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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The osteoclastogenic factor of osteoblastic origin has recently been elucidated as a novel Tumor Necrosis Factor (TNF)-ligand family member, termed osteoclast differentiation factor (ODF). Using a semiquantitative RT-PCR approach, we sought to determine the mRNA expression of ODF and its decoy receptor, osteoprotegerin (OPG), in a selection of osteoblastic cell lines and in response to three factors representative of different signal transduction pathways, vitamin D receptor, protein kinase A or gp130. Each osteotropic agent, either 1,25-(OH)2D3, PTH or IL-11, promoted an increase in the ratio of ODF:OPG, with maximal stimulation occurring at 24 h, 4 h, and 8 h, respectively, and furthermore each was shown to act in a dose-dependent manner. This report establishes that osteoblastic cell lines incapable of supporting osteoclast formation have markedly reduced ODF expression and also illustrates the importance of the relative abundance of ODF compared with the levels of OPG for the induction of osteoclastogenesis.
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PMID:Osteotropic agents regulate the expression of osteoclast differentiation factor and osteoprotegerin in osteoblastic stromal cells. 979 88

Reflecting the prime role of 1alpha,25(OH)2D3 in calcium homeostasis, the activity of 25-hydroxyvitamin D3 1alpha-hydroxylase, a key enzyme for 1alpha,25(OH)2D3 biosynthesis, is tightly regulated by 1alpha,25(OH)2D3, PTH and calcitonin. Its significant activity is found in kidney, though the enzymatic activity is also reported in extra-renal tissues. In the present study, we found that the 1alpha-hydroxylase gene abundantly expresses in kidney, and at low levels in other tissues and in some cell lines. Positive and negative regulations of 1alpha-hydroxylase gene by PTH, calcitonin, or 1alpha,25(OH)2D3 were observed at transcriptional levels in kidneys of animals and in a mouse proximal tubule cell line. Moreover, the protein kinase A inhibitor abrogated the PTH-mediated positive regulation. In mice lacking the vitamin D receptor, the 1alpha-hydroxylase gene expression was overinduced, and the inducible effect of either PTH or calcitonin, but not the repression by 1alpha,25(OH)2D3, was evident. Thus, vitamin D receptor is essential for the negative regulation by 1alpha,25(OH)2D3. Moreover, we demonstrate that renal 1alpha-hydroxylase gene expression in chronic renal failure model rats was decreased and the positive effect by PTH and calcitonin was diminished. The present study demonstrates that PTH and calcitonin positively regulate renal 1alpha-hydroxylase gene expression via PKA-dependent and independent pathway, respectively, and that 1alpha,25(OH)2D3 negatively regulates it mediated by vitamin D receptor. Furthermore, in a moderate state of chronic renal failure, renal cells expressing the 1alpha-hydroxylase gene appear to have diminished potential in response to PTH and calcitonin.
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PMID:Positive and negative regulations of the renal 25-hydroxyvitamin D3 1alpha-hydroxylase gene by parathyroid hormone, calcitonin, and 1alpha,25(OH)2D3 in intact animals. 1021 75

Nuclear steroid/thyroid/retinoid receptors and c-erbB membrane receptor tyrosine kinases control epithelial growth and differentiation. Retinoid receptors can dimerize with the vitamin D receptor, the glucocorticoid receptor or the thyroid receptor. Furthermore, multiple c-erbB receptor dimers have been identified. It has been shown that some of these receptor pathways communicate with each other via cross-connected regulatory networks. Molecular interactions between retinoid receptors or estrogen receptors (ER) and c-erbB-2, and between ER and retinoic acid receptor(RAR)-alpha have been reported. Here, we demonstrate the effects of steroids/thyroids/retinoids and of activators of protein kinase A (forskolin, Forsk) and C (12-O-tetradecanoylphorbol-13-acetate, TPA), on growth and expression of c-erbB and RARs in MCF-7 breast cancer cells, which contain high levels of RAR-alpha and -gamma, and which express significant amounts of c-erbB-2 and -3. All trans-retinoic acid (tRA), the anti-estrogen ICI 182 780 (ICI), Forsk and TPA reduced, whereas triiodothyronine and 17beta-estradiol (E2) stimulated cell growth. Flow cytometry revealed that tRA and E2 reduced c-erbB-2 and -3, whereas tamoxifen, Forsk and TPA up-regulated c-erbB-2. c-erbB-3 was co-regulated with c-erbB-2. Northern analysis demonstrated that RAR-alpha was down-regulated by dexamethasone, ICI, and TPA, whereas vitamin D3 and E2 up-regulated RAR-alpha. RAR-gamma expression was less responsive to such treatment, being reduced only by ICI and Forsk. These data indicate that nuclear receptor and protein kinase signaling communicate with each other and control the expression of RARs and c-erbB receptors. Efficient growth control requires the coordinated interplay of both receptor systems.
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PMID:Involvement of nuclear steroid/thyroid/retinoid receptors and of protein kinases in the regulation of growth and of c-erbB and retinoic acid receptor expression in MCF-7 breast cancer cells. 1067 83

Secondary hyperparathyroidism (SH) and hyperplasia of the parathyroid glands (PTG) are universal complications in patients with CRF. In early renal failure, reduction in serum calcitriol and moderate decreases in ionized calcium contribute to greater synthesis and secretion of PTH. As renal disease progresses, a reduction in parathyroid expression of vitamin D receptor and calcium receptor renders the PTG more resistant to both calcitriol and calcium. High dietary phosphorus (P), independent of calcium and calcitriol, further enhances uremia-induced PTG hyperplasia and PTH synthesis and secretion, the latter by posttranscriptional mechanisms. Once SH develops, dietary P restriction can return the high serum PTH levels toward normal, however, parathyroid hyperplasia persists. Studies in our laboratory identified 2 of the mechanisms involved in the opposing effects of high and low dietary P content on PTG growth. Whereas high dietary P increases parathyroid expression of transforming growth factor alpha (TGFalpha), a growth promoter, P restriction induces the cyclin-dependent kinase inhibitor p21, an inducer of growth arrest. Both effects of P are specific for the PTG. No increase in either protein was observed in liver or intestine. TGFalpha induction of hyperplasia involves binding to the epidermal growth factor receptor and activation of mitogen activated protein (MAP) kinases cascades. p21 blocks progression through the cycle and cell division by inactivating cyclin/cyclin-dependent kinase complexes. Preventing hyperphosphatemia and elevated Ca x P product in renal failure not only ameliorates the progression of SH and bone disease but also the morbidity and mortality resulting from vascular calcification.
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PMID:Role of phosphorus in the pathogenesis of secondary hyperparathyroidism. 1115 62

Two controversial aspects in the mechanism of human vitamin D receptor (hVDR) action are the possible significance of VDR homodimers and the functional role of receptor phosphorylation. To address these issues, milligram quantities of baculovirus-expressed hVDR were purified to 97% homogeneity, and then tested for binding to the rat osteocalcin vitamin D responsive element (VDRE) via electrophoretic mobility shift and half-site competition assays in the presence or absence of a CV-1 nuclear extract containing retinoid X receptor (RXR). Methylation interference analysis revealed that both the hVDR homodimer and the VDR-RXR heterodimer display similar patterns of VDRE G-base protection. However, in competition studies, the relative dissociation of the homodimeric hVDR complex from the VDRE was extremely rapid (t1/2 < 30 s) compared to the dissociation of the heteromeric complex (t1/2 > 5 min), thus illustrating the relative instability and low affinity of homodimeric VDR binding to DNA. These results indicate that VDR-RXR heterodimers are the preferred VDRE binding species. Further, two dimensional gel electrophoresis of hVDR demonstrated several isoelectric forms of the receptor, suggesting that it is subject to multiple phosphorylation events. In vitro kinase assays confirmed that purified hVDR is an efficient substrate for protein kinases A and Cbeta, as well as casein kinase II. In vivo studies of the expressed receptor in intact cells, namely baculovirus vector infected Sf9 insect cells and transfected mammalian COS-7 cells, demonstrated that hVDR was phosphorylated in a hormone-enhanced fashion. Functional consequences of hVDR phosphorylation were suggested by the observations that: (i) potato acid phosphatase (PAP)-treated hVDR no longer interacted with the VDRE as either a homodimer or a heteromeric complex with RXR, and (ii) treatment of transfected COS-7 cells with a phosphatase inhibitor (okadaic acid) along with 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) resulted in a synergistic enhancement of both hVDR phosphorylation and transactivation of a VDRE-linked reporter gene, compared to the effect of treatment with either agent alone. These studies point to a significant role for phosphorylation of VDR in regulating high-affinity VDR-RXR interactions with VDREs, and also in modulating 1,25(OH)2D3-elicited transcriptional activation in target cells.
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PMID:Isolation of baculovirus-expressed human vitamin D receptor: DNA responsive element interactions and phosphorylation of the purified receptor. 1194 98

Vitamin D is a secosteroid that is metabolically activated and degraded through the actions of three cytochrome P450 hydroxylase enzymes. Bioactivation occurs through the sequential actions of cytochromes P450C25 and P450C1, resulting in synthesis of the pleiotropic hormone 1,25-dihydroxyvitamin D (1,25VD), which regulates over 60 genes whose actions include those associated with calcium homeostasis and immune responses as well as cellular growth, differentiation, and apoptosis. Inactivation of 1,25VD occurs by C23/C24 oxidation pathways that are catalyzed by the multifunctional cytochrome P450C24 enzyme. Both P450C1 and P450C24 are highly regulated enzymes whose differential expression is controlled in response to numerous cellular modulatory agents such as parathyroid hormone (PTH), calcitonin, interferon gamma, calcium, phosphorus, and pituitary hormones as well as the secosteroid hormone 1,25VD. Most thoroughly studied at the molecular level are the actions of PTH to upregulate P450C1 gene expression and 1,25VD to induce the expression of P450C24. The regulatory action of PTH is mediated through the protein kinase A pathway and involves the phosphorylation of transcription factors that function at the proximal promoter of the P450C1 gene. The upregulation of P450C24 by 1,25VD has both a rapid nongenomic and a slower genomic component that are functionally linked. The rapid response involves protein kinase C and mitogen-activated protein kinase (MAPK) pathways that direct the phosphorylation of nuclear transcription factors. The slower genomic actions are linked to the binding of 1,25VD to the vitamin D receptor (VDR) and the interaction of the VDR-1,25VD complex with its heterodimer partner retinoid-X-receptor and associated coactivators. The regulatory complex is assembled on vitamin D response elements in the proximal promoter of the P450C24 gene and functions to increase the transcription rate.
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PMID:Hydroxylase enzymes of the vitamin D pathway: expression, function, and regulation. 1205 41

Expression of cytochrome P450 3A4 (CYP3A4) is induced by 1,25-dihydroxyvitamin D(3)(1,25(OH)(2)D(3)) in Caco-2 cells. However, since a typical vitamin D responsive element has not been found in the 5(')-flanking region of the CYP3A4 gene, the mechanism of 1,25(OH)(2)D(3)-induced CYP3A4 mRNA expression is poorly understood. In the present study, we demonstrated that vitamin D receptor (VDR) is a critical factor for the induction using the antisense oligonucleotide technique. In addition, we found that treatment of Caco-2 cells with the protein kinase C (PKC) inhibitors, staurosporine and GF109203X, and the tyrosine kinase inhibitor, genistein, but not with the protein kinase A inhibitor, H-89, suppressed CYP3A4 mRNA induction by 1,25(OH)(2)D(3). The depletion of PKC by prolonged treatment with phorbol ester abolished the induction. On the other hand, protein kinase inhibitors used had no effects on the constitutive expression of VDR mRNA. Therefore, these observations suggest that 1,25(OH)(2)D(3)-induced CYP3A4 mRNA expression might be involved in phosphorylation events in addition to transcriptional regulation via VDR. However, 1,25(OH)(2)D(3) did not rapidly activate PKC in the Caco-2 cells used, while the treatment with staurosporine and GF109203X, but not genistein, decreased basal PKC activity by approximately 30% of the controls. Taken together, these findings suggest that the change in the phosphorylation state via PKC and tyrosine kinase might, at least in part, modulate 1,25(OH)(2)D(3)-induced CYP3A4 mRNA expression via VDR.
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PMID:Alteration of cellular phosphorylation state affects vitamin D receptor-mediated CYP3A4 mRNA induction in Caco-2 cells. 1214 48

Parathyroid hormone (PTH) or activators of protein kinase A (PKA) up-regulate the vitamin D receptor (VDR) and augment the induction by 1,25-dihydroxyvitamin D(3) of the expression of target genes (24-hydroxylase and osteopontin) in osteoblastic cells. To understand regulatory mechanisms involved, we asked whether the inducible cAMP early repressor (ICER), which serves as a dominant negative regulator of cAMP-induced transcription in other endocrine systems, may similarly play a role in modulation of vitamin D hormone action. In this study we demonstrate that PTH or 8-bromo-cAMP rapidly induces ICER mRNA and protein in osteoblastic cells. In UMR 106 osteoblastic cells transfected with an expression vector containing the ICER II-gamma coding sequence, cAMP or PTH enhancement of 1,25-dihydroxyvitamin D(3)-induced osteopontin and 24-hydroxylase mRNA and transcription is inhibited. The vitamin D response element is sufficient for the PKA enhancement of VDR-mediated transcription and is also sufficient to observe the inhibitory effect of ICER. Our data indicate that the mechanism of the inhibitory effect of ICER involves an inhibition of PKA-induced VDR transcription, and this inhibition may be mediated in part by binding of ICER to a cAMP response element-like sequence in the VDR promoter. This study provides evidence for the first time that ICER has a key regulatory role in the PKA enhancement of VDR transcription and therefore in the cross-talk between the PKA signaling pathway and the vitamin D endocrine system.
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PMID:Evidence for a regulatory role of inducible cAMP early repressor in protein kinase a-mediated enhancement of vitamin D receptor expression and modulation of hormone action. 1219 42

Epidemiologic data suggest that low exposure to vitamin D or 1alpha,25-dihydroxycholecalciferol (calcitriol) increases the risk of prostate cancer. Calcitriol, a central factor in bone and mineral metabolism, is also a potent antiproliferative agent in a wide variety of malignant cell types. We have demonstrated that calcitriol has significant antitumor activity in vitro and in vivo in prostate and squamous cell carcinoma model systems. Calcitriol, in these models, induces a significant G0/G1 arrest and modulates p21(Waf1/Cip1) and p27(Kip1), the cyclin-dependent kinase inhibitors. Calcitriol induces poly (adenosine diphosphate-ribose) polymerase cleavage, increases bax/bcl-2 ratio, reduces levels of phosphorylated mitogen-activated protein kinases (P-MAPKs; also known as extracellular signal-related kinase [ERK] 1/2) and phosphorylated Akt, induces caspase-dependent mitogen-activated protein kinase kinase (MEK) cleavage and upregulation of MEK kinase-1, all potential markers of the apoptotic pathway. We also have demonstrated that dexamethasone (dex) potentiates the antitumor effect of calcitriol through effects on the vitamin D receptor and decreases calcitriol-induced hypercalcemia. We initiated phase 1 and phase 2 trials of calcitriol, either alone or in combination with carboplatin, paclitaxel, or dex. Data from these studies indicate that high-dose calcitriol is feasible on an intermittent schedule, the maximum tolerated dose (MTD) is unclear, and dex or paclitaxel appear to ameliorate hypercalcemia. Studies continue to define the MTD of calcitriol on this intermittent schedule, either alone or with other agents, and to evaluate the mechanisms of calcitriol effects in prostate cancer models.
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PMID:Vitamin D receptor: a potential target for intervention. 1223 Oct 68

To study the physiological relevance of membrane-initiated steroid signaling, we investigated the correlation of age in male chickens with the magnitude of responses to 1,25-dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)] in duodena from 7-, 14-, 28-, and 58-wk-old birds. Measurements of 1,25-(OH)(2)D(3) (130 pM) responsiveness as a function of age, showed a decreased intestinal Ca(2+) transport. Western analyses of isolated basal lateral membranes indicated a decreased expression of the membrane-associated rapid response binding protein with increasing age. Saturation analyses of [(3)H]1,25-(OH)(2)D(3) binding to basal lateral membranes, revealed an allosteric interaction identified as cooperative binding. A significant increase in K(d) was observed with increasing age, indicating decreasing affinity. Determinations of the number of binding sites yielded a binding capacity of 190-250 fmol/mg protein during growth and maturation, whereas in adulthood (58 wk) saturable binding was no longer observed. Data obtained in parallel analyses of binding of [(3)H]1,25-(OH)(2)D(3) to nuclear fraction vitamin D receptor, in contrast, indicated an absence of cooperative binding and an absence of significant changes in K(d) or binding capacity with age. Membrane-initiated signal transduction by 1,25-(OH)(2)D(3) was assessed by determination of protein kinase C and A activities. Stimulation of protein kinase C activity in response to 1,25-(OH)(2)D(3) decreased with age, whereas no age-correlated changes in steroid-stimulated protein kinase A activities were observed. Thus, in conclusion, our experiments demonstrate that there is a decrease in responsiveness to exogenous 1,25-(OH)(2)D(3) as a function of age in duodena of male chickens, which can be correlated to a decreased affinity for 1,25-(OH)(2)D(3), a reduced expression of membrane-associated rapid response binding protein, and a decreased protein kinase C activity.
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PMID:Effect of growth and maturation on membrane-initiated actions of 1,25-dihydroxyvitamin D(3). I. Calcium transport, receptor kinetics, and signal transduction in intestine of male chickens. 1269 77


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