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

---

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

We have demonstrated previously that cultured rat ovarian granulosa cells synthesize and secrete apoE, and this production of apoE is increased by agents that stimulate protein kinase A (cyclic AMP-dependent enzyme) (for example, cholera toxin) and protein kinase C (Ca2+/phospholipid-dependent enzyme) (for example, 12-O-tetradecanoylphorbol-13-acetate, a phorbol ester). In the studies presented in this report, we have examined the effect of changes in cell cholesterol synthesis on the production of apoE by rat ovarian granulosa cells. Mevinolin, an inhibitor of hydroxymethylglutaryl (HMG)-CoA reductase (the rate-limiting enzyme in cholesterol synthesis), and 4,4,10 beta-trimethyl-trans-decal-3 beta-ol, an inhibitor of squalene cyclization, both attenuate the cholera toxin or 12-O-tetradecanoylphorbol-13-acetate stimulation of granulosa cell apoE secretion and apoE mRNA content in a dose-responsive manner. The inhibitory effect of mevinolin is reversed by the concomitant administration of mevalolactone, which provides the cells with the product of the reaction catalyzed by HMG-CoA reductase. Steroidogenesis per se has no effect on apoE production. Aminoglutethimide, which blocks the rate-limiting step in steroidogenesis, has no effect on apoE or apoE mRNA. The data indicate that products of HMG-CoA reductase (isoprenes, cholesterol and/or cholesterol metabolites) are required along with stimulators of protein kinases A and C, to regulate ovarian granulosa cell apoE production.
...
PMID:Rat granulosa cell apolipoprotein E secretion. Regulation by cell cholesterol. 277 96

L-Selectin initiates leukocyte attachment to venular endothelium during lymphocyte recirculation through lymph nodes, leukocyte recruitment into sites of inflammation, and the hematogenous spread of lymphoid malignancies. The density of L-selectin at the cell surface is a major determinant of binding activity and entry into tissues. Post-transcriptional shedding is one control mechanism; however, the extent and physiologic relevance of pre-translational regulation has not been defined. The current study shows that mitogen-/IL-2-driven proliferation of human T cells first increased then markedly decreased the expression of L-selectin on the blast population. The prevalence of specific mRNA showed parallel changes, implying that receptor density is controlled, in part, at the pretranslational level. We used the IL-2-independent Jurkat cell line to determine whether signaling through C-type protein kinases and intracellular calcium regulated L-selectin mRNA directly. Selective pharmacologic activation of these pathways with phorbol esters and calcium ionophore, respectively, resulted in opposite effects on both L-selectin density and mRNA levels. Phorbol esters induced receptor shedding followed by progressive increases in L-selectin density and steady state levels of mRNA. Addition of a calcium ionophore with the phorbol ester blocked both the reexpression of surface receptor and the increase in mRNA. Treatment with ionophore alone resulted in a steady decline in L-selectin expression and mRNA levels. Cyclosporin A, a specific inhibitor of calcineurin, blocked the impact of ionophore on both basal and phorbol-induced levels of L-selectin mRNA. Ionophore alone did not induce apoptosis, significantly alter cell cycle kinetics, or increase transcription of the IL-2 gene under conditions that suppressed L-selectin. Thus, calcineurin seems to be a proximal enzyme in a novel regulatory cascade that suppresses L-selectin expression independent of its known effects on proliferating T cells. In light of the findings in Jurkat, we propose that the protein kinase pathway up-regulates L-selectin mRNA and surface expression early in mitogen-driven T cell proliferation. Chronic elevation of intracellular calcium in repeatedly stimulated T cells then down-regulates expression at the pretranslational level through prolonged activation of calcineurin.
...
PMID:Regulation of L-selectin mRNA in Jurkat cells. Opposing influences of calcium- and protein kinase C-dependent signaling pathways. 753 69

Lovastatin, a cholesterol-lowering drug, has antiproliferative properties that may be related to its inhibition of protein isoprenylation. We examined the effects of lovastatin on signal transduction via the T-cell antigen receptor (TCR). Lovastatin inhibited both proximal and distal TCR-mediated signaling events in a time- and concentration-dependent manner in the human Jurkat T-cell line. Upregulation of CD69 surface expression after TCR stimulation was blocked by lovastatin, although no inhibition of phorbol ester-induced CD69 expression was noted. Proximal TCR-mediated signaling events, including intracellular calcium mobilization, inositol phosphate production, and tyrosine phosphorylation of phospholipase Cgamma1, were similarly inhibited by lovastatin, although global protein tyrosine kinase activity remained intact. In a Jurkat variant transfected with the human type-1 muscarinic receptor, lovastatin also inhibited TCR-mediated calcium mobilization and inositol phosphate production but failed to affect muscarinic receptor-induced responses. Lovastatin, at similar doses, also disrupted post-translational processing of ras and inhibited ras-dependent signals, including phosphorylation and activation of mitogen-associated protein kinase after TCR stimulation. These findings suggest that the antiproliferative properties of lovastatin may be independent of ras and could result from uncoupling protein tyrosine kinases from distinct signal transduction pathways.
...
PMID:Lovastatin inhibits T-cell antigen receptor signaling independent of its effects on ras. 897 53

Anti-tumor effects of agents known to intervene with signal transduction pathways (ras and protein kinase c cascades) were examined in the B16 melanoma cell model. The compounds examined included: lovastatin, an inhibitor of HMG-CoA reductase, which interferes with membrane localization of p21 ras protein; H-7, a classic inhibitor of protein kinase C; and tiazofurin, a GTP depleting agent, that might affect the GTP/GDP ratio on p21ras. The three agents were found to inhibit the proliferation of B16 melanoma cells. Only tiazofurin, as expected, induced a significant decrease in GTP levels. Lovastatin and H-7 altered p21 subcellular localization. They reduced membrane expression of p21 ras, while increasing its expression in the cytosol. Following tiazofurin treatment a trend towards increased membranal p21 was observed. These results suggest that p21 is a target for the action of signal transduction inhibitors. However, the relationship between growth inhibition and altered p21 expression is not yet clear.
...
PMID:Inhibition of B16 melanoma cell proliferation and alterations in p21 ras expression induced by interceptors of signal transduction pathways. 900 43

Mesangial cell proliferation is a key feature of glomerulonephritis. The hydroxymethylglutaryl-coenzyme A reductase inhibitor lovastatin is known to inhibit cell cycle progression. To determine the inhibitory mechanisms of mesangial cell proliferation by lovastatin, the cyclin-dependent kinase (CDK) activity, and expression of CDK inhibitor (p27Kip1, p21Cip1, and p16INK4) mRNA and protein were measured. Lovastatin inhibited phosphorylation of retinoblastoma protein and mesangial cell proliferation dose dependently. Lovastatin increased the p27Kip1 protein level but produced no changes in the abundance of the p27Kip1 mRNA level both in the presence and absence of mitogens. Treatment with lovastatin revealed the increment of both CDK2- and CDK4-bound-p27Kip1. The experiment using antisense oligonucleotide against p27Kip1 showed significant amelioration of lovastatin-induced cell cycle arrest. Lovastatin reduced both platelet-derived growth factor-stimulated CDK2 and CDK4 kinase activities. In conclusion, lovastatin inhibited mesangial proliferation via translational upregulation or impairment of p27Kip1 protein degradation. Lovastatin serves as a potential therapeutic approach to mesangial proliferative disease.
...
PMID:Lovastatin inhibits mesangial cell proliferation via p27Kip1. 984 77

In this paper we present the finding that lovastatin arrests cells by inhibiting the proteasome, which results in the accumulation of p21 and p27, leading to G1 arrest. Lovastatin is an inhibitor of hydroxymethyl glutaryl (HMG)-CoA reductase, the rate-limiting enzyme in cholesterol synthesis. Previously, we reported that lovastatin can be used to arrest cultured cells in the G1 phase of the cell cycle, resulting in the stabilization of the cyclin-dependent kinase inhibitors (CKIs) p21 and p27. In this report we show that this stabilization of p21 and p27 may be the result of a previously unknown function of the pro-drug, beta-lactone ring form of lovastatin to inhibit the proteasome degradation of these CKIs. The lovastatin mixture used in this study is 80% open-ring form and 20% pro-drug, beta-lactone form. We show that while the lovastatin open-ring form and pravastatin (a lovastatin analogue, 100% open ring) inhibit the HMG-CoA reductase enzyme, lovastatin pro-drug inhibits the proteasome but does not inhibit HMG-CoA reductase. In addition, many of the properties of proteasome inhibition by the pro-drug are the same as the specific proteasome inhibitor lactacystin. Lastly, mevalonate (used to rescue cells from lovastatin arrest) unexpectedly abrogates the lactacystin and lovastatin pro-drug inhibition of the proteasome. Mevalonate increases the activity of the proteasome, which results in degradation of the CKIs, allowing lovastatin- and lactacystin-arrested cells to resume cell division. The lovastatin-mediated inhibition of the proteasome suggests a unique mechanism for the chemopreventative effects of this agent seen in human cancer.
...
PMID:Lovastatin-mediated G1 arrest is through inhibition of the proteasome, independent of hydroxymethyl glutaryl-CoA reductase. 1039 1

An inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, lovastatin, induces growth arrest and cell death in a wide variety of malignant cells in vitro. We analyzed the effect of lovastatin on myeloid leukemic cell lines. Lovastatin significantly inhibited the proliferation of 7 cell lines among 11 myeloid leukemic cell lines in a dose-dependent manner. In order to address the mechanism of antileukemic effect of lovastatin, cell cycle analysis was attempted in HL-60 cells, showing that lovastatin induced G1 arrest in HL-60 cells following 72 h of drug exposure (1.5 microM, 5 microM and 10 microM) in a dose-dependent manner. Analysis of G1 regulatory proteins demonstrated that the protein levels of cyclin-dependent kinase (CDK) 2, CDK4, CDK6 and cyclin E were decreased after treatment with lovastatin (10 microM) in a time-dependent manner, but not cyclin D1. In addition, lovastatin increased the protein level of the cyclin-dependent kinase inhibitor (CDKI), p27, and markedly enhanced the binding of p27 with CDK2 and CDK4 more than CDK6 after 24 h exposure. At higher doses of lovastatin (50 mM, 100 mM, 200 mM), a significant apoptosis was observed as evidenced by FACS analysis with annexin V staining, which was associated with downregulation of Bcl-2 protein. These results suggest that lovastatin inhibits the proliferation of myeloid leukemic cells via G1 arrest in association with p27 induction and is an effective inducer of apoptosis in HL-60 cells.
...
PMID:Lovastatin-induced inhibition of HL-60 cell proliferation via cell cycle arrest and apoptosis. 1065 2

Tumor production of parathyroid hormone-related protein (PTHRP) is responsible for most cases of hypercalcemia of malignancy. The transplantable rat Leydig tumor H-500 is known to cause hypercalcemia in rats by the release of abundant PTHRP and to closely reproduce the human syndrome. We have demonstrated recently that Ras oncogene can stimulate PTHRP gene expression in Fr3T3 fibroblasts in vitro and cause hypercalcemia in vivo. Using rat Leydig tumor H-500 cells, we have investigated the role of effector pathways downstream of Ras in serum-induced PTHRP expression. The Ras inhibitors B-1086 and Lovastatin decreased PTHRP mRNA expression. i.p. administration of B-1086 (50-100 mg/kg/day) into H-500 tumor-bearing male Fischer rats resulted in a dose-dependent reduction in tumor volume, serum calcium, plasma PTHRP, and tumoral PTHRP mRNA expression. Transient transfection of dominant-negative Ras (Ras N17) and Raf (Raf C4B) reduced, whereas activated Raf-1 (Raf BXB) increased, basal expression of PTHRP in H-500 cells. A similar decrease in PTHRP production was seen with a mitogen-activated protein kinase kinase (MEK) inhibitor (PD 098059), implicating the involvement of Ras/Raf/MEK/extracellular signal-regulated kinase (ERK) pathway. In addition, stimulation with UV light, which can activate c-Jun NH2-terminal kinase (JNK), or expression of an activated form of Rac (Rac V12) was sufficient to increase PTHRP mRNA. Moreover, a dominant-negative Rac (Rac N17) blocked serum-induced PTHRP gene expression. Collectively, these results demonstrate that PTHRP is induced via both Raf-ERK and Rac-JNK mediated pathways, effects which can be blocked by chemical inhibitors and dominant-negative mutants of these pathways in vitro and in vivo. Availability of selective inhibitors of Ras signaling molecules may therefore add to our existing armamentarium to control hypercalcemia of malignancy.
...
PMID:Role of mitogen-activated protein kinases in the induction of parathyroid hormone-related peptide. 1074 50

The surprising discovery that nitrogen-containing bisphosphonates (N-BPs) act via inhibition of the mevalonate-to-cholesterol pathway raised the possibility that esophageal irritation by N-BPs is mechanism-based. We used normal human epidermal keratinocytes (NHEKs) to model N-BP effects on stratified squamous epithelium of the esophagus. The N-BPs alendronate and risedronate inhibited NHEK growth in a dose-dependent manner without inducing apoptosis. N-BPs (30 microM) caused accumulation of cells in S phase and increased binucleation (inhibited cytokinesis). Consistent with N-BP inhibition of isoprenylation, geranylgeraniol or farnesol prevented accumulation in S phase. Binucleation was also induced by the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor lovastatin and by the squalene synthase inhibitor zaragozic acid A and was prevented by adding low-density lipoprotein. At 300 microM, N-BPs reduced expression of cyclin-dependent kinase (cdk) 2 and cdk4 and enhanced expression of p21(waf1) and p27(kip1) and their binding to cdks with corollary hypophosphorylation of retinoblastoma. Lovastatin and zaragozic acid A produced similar effects, except that p21(waf1) expression and binding to cdks was not induced. Growth inhibition, but not binucleation, was also caused by the geranylgeranyl transferase I inhibitor, GGTI-298, which also enhanced cdk2 and cdk4 association with p27(kip1). These findings are consistent with suppression of epithelial cell growth by N-BPs via inhibition of the mevalonate pathway and the consequent reduction in cholesterol synthesis, which blocks cytokinesis, and in geranylgeranylation, which interferes with progression through the cell cycle.
...
PMID:Nitrogen-bisphosphonates block retinoblastoma phosphorylation and cell growth by inhibiting the cholesterol biosynthetic pathway in a keratinocyte model for esophageal irritation. 1116 Aug 53

Phosphorylation of cdk2 on threonine 160 is essential for kinase activity. Mevastatin, an inhibitor of cholesterol synthesis, inhibits cell growth through inhibition of cdk2 and this has been suggested to be due to enhancement of p21 levels. In a prostate cancer cell line, PC3, mevastatin treatment led to elevated levels of p21 and caused a small increase in the p21 associated with cdk2. However, this increase in the associated p21 appeared out of proportion with the resulting dramatic inhibition of kinase activity. Using RNA interference we show that mevastatin inhibits cdk2 activity despite lack of induction of p21, p27, and p57. Instead the kinase was inhibited due to a decrease in activating phosphorylation. Phosphorylation of cdk2 from mevastatin-treated cells with exogenous cyclin-dependent kinase (cdk)-activating enzymes restored its functional activity. The only known mammalian cyclin H.cdk7.mat1 complex (cdk2-activating kinase, Cak), was not inhibited by mevastatin, suggesting either that a different CAK is responsible for cdk2 phosphorylation in vivo or that the regulation is at the level of substrate accessibility or of cdk2 dephosphorylation. These results suggest that mevastatin inhibits cdk2 activity in PC3 cells through the inhibition of Thr-160 phosphorylation of cdk2, providing a novel example of regulation of cdk2 at this level.
...
PMID:Inhibition of cdk2 activating phosphorylation by mevastatin. 1247 85


1 2 Next >>

---