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)

Chaperone proteins in the heat shock protein-70 family possess endogenous ATP binding and ATPase activity and interact with intracellular protein substrates in an ATP-dependent manner; the hydrolysis of ATP to ADP results in an increase in the affinity of the chaperone for protein substrates. Heat shock protein-70s can also specifically interact with 25-hydroxylated vitamin D metabolites. Using constitutively expressed heat shock protein-70 (hsc70) as chaperone, here we demonstrate that vitamin D metabolite binding to hsc70 is also ATP dependent. Transient overexpression of an hsc70-green fluorescent protein chimeric construct in primate kidney cells resulted in a 6-fold increase in specific, extractable 25-hydroxyvitamin D(3) binding. When ATPase capability of hsc70 was disabled, this increase was completely blocked. In solution, the binding of 25-hydroxylated vitamin D metabolites to hsc70 was significantly increased (P < 0.01) in the presence of ATP and a nonmetabolizable ATP analog. The ATP-directed increase in specific binding resulted from an increase in the abundance of relatively high-affinity hormone-binding sites (K(d), approximately 0.24 nM). These results suggest that ATP hydrolysis to ADP would favor the release of vitamin D from a donor hsc70 molecule at a time when an hsc70-bound acceptor protein substrate is anchored to the chaperone with relative avidity. We theorize that the endogenous ATPase activity of hsc70 promotes the transfer of vitamin D sterols to other intracellular vitamin D binding proteins, such as the vitamin D receptor and vitamin D hydroxylases, to which hsc70 is known to bind.
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PMID:Adenosine 5'-triphosphate-dependent vitamin D sterol binding to heat shock protein-70 chaperones. 1614 93

The osteoclast is a specialized multinucleated variant of the macrophage family. It degrades mineralized tissue, and is required for modeling and remodeling of bone. The osteoclast has long been known to require vitamin D for its differentiation and to be regulated by parathyroid hormone via circulating Ca(2+) levels. Two local signals important in osteoclast survival and differentiation, CSF-1 and RANKL, were characterized by the mid-1990 s. A basic framework of specialized cell attachment and resorption molecules was also clear by that time, including the alpha(v)beta(3) integrin, the key adhesion molecule of the mature osteoclast, the highly expressed vacuolar-type H(+)-ATPase that drives acid secretion to dissolve mineral, and cathepsin K, the predominant acid proteinase for collagenolysis. Recently, additional detail has been added to this framework, showing that the osteoclast has more complex regulation than was previously believed. These include the findings that one component of the V-H(+)-ATPase is unique to the osteoclast, that chloride transport and probably Cl(-)/H(+) exchange are also required for mineral degradation, and that additional receptors besides RANK and Fms regulate osteoclast formation and survival. Additional receptors include estrogen receptor-alpha, TNF-family receptors other than RANK, and, at least in some cases, glycoprotein hormone receptors including the TSH-R and the FSH-R. Challenges in understanding osteoclast biology include how the signalling mechanisms function cooperatively. Recent findings suggest that there is a network of cytoplasmic adapters, including Gab-2 and BCAR1, which are modified by multiple signalling mechanisms and which serve to integrate the signalling pathways.
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PMID:Osteoclastic differentiation and function regulated by old and new pathways. 1711 68

TRPV5 is a Ca(2+)-selective channel involved in transcellular Ca(2+) absorption expressed in kidney and in the ruffled border of osteoclasts. Studies in hypercalciuric TRPV5 knockout (TRPV5(-/-)) mice, which display significantly increased vitamin D levels, showed that TRPV5 ablation increases number and size of osteoclasts but impairs osteoclast-mediated bone resorption. The latter is not in line with the observed decreased bone thickness in TRPV5(-/-) mice. Bisphosphonates also inhibit osteoclast-mediated bone resorption. The aim of this study was to evaluate the effect of alendronate on the expression of the Ca(2+) transporters in bone, kidney, and duodenum and, importantly, the bone phenotype in TRPV5(-/-) mice. Wildtype (TRPV5(+/+)) and TRPV5(-/-) mice were treated during 10 wk with 2 mg/kg alendronate or vehicle weekly and housed in metabolic cages at the end of treatment. Urine and blood samples were taken for biochemical analysis, and duodenum, kidney, and femur were sampled. Expression of Ca(2+) transporters and osteoclast ruffled border transporters in bone and cultured osteoclasts was determined by QPCR analysis. Femurs were scanned using muCT, and resorption pit assays were performed in bone marrow cultures isolated from TRPV5(+/+) and TRPV5(-/-) mice. Alendronate treatment enhanced bone thickness in TRPV5(+/+) mice but also normalized the disturbed bone morphometry parameters in TRPV5(-/-) mice. Bone TRPV5 expression was specifically enhanced by alendronate, whereas the expression of Ca(2+) transporters in kidney and intestine was not altered. The expression of the osteoclast ruffled border membrane proteins chloride channel 7 (CLC-7) and the vacuolar H(+)-ATPase did not differ between both genotypes, but alendronate significantly enhanced the expression and PTH levels in TRPV5(-/-) mice. The expression of TRPV5, CLC-7, and H(+)-ATPase in osteoclast cultures was not affected by alendronate. The number of resorption pits was reduced in TRPV5(-/-) bone marrow cultures, but the response to vitamin D was similar to that in TRPV5(+/+) cultures. The alendronate-induced upregulation of TRPV5 in bone together with the decreased resorptive capacity of TRPV5(-/-) osteoclasts in vitro suggests that TRPV5 has an important role in osteoclast function. However, our data indicate that significant bone resorption still occurs in TRPV5(-/-) mice, because alendronate treatment normalized bone thickness in these mice. Thus, TRPV5(-/-) mice are able to rescue the resulting defect in osteoclast-mediated bone resorption, possibly mediated by the long-term hypervitaminosis D or other (non)hormonal compensatory mechanisms.
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PMID:Bone resorption inhibitor alendronate normalizes the reduced bone thickness of TRPV5(-/-) mice. 1859 25

Egg laying and shell calcification impose severe extra demands on ionic calcium (Ca2+) homeostasis; especially in birds characterized by their long clutches (series of eggs laid sequentially before a "pause day"). These demands induce vitamin D metabolism and expression. The metabolism of vitamin D is also altered indirectly, by other processes associated with increased demands for calcium, such as growth, bone formation and egg production. A series of intestinal, renal or bone proteins are consequently expressed in the target organs via mechanisms involving a vitamin D receptor. Some of these proteins (carbonic anhydrase, calbindin and calcium-ATPase) are also found in the uterus (eggshell gland) or are believed to be involved in calcium transport in the intestine or kidney (calcium channels). The present review deals with vitamin D metabolism and the expression of the above-mentioned proteins in birds, with special attention to the strongly calcifying laying bird.
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PMID:Calcium homeostasis and vitamin D metabolism and expression in strongly calcifying laying birds. 1868 98

Erythrocyte-derived depressing factor (EDDF) shows significant protective effects on blood vessels from hypertensive rats, by regulating vascular reactivity, calcium homeostasis, DNA synthesis, and cell cycle progression in vascular smooth muscles (VSMCs). Arteries from hypertensive and aging people have high levels of accumulated calcium. However, in the life span of experimental animals commonly used, arterial calcium content does not reach cytotoxic levels observed in human. An overdose of vitamin D(3) results in a rapid arterial calcium overload. Using rats with arterial calcinosis and age- and gender-matched Wistar controls, we investigated whether EDDF has beneficial effect on blood vessels from animals with arterial calcinosis. Blood vessel functions were impaired in rats with arterial calcinosis, as indicated by decreased Ca(2+)-ATPase activity, increased vasoconstrictor responses to alpha1 adrenoceptor agonist phenylephrine and increased ERK1/2 phosphorylation. Arterial calcium overload also impaired the morphological integrity of VSMCs. EDDF restored the abovementioned abnormalities caused by arterial calcinosis, and inhibited cell cycle progression of VSMCs induced by angiotensin II. In conclusion, EDDF may protect blood vessels from animals with arterial calcinosis, which is mediated by regulating calcium homeostasis, vascular reactivity and cell cycle progression as well as by improving morphological integrity of VSMCs.
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PMID:Experimental vasoprotection by a novel erythrocyte-derived depressing factor in rats with arterial calcinosis. 1899 68

Numerous studies have shown that the active form of vitamin D, 1,25(OH)(2)D(3), can exert growth inhibitory effects on human breast cancer cells and mammary tumor growth. However, the molecular mechanisms remain to be fully delineated. This study demonstrates for the first time that CCAAT enhancer-binding protein alpha (C/EBPalpha), a member of the C/EBP family of transcription factors, is induced by 1,25(OH)(2)D(3) and is a potent enhancer of VDR transcription in MCF-7 breast cancer cells. 1,25(OH)(2)D(3) was found to induce C/EBPalpha as well as VDR expression in MCF-7 cells. C/EBPalpha was not detected in MDA-MB-231 cells that are poorly responsive to 1,25(OH)(2)D(3). Antiproliferative effects of 1,25(OH)(2)D(3) and induction of VDR were observed in MDA-MB-231 cells transfected with C/EBPalpha, and knockdown of C/EBPalpha suppressed VDR and antiproliferative effects of 1,25(OH)(2)D(3) in MCF-7 cells. Transfection of C/EBPalpha in MCF-7 cells resulted in a dose-dependent enhancement of hVDR transcription. Our studies show that C/EBPalpha can bind to Brahma (Brm), an ATPase that is a component of the SWI/SNF complex, and cooperate with Brm in the regulation of hVDR transcription in MCF-7 cells. Because the levels of VDR in MCF-7 breast cancer cells correlate with the antiproliferative effects of 1,25(OH)(2)D(3) and because C/EBPalpha has been suggested as a potential tumor suppressor in breast cancer, these findings provide important mechanisms whereby 1,25(OH)(2)D(3) may act to inhibit growth of breast cancer cells. These findings also identify C/EBPalpha as a 1,25(OH)(2)D(3) target in breast cancer cells and provide evidence for C/EBPalpha as a candidate for breast cancer treatment.
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PMID:CCAAT enhancer-binding protein alpha is a molecular target of 1,25-dihydroxyvitamin D3 in MCF-7 breast cancer cells. 1905 66

The discovery that two recently identified molecules, klotho and fibroblast growth factor 23 (FGF23), played an important role in calcium, phosphate, and vitamin D metabolism has transformed our traditional physiological view in which bone and mineral homeostasis was mainly regulated by parathyroid hormone, vitamin D, and calcitonin, according to mineral body needs. FGF23 is a 251-amino acid secreted protein produced by osteoblasts and osteocytes in bone following the stimulation by phosphate and vitamin D or the inhibition by dentin matrix protein 1. Originally isolated from tumoral cells of patients with tumor-induced osteomalacia and hypophosphatemia, FGF23 inhibits phosphate reabsorption in renal proximal tubular cells and 1alpha-hydroxylase activity, resulting in decreased synthesis of calcitriol. To exert these actions, FGF23 requires the conversion, by klotho, of the canonical FGF receptor 1 (IIIc) in a specific high affinity FGF23 receptor. On the other hand, klotho is a putative antiaging gene identified in 1997 when a particular mouse strain, created by random insertion mutagenesis, was found to be short-lived and displayed premature atherosclerosis, osteopenia, skin atrophy, pulmonary emphysema, hyperphosphatemia, hypercalcemia, and high serum calcitriol levels. The gene of klotho encodes a 1012-amino acid cell-surface protein with a short cytoplasmic tail and an extracellular domain that consists in tandem duplicated copies of a beta-glucuronidase-like sequence, which can be released into the circulation as soluble forms after being cleaved by metalloproteinases such as ADAM10 and ADAM17. By modulating FGF23 action, klotho regulates urinary phosphate excretion and calcitriol synthesis. By virtue of its beta-glucuronidase activity, klotho deglycosylates the calcium channel TRPV5 (transient receptor potential vallinoid-5) and regulates urinary calcium excretion. klotho also binds to Na(+),K(+)-ATPase in parathyroid cells and regulates calcium-stimulated PTH secretion. Finally, klotho extends life span via several mechanisms, including the reduction of calcitriol synthesis, serum calcium, and phosphorus levels; the induction of insulin resistance; and by increasing the resistance to oxidative stress.
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PMID:Klotho gene, phosphocalcic metabolism, and survival in dialysis. 1912 71

The active form of vitamin D(3), 1alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], is a potent ligand for the nuclear receptor vitamin D receptor (VDR) and induces myeloid leukemia cell differentiation. The cardiotonic steroid bufalin enhances vitamin D-induced differentiation of leukemia cells and VDR transactivation activity. In this study, we examined the combined effects of 1,25(OH)(2)D(3) and bufalin on differentiation and VDR target gene expression in human leukemia cells. Bufalin in combination with 1,25(OH)(2)D(3) enhanced the expression of VDR target genes, such as CYP24A1 and cathelicidin antimicrobial peptide, and effectively induced differentiation phenotypes. An inhibitor of the Erk mitogen-activated protein (MAP) kinase pathway partially inhibited bufalin induction of VDR target gene expression. 1,25(OH)(2)D(3) treatment induced transient nuclear expression of VDR in HL60 cells. Interestingly, bufalin enhanced 1,25(OH)(2)D(3)-induced nuclear VDR expression. The MAP kinase pathway inhibitor increased nuclear VDR expression induced by 1,25(OH)(2)D(3) and did not change that by 1,25(OH)(2)D(3) plus bufalin. A proteasome inhibitor also enhanced 1,25(OH)(2)D(3)-induced CYP24A1 expression and nuclear VDR expression. Bufalin-induced nuclear VDR expression was associated with histone acetylation and VDR recruitment to the CYP24A1 promoter in HL60 cells. Thus, the Na(+),K(+)-ATPase inhibitor bufalin modulates VDR function through several mechanisms, including Erk MAP kinase activation and increased nuclear VDR expression.
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PMID:Increased nuclear expression and transactivation of vitamin D receptor by the cardiotonic steroid bufalin in human myeloid leukemia cells. 1942 44

Since the discovery of alphaklotho-mutant mice, it has been questioned whether the responsible gene, alphaklotho, makes any effect on 'intrinsic aging' process. So far we found that alphaKlotho regulates transcellular calcium transport by mediating Na,K-ATPase activity and dominates mineral-regulating hormones such as PTH, vitamin D and FGF23. A new concept is now emerged that alphaklotho integrates mineral homeostasis. Findings of human cases with mineral disorders revealed impairment of alphaklotho expression as a pathological cause. Mineral metabolic system contributes to health and thus its disruption should result in acceleration of aging and disease.
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PMID:[Aspects of mammalian aging from alphaklotho study]. 1959 Dec 73

Calcium absorption by the intestine is necessary for bone mineralization. Much has been learned about this process and the role of vitamin D metabolites in gene transcription from animal studies, but the molecular mechanisms in humans are less well understood. We have used samples of normal human duodenal mucosa, obtained at endoscopy, to investigate the effects of the vitamin D metabolites, 1alpha-dihydroxycholecalciferol [1,25(OH)(2)D(3)] and 25-hydroxycholecalciferol (25OHD), on transcripts on genes involved in calcium absorption and vitamin D metabolism. TRPV6 transcripts were significantly higher after incubation for 6 h with 1,25(OH)(2)D(3) (10(-9) mol/l) than after control incubations (median difference 3.1-fold, P < 0.001). Unexpectedly, TRPV6 expression was also higher (2.4-fold, P < 0.02) after incubation with 25OHD (10(-7) mol/l). Transcripts for the calcium-ATPase, PMCA1, were significantly higher with 1,25(OH)(2)D(3); CYP24 transcripts were reliably detected after incubation with either metabolite, but calbindin-D9k transcripts were unaffected. The response of TRPV6 to 25OHD and the expression of transcripts for CYP27B1, the 25OHD-1alpha-hydroxylase, were significantly correlated (r = 0.82, P < 0.02). Basal duodenal expression of TRPV6 and CYP27B1 were significantly associated (r = 0.72, P < 0.001) in a separate previously reported series of subjects. Multiple regression analysis of the associations with basal duodenal TRPV6 expression identified CYP27B1 expression and serum 1,25(OH)(2)D as major factors. Expression of the CYP27B1 protein was demonstrated immunohistochemically in duodenal mucosa. This study has shown that human duodenal TRPV6, PMCA1, and CYP24 transcripts respond rapidly to 1,25(OH)(2)D(3) and provides evidence suggesting that local duodenal production of 1,25(OH)(2)D(3) by 25OHD-1alpha-hydroxylase may have a role in human calcium absorption.
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PMID:Human duodenum responses to vitamin D metabolites of TRPV6 and other genes involved in calcium absorption. 1977 13


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