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:3.4.11.18 (MAP)
7,412 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The steroid/thyroid hormone receptor superfamily of ligand-activated transcription factors encompasses not only the receptors for steroids, thyroid hormone, retinoids and vitamin D, but also a large number of proteins whose functions and/or ligands are unknown and which are thus termed orphan receptors. Recent studies have highlighted the importance of phosphorylation in receptor function. Although most of the phosphorylation sites are serine and threonine residues, a few of the family members are also phosphorylated on tyrosine. Those steroid receptor family members that are bound to heat-shock proteins in the absence of ligand typically are basally phosphorylated and exhibit increases in phosphorylation upon ligand binding. Most of these sites contain Ser-Pro motifs, and there is evidence that cyclin-dependent kinases and MAP kinases (mitogen-activated protein kinases) phosphorylate subsets of these sites. In contrast, phosphorylation sites identified thus far in members of the family that bind to DNA in the absence of hormone typically do not contain Ser-Pro motifs and are frequently casein kinase II or protein kinase A sites. Phosphorylation has been implicated in DNA binding, transcriptional activation and stability of the receptors. The finding that some of the steroid receptor family members can be activated in the absence of ligand by growth factors or neurotransmitters that modulate kinase and/or phosphatase pathways underscores the role of phosphorylation in receptor function. Hence this family of transcription factors integrates signals from ligands as well as from signal transduction pathways, resulting in alterations in mRNA and protein expression that are unique to the complex signals received.
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PMID:Steroid hormone receptors and their regulation by phosphorylation. 892 Sep 64

Vitamin D(3) produces biologic responses as a consequence of its metabolism into 1alpha,25(OH)(2)-vitamin D(3) [1alpha,25(OH)(2)D(3)] and 24R,25(OH)(2)-vitamin D(3). The metabolic production of these two seco steroids and their generation of the plethora of biologic actions that are attributable to the parent vitamin D(3) are orchestrated via the integrated operation of the vitamin D endocrine system. This system is very similar in its organization to that of classic endocrine systems and is characterized by an endocrine gland (the kidney, the source of the two steroid hormones), target cells which possess receptors for the steroid hormones, and a feed-back loop involving changes in serum Ca(2+) that alter the secretion of parathyroid hormone (a stimulator of the renal 1-hydroxylase) which modulates the output by the kidney of the steroid hormones. There are, however, at least two unique aspects to the vitamin D endocrine system. (a) The chemical structures of vitamin D and its steroid hormones dictate that these be highly conformationally flexible molecules present a wide variety of shapes to their biologic environments. (b) It is now believed that 1alpha,25(OH)(2)D(3) produces biologic responses through two distinct receptors which recognize totally different shapes of the conformationally flexible 1alpha,25(OH)(2)D(3). Thus, the classic actions of 1alpha,25(OH)(2)D(3) to regulate gene transcription occur as a consequence of the stereospecific interaction of a modified 6-s-trans bowl-shape of 1alpha,25(OH)(2)D(3) with its nuclear receptor (VDR(nuc)). The ability of 1alpha,25(OH)(2)D(3) to generate a variety of rapid (seconds to minutes) biologic responses (opening of chloride channels, activation of PKC and MAP kinases) requires a planar 6-s-cis ligand shape which is recognized by a putative plasma membrane receptor (VDR(mem)) to initiate appropriate signal transduction pathways. This report summarizes the evidence for the specificity of different ligand shapes and the operation of the two receptor families for 1alpha,25(OH)(2)D(3).
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PMID:Different shapes of the steroid hormone 1alpha,25(OH)(2)-vitamin D(3) act as agonists for two different receptors in the vitamin D endocrine system to mediate genomic and rapid responses. 1117 22

A study was made of the influence of a long-term exposure of 1,25-dihydroxyvitamin D3 and 17 beta-estradiol on deactivation of MAP kinases in correlation with proliferation of cancer cells. The obtained results illustrate inhibition of cell growth after vitamin D treatment. Mechanisms of such an inhibition are discussed.
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PMID:[Long-term action of vitamin D suppresses the estradiol-induced activity of erk-1 MAPK and proliferation of MCF-7 and LNCaP cancer cells]. 1120 Jan 37

1 alpha,25(OH)(2)D(3) and 24R,25(OH)(2)D(3) mediate their effects on chondrocytes and osteoblasts in part through increased activity of protein kinase C (PKC). For both cell types, 1 alpha,25(OH)(2)D(3) exerts its effects primarily on more mature cells within the lineage, whereas 24R,25(OH)(2)D(3) exerts its effects primarily on relatively immature cells. Studies using the rat costochondral cartilage growth plate as a model indicate that the two metabolites increase PKC activity by different mechanisms. In growth zone cells (prehypertrophic/upper hypertrophic cell zones), 1 alpha,25(OH)(2)D(3) causes a rapid increase in PKC that does not involve new gene expression. 1 alpha,25(OH)(2)D(3) binds its membrane receptor (1,25-mVDR), resulting in activation of phospholipase A(2) and the rapid release of arachidonic acid, as well as activation of phosphatidylinositol-specific phospholipase C, resulting in formation of diacylglycerol and inositol-1,4,5-tris phosphate (IP(3)). IP(3) leads to release of intracellular Ca(2+) from the rough endoplasmic reticulum, and together with diacylglycerol, the increased Ca(2+) activates PKC. PKC is then translocated to the plasma membrane, where it initiates a phosphorylation cascade, ultimately phosphorylating the extracellular signal-regulated kinase-1 and -2 (ERK1/2) family of MAP kinases (MAPK). PKC increases are maximal at 9 min, and MAPK increases are maximal at 90 min in these cells. By contrast, 24R,25(OH)(2)D(3) increases PKC through activation of phospholipase D in resting zone cells. Peak production of diacylglycerol via phospholipase D2 is at 90 min, as are peak increases in PKC. Some of the effect is direct on existing plasma membrane PKC, but most is due to new PKC expression; translocation is not involved. Arachidonic acid and its metabolites also play differential roles in the mechanisms, stimulating PKC in growth zone cells and inhibiting PKC in resting zone cells. 24R,25(OH)(2)D(3) decreases phospholipase A(2) activity and prostaglandin production, thereby overcoming this potential inhibitory component, which may account for the delay in the PKC response. Ultimately, ERK1/2 is phosphorylated. PKC-dependent MAPK activity transduces some, but not all, of the physiological responses of each cell type to its respective vitamin D metabolite, suggesting that the membrane receptor(s) and nuclear receptor(s) may function interdependently to regulate proliferation and differentiation of musculoskeletal cells, but different pathways are involved at different stages of phenotypic maturation.
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PMID:Membrane mediated signaling mechanisms are used differentially by metabolites of vitamin D(3) in musculoskeletal cells. 1196 Jun 17

The steroid hormone 1 alpha,25(OH)(2)-vitamin D(3) [1 alpha,25(OH)(2)D(3)] mediates through its widely distributed nuclear receptor (VDR(nuc)) regulation of gene transcription (genomic responses) and through a putative membrane receptor (VDR(mem)) a variety of rapid responses. Rapid responses studied in our laboratories include opening of voltage-gated calcium and chloride channels in ROS 17/2.8 osteoblast cells, activation of MAP-kinase in human leukemia NB4 cells and chick intestinal cells, release of insulin by rat pancreatic beta-cells, and in chick duodena transcaltachia (the rapid hormonal stimulation of intestinal Ca(2+) transport). 1 alpha,25(OH)(2)D(3) is conformationally flexible (side chain, seco B-ring and A-ring) and accordingly is able to generate a large array of different shapes to serve as ligands for available receptors (VDR(nuc) and VDR(mem)) in the vitamin D endocrine system. Our laboratories have utilized a number of conformationally restricted analogs of 1 alpha,25(OH)(2)D(3) (from a library of several hundred analogs) to evaluate the preferred shape of the ligands for rapid and genomic responses. The determination of the X-ray structure of the 1 alpha,25(OH)(2)D(3)-occupied VDR(nuc) revealed that the preferred ligand shape was a twisted 6-s-trans bowl shape [Molecular Cell 5 (2000) 173-179]. Optimal agonists for genomic responses include 1 alpha,25(OH)(2)D(3) and other side chain conformationally flexible analogs such as 20-epi-1 alpha,25(OH)(2)D(3) [approximately equal to 200-500-fold more potent than 1 alpha,25(OH)(2)D(3)] and 21-(3'-hydroxy-3-methylbutyl)-1 alpha,25(OH)(2)D(3) [an analog with two side chains] all which can achieve the preferred VDR(nuc) shape. In contrast, rapid responses require a 6-s-cis shape of the agonist ligand such as can be achieved by the natural hormone 1 alpha,25(OH)(2)D(3) or by analogs permanently locked in the 6-s-cis shape such as 1 alpha,25(OH)(2)lumisterol(3) or 1 alpha,25(OH)(2)-7-dehydrocholesterol. Additionally, we have discovered analogs that are specific in their antagonist properties for either rapid or genomic responses. Thus, 1 beta,25(OH)(2)D(3) is an antagonist of only rapid responses [via the VDR(mem)], while 23S-25-dehydro-1 alpha,25(OH)D(3)-26,23-lactone is an antagonist of only nuclear responses [via the VDR(nuc)]. In conclusion, we have presented evidence that 1 alpha,25(OH)(2)D(3) mediated rapid response and genomic response signal transduction pathways utilize differing shapes of ligand, both as agonists and antagonists.
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PMID:Molecular tools for study of genomic and rapid signal transduction responses initiated by 1 alpha,25(OH)(2)-vitamin D(3). 1196 Jun 21

All biologic responses to vitamin D are now known to arise as a consequence of the metabolism of this seco-steroid into its two principal biologically active metabolites 1alpha,25(OH)(2)-vitamin D(3) (1ALPHA;,25(OH)(2)D(3)) and 24R,25(OH)(2)-vitamin D(3) (24R,25(OH)(2)D(3)). 1alpha,25(OH)(2)D(3) is the dominant metabolite and produces a wide array of biological responses via interacting both with the classical vitamin D nuclear receptor (VDR(nuc)) that regulates gene transcription in over 30 target organs and with a putative cell membrane receptor (VDR(mem1,25)) that mediates rapid (within seconds to minutes) biological responses. Ligand occupancy of VDR(mem1,25) is linked to signal transduction systems that can mediate the opening of Ca(2+) and chloride voltage gated channels as well as activation of MAP-kinase. MAP-kinase activation in some cells containing VDR(mem1,25)+VDR(nuc) then results in "cross-talk" from VDR(mem1,25) to VDR(nuc) which modulates transactivation of 1alpha,25(OH)(2)D(3) responsive gene promoters. The 24R,25(OH)(2)D(3) metabolite has been shown to be an essential hormone for the process of bone fracture healing. The activity of the enzyme responsible for the production of 24R,25(OH)(2)D(3), the renal 25(OH)D-24-hydroxylase, becomes elevated within 4-11 days after imposition of a tibial fracture, thereby increasing the blood concentrations of 24R,25(OH)(2)D(3) by threefold. The 24R,25(OH)(2)D(3) likely initiates its biological responses via binding to the ligand binding domain of a second cell membrane receptor, the VDR(mem24,25), which is stereospecific for 24R,25(OH)(2)D(3) in comparison with 24S,25(OH)(2)D(3) and 1alpha,25(OH)(2)D(3). This report summarizes the status of several current research frontiers in this arena of the vitamin D endocrine system.
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PMID:Update on biological actions of 1alpha,25(OH)2-vitamin D3 (rapid effects) and 24R,25(OH)2-vitamin D3. 1243 90

In the current study, we have probed the role of cytosolic phospholipase A2 (cPLA2) activity in the cellular response to the calciotropic hormones, 1alpha,25,dihydroxy-vitamin D(3) [1alpha,25(OH)(2)D(3)] and PTH. Stimulation of rat enterocytes with either hormone, increased release of arachidonic acid (AA) 3H-AA] one-two fold in a concentration and time-dependent manner. The effect of either hormone on enterocytes was totally reduced by preincubation with the intracellular Ca(2+) chelator BAPTA-AM (5 microM), suggesting that the release of AA following cell exposure to the calciotropic hormones occurs mainly through a Ca(2+)-dependent mechanism involving activation of Ca(2+)-dependent cPLA2. Calciotropic homone stimulation of rat intestinal cells increases cPLA2 phosphorylation (three to four fold). This effect was decreased by PD 98059 (20 microM), a MAP kinase inhibitor, indicating that this action is, in part, mediated through activation of the MAP kinases ERK 1 and ERK2. Enterocytes exposure to 1alpha,25(OH)(2)D(3) (1nM) or PTH (10 nM) also resulted in P-cPLA2 translocation from cytosol to nuclei and membrane fractions, where phospholipase subtrates reside. Collectively, these data suggest that PTH and 1alpha,25(OH)(2)D(3) activate in duodenal cells, a Ca(2+)-dependent cytosolic PLA2 and attendant arachidonic acid release and that this activation requieres prior stimulation of intracellular ERK1/2. 1alpha,25(OH)(2)D(3) and PTH modulation of cPLA2 activity may change membrane fluidity and permeability and thereby affecting intestinal cell membrane function.
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PMID:1alpha,25(OH)2D3 and parathyroid hormone (PTH) signaling in rat intestinal cells: activation of cytosolic PLA2. 1522 89

1alpha-25-Dihydroxyvitamin D3 (calcitriol), the biologically active metabolite of vitamin D, is known to regulate calcium and phosphate levels in bone metabolism. It is also known to influence proliferation and differentiation in carcinoma cells mediated by the vitamin D receptor (VDR). The antiproliferative effects of calcitriol are believed to be mediated by the nuclear pathway via binding the activated receptor to vitamin D-responsive elements. This induces the vitamin D-responsive genes. Another possible pathway might be the MAPK-cascade or rapid response pathway. The interaction of calcitriol and the MAP-kinase-cascade was evaluated on VDR-positive MCF-7 cells and VDR-negative MDA-MB-231 breast cancer cells. The cells were incubated with calcitriol solution at 10(-7) M and 10(-9) M, or ethanol as controls, for up to 48 h. The effects of calcitriol were measured by semi-quantitative Western blotting. Calcitriol stimulated the MAP-kinases ERK1 and ERK2. A biphasic activation was found for calcitriol in VDR-positive cells after incubation for 5 to 20 min and from 2 to 24 h. However, early activation of ERK1 and ERK2 was also demonstrated in VDR-negative cells. In the controls, ethanol also induced the MAPK-cascade at 5 to 10 min. Calcitriol induction was demonstrated after incubation from 2 to 24 h. In conclusion, it seems that the early induction of the MAPK-cascade was independent of the VDR. A calcitriol-induced MAPK activation was shown after 4 h, which may have been caused by activation of the nuclear receptor pathway.
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PMID:Modulation of MAPK ERK1 and ERK2 in VDR-positive and -negative breast cancer cell lines. 1688 87

Spontaneously hypertensive rats (SHR) are characterized by impaired erectile function and overactivity of the procontractile RhoA/Rho-associated, coiled-coil-containing protein kinase (RhoA/ROCK) pathway, as compared with their normotensive counterpart, Wistar-Kyoto rats. By measuring the intracavernous pressure:mean arterial pressure (ICP:MAP) ratio after electrostimulation of the cavernous nerve, we confirmed these findings and showed that responsiveness to sildenafil (25 mg/kg by oral gavage) also is hampered in SHR. A 2-week treatment with atorvastatin (5 and 30 mg/kg) improved the sildenafil-induced ICP:MAP increase and normalized RhoA and ROCK2 overexpression in SHR corpora cavernosa (CC). Conversely, other genes, neuronal nitric oxide synthase (NOS), endothelial NOS, and phosphodiesterase 5, were unaffected. In human fetal smooth muscle cells derived from CC (hfPSMC), atorvastatin inhibited RhoA membrane translocation and ROCK activity, as well as RhoA-dependent biologic functions like cell migration and cell proliferation. Atorvastatin's effect on migration was rescued in a dose-dependent manner by geranylgeranyl pyrophosphate, suggesting the involvement of RhoA geranylgeranylation. In hfPSMC, atorvastatin decreased the expression of RhoA-dependent genes such as ROCK2, desmin, alpha-smooth muscle actin, SM22alpha, and myocardin. In contrast to atorvastatin, elocalcitol, a vitamin D analog that also interferes with RhoA activation in SHR bladder, was unable to restore penile responsiveness to sildenafil. In conclusion, atorvastatin, but not elocalcitol, ameliorates sildenafil-induced penile erections in SHR, likely by interfering with RhoA/ROCK signaling within the penis.
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PMID:Atorvastatin but not elocalcitol increases sildenafil responsiveness in spontaneously hypertensive rats by regulating the RhoA/ROCK pathway. 1769 3

Calcitriol, the hormonally active form of vitamin D, inhibits the growth and development of several cancers. Inflammation has been implicated in the development and progression of many cancers, including prostate cancer (PCa). Recent research from our laboratory suggests that calcitriol exhibits anti-inflammatory actions that may contribute to its inhibitory effects in PCa. We found that calcitriol inhibits the synthesis and actions of pro-inflammatory prostaglandins (PGs) by three mechanisms: (1) inhibition of the expression of cyclooxygenase-2 (COX-2), the enzyme that synthesizes PGs, (2) induction of the expression of 15-prostaglandin dehydrogenase (15-PGDH), the enzyme that inactivates PGs, and (3) decreasing the expression of prostaglandin E and prostaglandin F PG receptors, which are the mediators of PG signaling. The combination of calcitriol and nonsteroidal anti-inflammatory drugs (NSAIDs) result in a synergistic inhibition of PCa cell growth and offers a potential therapeutic strategy. Acting on a separate anti-inflammatory pathway, calcitriol induces the expression of mitogen-activated protein kinase phosphatase 5 (MKP5), a member of a family of phosphatases that are negative regulators of MAP kinases, causing the selective dephosphorylation and inactivation of the stress-activated protein kinase p38. Because p38 activation may be both procarcinogenic and promote inflammation, this calcitriol action, especially coupled with the inhibition of the PG pathway, may contribute to the chemopreventive activity of calcitriol. We conclude that calcitriol exerts several anti-inflammatory actions in prostate cells, which contribute to its potential as a chemopreventive and therapeutic agent in PCa.
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PMID:Calcitriol as a chemopreventive and therapeutic agent in prostate cancer: role of anti-inflammatory activity. 1829 Jul 27


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