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)

To characterize further the function of the intracellular vitamin D receptor (VDR), we have developed stable transfectant variants of a vitamin D-responsive cell line (U937) which express either decreased or increased numbers of VDR. In this study we have analyzed changes in gene expression associated with this variable VDR expression. Initial experiments indicated that a 50% decrease in VDR levels was associated with a 2-fold increase in cell proliferation and a similar rise in c-myc mRNA expression. Further studies were carried out using differential RNA display (DD). Sequence analysis of DD products revealed two cDNAs with identity to known gene products: the catalytic sub-unit of DNA-protein kinase (DNA-PK(CS)), and the peroxisomal enzyme 17beta-hydroxysteroid dehydrogenase type IV (17beta-HSD IV). Northern analysis confirmed that expression of both mRNAs was reduced in cells with decreased numbers of VDR. Down-regulation of 17beta-HSD IV mRNA expression was associated with enhanced estradiol inactivation by U937 cells, suggesting a link between estrogenic pathways and cell proliferation. Further Northern analyses indicated that there was no significant change in 17beta-HSD IV or DNA-PK(CS) mRNA levels following treatment with 1,25(OH)2D3, although expression of both genes varied with changes in cell proliferation. These data suggest that, in addition to its established role as a hormone-dependent trans-activator, VDR may influence gene expression by ligand-independent mechanisms.
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PMID:Differential RNA display identifies novel genes associated with decreased vitamin D receptor expression. 978 9

The vitamin D endocrine system has been involved in the impairment of intestinal calcium absorption during aging. Alterations in the nongenomic mechanism of calcitriol (1,25-dihydroxy-vitamin D3; [1, 25(OH)2D3] have been recently evidenced. In enterocytes isolated from aged rats, 1,25(OH)2D3 stimulation of Ca2+ channels through the cAMP/PKA pathway is blunted. We have now investigated whether in vivo administration of calcitriol to senescent rats reverses the absence of hormonal effects in isolated intestinal cells. In enterocytes from 20-24-month-old rats given 1,25(OH)2D3 for 3 days (30 ng/100 g bw/day), calcitriol (10(-10) M, 3-5 minutes) stimulated Ca2&plus uptake and intracellular cAMP to the same degree and protein quinase A (PKA) activity to a lesser degree than in enterocytes from young animals. Significantly higher basal levels of cAMP and PKA detected in enterocytes from old rats were not affected by prior injection of animals with 1,25(OH)2D3. When the aged rats were injected with 25(OH)D3, similar Ca2+ influx, cAMP, and PKA responses to in vitro stimulation with calcitriol were obtained. 1, 25(OH)2D3-dependent changes in Ca2+ uptake by enterocytes from both young and old rats treated with calcitriol were totally suppressed by the cAMP antagonist Rp-cAMPS, whereas the response to the agonist Sp-cAMPS was markedly depressed in aged animals. These results suggest that intestinal resistance to nongenomic 1,25(OH)2D3 stimulation of duodenal cell Ca2+ uptake develops in rats upon aging and show that in vivo administration of 1,25(OH)2D3 or its precursor to senescent rats restores the ability of the hormone to stimulate duodenal cell calcium influx through the cAMP messenger system.
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PMID:In vivo treatment with calcitriol (1,25(OH)2D3) reverses age-dependent alterations of intestinal calcium uptake in rat enterocytes. 991 27

The hormonal form of vitamin D, 1,25-dihydroxyvitamin D3 [1, 25(OH)2D3], is a potent inhibitor of cellular proliferation as well as an inducer of differentiation of myeloid leukemic cells to macrophages. We have previously reported that a number of genes are upregulated by 1,25(OH)2D3 during myeloid differentiation, including the cyclin-dependent kinase (CDK) inhibitors p21, p27, 15, and p18, suggesting that cell cycle arrest and differentiation are tightly linked processes. We further explore here the relationship between growth inhibition and differentiation. We report that, upon 1, 25(OH)2D3 treatment, U937 cells exhibited an early proliferative burst followed by growth inhibition and subsequent differentiation. Although CDK levels remain constant throughout, this transient increase in proliferation was accompanied by increases in cyclin A, D1, and E protein levels. p21 and p27 levels were also elevated during both the proliferative burst and subsequent inhibition of cell growth. Ectopic overexpression of p21 and/or p27 in U937 cells, in the absence of hormone, resulted in an induction of the expression of monocyte/macrophage-specific markers, whereas overexpression of p15 and p18 had no effect, suggesting that a subset of CDK inhibitors are important for both growth arrest and differentiation and that an early increase in proliferation is somehow a prerequisite for subsequent differentiation. However, no such biphasic behavior was detected in cells that are growth inhibited by 1,25(OH)2D3 but do not differentiate, such as MCF-7 cells. Taken together, these results indicate that both growth stimulation and subsequent inhibition precede differentiation and involve induction of both cyclins and p21 and p27, whereas cell cycle arrest of differentiated cells can be achieved simply by elevations in CDK inhibitors.
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PMID:Induced differentiation of U937 cells by 1,25-dihydroxyvitamin D3 involves cell cycle arrest in G1 that is preceded by a transient proliferative burst and an increase in cyclin expression. 1019 52

Prior studies have shown that 24,25-dihydroxyvitamin D3 [24,25-(OH)2D3] plays a major role in resting zone chondrocyte differentiation and that this vitamin D metabolite regulates both phospholipase A2 and protein kinase C (PKC) specific activities. Arachidonic acid is the product of phospholipase A2 action and has been shown in other systems to affect a variety of cellular functions, including PKC activity. The aim of the present study was to examine the interrelationship between arachidonic acid and 24,25-(OH)2D3 on markers of proliferation, differentiation, and matrix production in resting zone chondrocytes and to characterize the mechanisms by which arachidonic acid regulates PKC, which was shown previously to mediate the rapid effects of 24,25-(OH)2D3 and arachidonic acid on these cells. Confluent, fourth passage resting zone cells from rat costochondral cartilage were used to evaluate these mechanisms. The addition of arachidonic acid to resting zone cultures stimulated [3H]thymidine incorporation and inhibited the activity of alkaline phosphatase and PKC, but had no effect on proteoglycan sulfation. In contrast, 24,25-(OH)2D3 inhibited [3H]thymidine incorporation and stimulated alkaline phosphatase, proteoglycan sulfation, and PKC activity. In cultures treated with both agents, the effects of 24,25-(OH)2D3 were reversed by arachidonic acid. The PKC isoform affected by arachidonic acid was PKCalpha; cytosolic levels were decreased, but membrane levels were unaffected, indicating that translocation did not occur. Arachidonic acid had a direct effect on PKC in isolated plasma membranes and matrix vesicles, indicating a nongenomic mechanism. Plasma membrane PKCalpha was inhibited, and matrix vesicle PKCzeta was stimulated; these effects were blocked by 24,25-(OH)2D3. Studies using cyclooxygenase and lipoxygenase inhibitors indicate that the effects of arachidonic acid are due in part to PG production, but not to leukotriene production. This is supported by the fact that H8-dependent inhibition of protein kinase A, which mediates the effects of PGE2, had no effect on the direct action of arachidonic acid but did mediate the role of arachidonic acid in the cell response to 24,25-(OH)2D3. Diacylglycerol does not appear to be involved, indicating that phospholipase C and/or D do not play a role. Gamma-linolenic acid, an unsaturated precursor of arachidonic acid, elicited a similar response in matrix vesicles but not plasma membranes, whereas palmitic acid, a saturated fatty acid, had no effect. These data suggest that arachidonic acid may act as a negative regulator of 24,25-(OH)2D3 action in resting zone chondrocytes.
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PMID:Arachidonic acid directly mediates the rapid effects of 24,25-dihydroxyvitamin D3 via protein kinase C and indirectly through prostaglandin production in resting zone chondrocytes. 1038 91

Studies were undertaken to determine whether 24,25-dihydroxyvitamin D3 (24,25(OH)2D3) modulates the rapid effects of 1, 25-dihydroxyvitamin D3 (1,25(OH)2D3) and parathyroid hormone (PTH) on calcium transport in the perfused chick intestine. Perfusion with control media resulted in a transport ratio (treated/average basal) of 1.07 +/- 0.06 at t = 40 minutes, while perfusion with 65, 130, 300, or 650 pM 1,25(OH)2D3 yielded ratios of 1.92 +/- 0.23, 2.6 +/- 0.4, 2.8 +/- 0.08, and 3.34 +/- 0.37, respectively. Simultaneous perfusion with each of these doses and 6.5 nM 24,25(OH)2D3 reduced treated/average basal ratios to approximately 1.4 after 40 minutes of perfusion. Vascular perfusion with 65 pM bovine PTH [bPTH(1-34)] stimulated intestinal calcium transport ratios to 3.0 +/- 0.5 after 40 minutes, while the inclusion of 6.5 nM 24,25(OH)2D3 reduced ratios at this time point to 0.56 +/- 0.19. To investigate the effect of these agents on signal transduction, isolated intestinal cells were monitored for intracellular calcium changes using the indicator dye fura-2. After establishing a stable baseline, addition of 130 pM 1,25(OH)2D3 induced rapid calcium oscillations. Intestinal cells exposed to 6.5 nM 24,25(OH)2D3 also exhibited rapid oscillations in fluorescence, which were not further altered by subsequent addition of 1,25(OH)2D3. Incubation of isolated cells with 130 pM 1,25(OH)2D3 was found to increase protein kinase C (PKC) activity within 5 minutes, and protein kinase A (PKA) activity within 7 minutes. Exposure of cells to 65 pM bPTH(1-34) had minimal effect on PKC activity, but resulted in pronounced increases in PKA activity. Stimulation of protein kinases by either secosteroid or peptide hormone was inhibited in the presence of 6.5 nM 24,25(OH)2D3. It is concluded that 24,25(OH)2D3 may exert endocrine actions on intestine.
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PMID:24,25-dihydroxyvitamin D3 suppresses the rapid actions of 1, 25-dihydroxyvitamin D3 and parathyroid hormone on calcium transport in chick intestine. 1046 82

In the rat thyroid FRTL-5 cell line calcitriol, the biologically most active of the naturally occurring vitamin D metabolites, attenuates both TSH-stimulated cAMP production and the effects of cAMP. Calcitriol treatment abolishes the upregulation of the TSHR number occurring in cells cultivated in the absence of TSH. In addition, the level of G(i-2)alpha increases, which may further attenuate the transmembrane signaling of TSH and facilitate the effects of IGFs. The effect of cAMP on PKAI stimulation is inhibited by increasing the level of the PKA subunit RIIbeta. Regulation of TSHR, G(i-2)alpha and RIIbeta is associated with altered cell proliferation and differentiation in several cells and tissues. Effects of calcitriol on these proteins indicate how the vitamin D endocrine system may regulate cAMP signaling in both classical and nonclassical target tissues.
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PMID:Vitamin D: a hormonal regulator of the cAMP signaling pathway. 1056 77

We examined the effects of cyclic adenosine 3',5'-monophosphate (cAMP) and protein kinase A (PKA) on the ligand-dependent transactivation mediated via the 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) receptor (VDR). A human VDR expression plasmid was transfected into HeLa, Saos-2 and MG63 cells with a luciferase reporter gene construct containing the vitamin D responsive element. With the addition of 0.5 mM 8 bromo-cAMP, the response to 1,25(OH)2D3 was suppressed to 61 and 78% in the HeLa and Saos-2 cells, respectively. The suppressive effect of 8 bromo-cAMP was observed without the introduction of the VDR expression plasmid in the MG63 cells. In the HeLa cells the co-expression of PKA reduced the ligand-inducible transactivation to 61% and the fold induction by 1,25(OH)2D3 to 89% of that without PKA. The CREB binding protein (CBP) was recently reported to integrate the intracellular signals via the cAMP/PKA cascade and nuclear hormone receptors. However, the suppressive effect of cAMP was not influenced by the co-expression of CBP. Lastly, we introduced point mutations at possible PKA phosphorylation sites into the VDR expression vector at serine-172 and threonine-175, but both mutant receptors still exhibited reduced transactivation with the co-expression of PKA. These results indicate that the phosphorylation of proteins other than the VDR may also be involved in the inhibitory effect mediated by the cAMP/PKA cascade.
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PMID:Effect of cyclic adenosine 3',5'-monophosphate and protein kinase A on ligand-dependent transactivation via the vitamin D receptor. 1068 51

A protamine kinase from HL60 cells was purified to near homogeneity by DEAE-Sephacel, protamine-agarose, Hydroxylapatite, and S-200 chromatography. It was purified by 75.8-fold through four chromatographic steps, and 0.67% of total activity was recovered. The purified enzyme had an apparent molecular mass of 120 kDa and was activated by Mg(2+) or Mn(2+), but inhibited by Ca(2+). Neither phospholipid nor phorbol ester significantly affected the enzyme activity. Staurosporine was the most potent inhibitor of the enzyme among the protein kinase inhibitors tested, K(252a), H(7), heparin, and staurosporine. The purified protamine kinase exhibited a maximum velocity of 5,000 pmol/min/mg and K(m) of 1.3 mM for protamine sulfate as a substrate. Myelin basic protein and protamine sulfate served as the best substrates for the protamine kinase among those tested. The activity of the protamine kinase remained unchanged upon treatment with PMA, retinoic acid, dimethyl sulfoxide, or 1,25 dihydroxy vitamin D(3) for 15 min, while treatment with a differentiating agent, 1,25 dihydroxy vitamin D(3), for one week increased its activity. These results suggest that protamine kinase in HL60 cells is involved in the late stage of the macrophage-monocytic differentiation pathway and may play a role in maintenance of the differentiation after HL60 cells are committed.
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PMID:Purification and characterization of a novel protamine kinase in HL60 cells. 1073 71

The effect of vitamin D status on levels of the putative 1, 25(OH)(2)D(3) membrane receptor (pmVDR) was studied in chick intestine, kidney, and brain. Western analyses and assays for specific [(3)H]1,25(OH)(2)D(3) binding indicated that, in intestine, pmVDR levels were greatest in -D chicks relative to +1,25D and +D animals (P < 0.05). In kidney, protein levels and specific binding followed the order +D > +1,25D, -D. In brain, vitamin D status did not affect protein levels or specific binding levels. In tissue from normal chicks, both protein and specific binding followed the order of intestine > kidney > brain membranes. Intestinal cells were further evaluated for the effect of 1,25(OH)(2)D(3) on selected "rapid responses." Extrusion of (45)Ca in response to 130 pM 1, 25(OH)(2)D(3) in vitro was greater in cells from -D chicks than from +1,25D or normal birds. Analyses of signal transduction events revealed diminished hormone-induced intracellular calcium oscillations (as assessed by fura-2 fluorescence), and lack of steroid-enhanced protein kinase (PK) A activity in intestinal epithelial cells from -D chicks relative to +D chicks. PK C activation by 130 pM 1,25(OH)(2)D(3) was approximately twofold in cells from +D or -D chicks. The combined results indicate that vitamin D status differentially affects the pmVDR in intestine, kidney, and brain. In intestine, vitamin D deficiency differentially affects (45)Ca handling, intracellular calcium oscillations, PK A and PK C activities in response to 1,25(OH)(2)D(3).
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PMID:Immunochemical studies on the putative plasmalemmal receptor for 1, 25-dihydroxyvitamin D(3). III. Vitamin D status. 1093 16

Following PTH treatment, immediate changes in osteoblast gene expression involve induction of primary response genes. Primary gene products subsequently mediate the osteoblast response to PTH. Using representational difference analysis (RDA) to isolate primary genes induced by PTH in osteoblasts, we identified Nurr1, a member of the NGFI-B nuclear orphan receptor subfamily. Nurr1 binds DNA as a monomer but also heterodimerizes with the 9-cis retinoic acid receptor (RXR). Nurr1's importance in retinoic acid, vitamin D, and thyroid hormone signaling has been hypothesized. Nurr1 messenger RNA (mRNA) levels were maximal at 1 h and at 10 nM of PTH in primary mouse osteoblasts (MOB). Activation of the PKA and PKC pathways by 10 microM forskolin and 1 microM PMA, respectively, induced Nurr1 mRNA levels. However, inhibition of the PKA but not the PKC pathway significantly inhibited the PTH induction of Nurr1. Moreover, PTH(3-34) at 1-100 nM did not induce Nurr1 mRNA levels. Thus, PTH induction of Nurr1 in primary mouse osteoblasts is mediated primarily through the cAMP/PKA pathway. PTH also stimulated Nurr1 protein in MOB cells and Nurr1 mRNA in calvarial organ cultures. Nurr1 induction represents a potential cross-talk mechanism between PTH and steroid hormone signaling at the transcription factor level.
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PMID:Parathyroid hormone induces expression of the nuclear orphan receptor Nurr1 in bone cells. 1115 37


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