (p < 0.01), and PICP values by 12.0 and 11.9% in the 60 and 90 mg ospemifene groups, respectively. Bone ALP decreased in 60 and 90 mg ospemifene groups by 1.9 and 2.6%, respectively (p < 0.05 for both dose levels when compared to placebo). These results show that ospemifene is effective in reducing bone turnover in postmenopausal women.
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PMID:Effects of ospemifene, a novel SERM, on biochemical markers of bone turnover in healthy postmenopausal women. 1525 84

To examine the effects of heavy metals such as cadmium and mercury on calcium homeostasis, plasma calcium and calcitonin were measured in goldfish. Cadmium induced hypocalcemia both at 4 and at 8 days. In methylmercury-treated goldfish, the plasma calcium level increased at 2 days and then decreased at 8 days. The plasma calcitonin level increased in correspondence with the increased plasma calcium by methylmercury treatment, although cadmium did not cause a significant change. To elucidate the mechanism in detail, fish scales, which have both osteoclasts and osteoblasts and are similar to mammalian membrane bone, were used in the present study. We measured tartrate-resistant acid phosphatase (TRAP) and alkaline phosphatase (ALP) activity as respective indicators of activity in both types of cells. TRAP activity in the scales decreased by treatment of cadmium and methylmercury at 6 h incubation. Particularly, cadmium (even at 10(-13) M) significantly suppressed TRAP activity, suggesting that this system is utilized as an acute biosensor for cadmium. ALP activity decreased after exposures of 64 and 96 h, although the activity did not change after 6, 18, and 36 h. In addition, mRNA expression of the estrogen receptor and insulin-like growth factor 1, which participate in osteoblastic growth and differentiation, was less than the control values by treatment with both metals. This study demonstrates that mercury directly acts on the bone cells and influences calcium homeostasis and indicates that, in a short-term exposure, mercury has a different action from that of cadmium and induces hypercalcemia.
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PMID:Both mercury and cadmium directly influence calcium homeostasis resulting from the suppression of scale bone cells: the scale is a good model for the evaluation of heavy metals in bone metabolism. 1531 64

The soybean phytoestrogen, genistein (Gen), has anabolic effects on bone through mechanisms that remain to be elucidated. We examined the role of nitric oxide (NO) and its downstream effector guanylyl cyclase (GC) in mediating the effects of Gen on the proliferation and osteoblastic maturation of primary mouse bone marrow-derived mesenchymal stem cells (BMSCs). Gen (10(-8) approximately 10(-6) M) resulted in a dose-dependent increase in cell proliferation as measured by increased [3H]thymidine incorporation, and stimulated osteoblastic maturation as assessed by culture duration-dependent increments in alkaline phosphatase (ALP) activity, calcium deposition into extracellular matrix and Runx2/Cbfa1 gene expression in BMSCs cultures. Gen also resulted in a dose-dependent increase in NO synthase (NOS) activity, NO formation, and cGMP production in BMSCs cultures. The effects of Gen were mimicked by 17beta-estradiol (E2, 10(-8) M). Concurrent treatment with the estrogen receptor (ER) antagonist ICI182,780 (10(-7) M) or the NOS inhibitor L-NAME (3 x 10(-3) M) diminished the Gen (10(-6) M)-mediated increase in NOS activity, NO production, and cGMP content. In contrast, a soluble GC inhibitor 1H-[1,2,4]oxadiazolo [4,3,-a]quinoxalin-1-one (ODQ, 10(-6) M) selectively blocked the Gen (10(-6) M)-mediated increase in cGMP content but not in NO production and NOS activity. Moreover, inhibition of ER, NOS activity or cGMP blocked Gen-induced proliferation and osteoblastic differentiation of BMSCs and Runx2/Cbfa1 gene expression in culture. Gen has estrogen-like activity and stimulates the proliferation and osteoblastic differentiation of mouse BMSCs at least in part through NO/cGMP pathway.
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PMID:Genistein stimulates the osteoblastic differentiation via NO/cGMP in bone marrow culture. 1552 88


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