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)

Previous studies have demonstrated that the alpha(1)-adrenergic receptor antagonist doxazosin (Dox) inhibits multiple mitogenic signaling pathways in human vascular smooth muscle cells. This broad antiproliferative activity of Dox occurs through a novel mechanism unrelated to its blocking the alpha(1)-adrenergic receptor. Flow cytometry demonstrated that Dox prevents mitogen-induced G(1)-->S progression of human coronary artery smooth muscle cells (CASMCs) in a dose-dependent manner, with a maximal reduction of S-phase transition by 88+/-10.5% in 20 ng/mL platelet-derived growth factor and 1 micromol/L insulin (P+I)-stimulated cells (P<0.01 for 10 micromol/L Dox versus P+I alone) and 52+/-18.7% for 10% FBS-induced mitogenesis (P<0.05 for 10 micromol/L Dox versus 10% FBS alone). Inhibition of G(1) exit by Dox was accompanied by a significant blockade of retinoblastoma protein (Rb) phosphorylation. Hypophosphorylated Rb sequesters the E2F transcription factor, leading to G(1) arrest. Adenoviral overexpression of E2F-1 stimulated quiescent CASMCs to progress through G(1) and enter the S phase. E2F-mediated G(1) exit was not affected by Dox, suggesting that it targets events upstream from Rb hyperphosphorylation. Downregulation of the cyclin-dependent kinase inhibitory protein p27 is important for maximal activation of G(1) cyclin/cyclin-dependent kinase holoenzymes to overcome the cell cycle inhibitory activity of Rb. In Western blot analysis, p27 levels decreased after mitogenic stimulation (after P+I, 43+/-1.8% of quiescent cells [P<0.01 versus quiescent cells]; after 10% FBS, 55+/-7.7% of quiescent cells [P<0. 05 versus quiescent cells]), whereas the addition of Dox (10 micromol/L) markedly attenuated its downregulation (after P+I, 90+/-8.3% of quiescent cells [P<0.05 versus P+I alone]; after 10% FBS, 78+/-8.3% of quiescent cells [P<0.05 versus 10% FBS alone]). Furthermore, Dox inhibited cyclin A expression, an E2F regulated gene that is essential for cell cycle progression into the S phase. The present study demonstrates that Dox inhibits CASMC proliferation by blocking cell cycle progression from the G(0)/G(1) phase to the S phase. This G(1)-->S blockade likely results from an inhibition of mitogen-induced Rb hyperphosphorylation through prevention of p27 downregulation.
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PMID:Doxazosin inhibits retinoblastoma protein phosphorylation and G(1)-->S transition in human coronary smooth muscle cells. 1080 36

The role of endogenous regucalcin, which is a regulatory protein in calcium signaling, in the regulation of protein kinase activity in the proliferation of the cloned rat hepatoma cells (H4-II-E) was investigated. Hepatoma cells were cultured for 6-72 h in the presence of fetal bovine serum (FBS; 1 or 10%). The number of cells and protein kinase activity in the 5500 g supernatant of cell homogenate was significantly increased 24 and 48 h after the culture with FBS (1 or 10%); the culture with 10% FBS was potent effect as compared with that of 1% FBS. FBS (10%)-increased protein kinase activity preceded a significant elevation of cell number of 6 h after culture. Serum stimulation-induced increase in protein kinase activity was significantly decreased in the presence of trifluoperazine (50 microM), staurosporine (10(-6) M) or genistein (10(-5) M) in the enzyme reaction mixture. The presence of anti-regucalcin monoclonal antibody (40 or 80 ng/ml) in the reaction mixture caused a significant increase in protein kinase activity in the cells cultured with FBS (1 or 10%). This increase was completely blocked by addition of regucalcin (10(-6) M), which can reveal an inhibitory effect on protein kinase activity. Moreover, the effect of antibody in increasing protein kinase activity was significantly inhibited in the presence of trifluoperazine, staurosporine, or genistein, indicating that endogenous regucalcin has an inhibitory effect on Ca(2+)/calmodulin-dependent protein kinase, protein kinase C, and protein tyrosine kinase. The present study suggests that endogenous regucalcin plays a suppressive role in the enhancement of various protein kinase activities associated with a proliferation of the cloned rat hepatoma cells (H4-II-E).
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PMID:Suppressive role of endogenous regucalcin in the enhancement of protein kinase activity with proliferation of cloned rat hepatoma cells (H4-II-E). 1145 66

The role of endogenous regucalcin in the regulation of deoxyribonuleic acid (DNA) synthesis in the nuclei of the cloned rat hepatoma cells (H4-II-E) with proliferative cells was investigated. Cells were cultured for 6-96 h in a alpha-minimum essential medium (alpha-MEM) containing fetal bovine serum (FBS; 1 or 10%). Cell number was significantly increased between 24 and 96 h after culture with 10% FBS; cell proliferation was markedly stimulated by culture with 10% FBS as compared with that of 1% FBS. In vitro DNA synthesis activity in the nuclei of cells was significantly elevated 6 h after culture with 10% FBS and its elevation was remarkable at 12 and 24 h after the culture. Nuclear DNA synthesis activity was significantly reduced in the presence of various protein kinase inhibitors (PD98059, staurosprine, or trifluoperazine) in the reaction mixture containing the nuclei of cells cultured for 12 and 24 h with FBS (1 and 10%). The addition of regucalcin (10(-7) and 10(-6)M) in the reaction mixture caused a significant inhibition of nuclear DNA synthesis activity. The presence of anti-regucalcin monoclonal antibody (25-100 ng/ml) in the reaction mixture containing the nuclei of cells cultured for 24 h with 10% FBS resulted in a significant increase in nuclear DNA synthesis activity. This increase was completely blocked by the addition of regucalcin (10(-6) M). The effect of anti-regucalcin antibody (100 ng/ml) in increasing nuclear DNA synthesis activity was significantly inhibited in the presence of various protein kinase inhibitors. DNA synthesis activity was significantly enhanced in the presence of anti-regucalcin antibody (100 ng/ml) in the reaction mixture containing the nuclei of cells cultured for 24 h with 10% FBS in the presence of Bay K 8644 (2.5 x 10(-6) M). Culture with Bay K 8644 did not cause a significant increase in DNA synthesis activity in the absence of anti-regucalcin antibody. The present study demonstrates that endogenous regucalcin plays a suppressive role in the enhancement of nuclear DNA synthesis with proliferative cells.
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PMID:Regulatory role of endogenous regucalcin in the enhancement of nuclear deoxyribonuleic acid synthesis with proliferation of cloned rat hepatoma cells (H4-II-E). 1150 Sep 48

The purpose of the present study was to examine the role of human heme oxygenase (human HO-1) in cell cycle progression following exposure to heme or human HO-1 gene transfer and to identify target genes associated with human HO-1-meditated increases in cell cycle progression using cDNA microarray technology. Heme-induced robust human HO-1 expression in quiescent human microvessel endothelial cells cultured in 1% FBS and the levels of human HO-1 expression progressively declined without a change in the cell cyclin. To identify genes regulated by human HO-1 in the cell cycle, human endothelial cells were transduced with a retroviral vector encoded with human HO-1 gene or an empty vector. Transgene expression and functionality of the recombinant protein were assessed by Western blotting, enzyme activity, carbon monoxide, cGMP production, and cell cycle analysis. Human cDNA gene array and quantitative real-time RT-PCR were used to identify both known and novel differentially expressed genes in cells overexpressing human HO-1. Major findings were upregulation of several genes associated with cell cycle progression, including cyclin E and D; downregulation of cyclin-dependent kinase inhibitors p21 and p27, cyclin-dependent kinases 2, 5, and 6, and monocyte chemoattractant protein-1; and upregulation of growth factors, including vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor I (VEGFRI), endothelial growth factor (EGF) and hepatic-derived growth factor (HDGF). These findings identify an array of gene responses to overexpression of human HO-1 and elucidate new aspects of human HO-1 signaling involved in cell growth.
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PMID:Human heme oxygenase: cell cycle-dependent expression and DNA microarray identification of multiple gene responses after transduction of endothelial cells. 1463 85

Apigenin, a dietary bioflavonoid with anticarcinogenic properties, was highly cytotoxic for HeLa cells (incubated with 0.5% FBS). This effect was accompanied with a marked increase in ERK1/2 but not MEK1/2 phosphorylation. The cytotoxic effects of apigenin were attenuated by the stimulation of these cells with 10% FBS, which provoked an increase in the phosphorylation levels of MEK1/2 and ERK1/2. The steps in the ERK1/2 pathway relevant to the cytotoxic effects of apigenin, as well as the contribution of other signaling pathways, were investigated. The activation of the pathway by transfection with the constitutively active Ras mutant (RasV12) conferred protection to serum-starved HeLa cells against apigenin, whereas the constitutively active MEK(E) mutant did not. MEK inhibitors (PD098059 or U0126) blocked ERK1/2 phosphorylation induced by apigenin and conferred partial protection against this flavonoid. The effects of apigenin did not involve p38-MAPK or JNK1/2, and were not simply due to inhibition of PI3kinase or protein kinase CK2. These data suggest that the deregulation of the ERK1/2 pathway, due to the potentiation of ERK1/2 phosphorylation without increasing MEK1/2 phosphorylation, is involved in apigenin-induced HeLa cell death.
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PMID:Unbalanced activation of ERK1/2 and MEK1/2 in apigenin-induced HeLa cell death. 1530 69

Labedipinedilol-A is a novel 1, 4-dihydropyridine type calcium antagonist with alpha-receptor blocking activity. This study investigates the effects of labedipinedilol-A on mitogen-induced proliferation of rat vascular smooth muscle cells (VSMCs). Labedipinedilol-A's inhibition on cell proliferation was measured by the tetrazolium salt (XTT) test. Labedipinedilol-A dose-dependently inhibited mitogen-induced DNA synthesis, determined by the incorporation of 5-bromo-2'-deoxyuridine (BrdU). Labedipinedilol-A was also found capable of inhibiting the migration of VSMCs induced by PDGF-BB with an IC50 value of 5.6 microM. In accordance with these findings, labedipinedilol-A revealed blocking of the FBS-inducible progression through G0/G1 to S phase of the cell cycle in synchronized cells. Labedipinedilol-A appeared to cause inhibition of mitogens-induced PKC translocation, suggesting the probable involvement of protein kinase C (PKC) in this cellular response. Labedipinedilol-A reduced both intracellular Ca and the phosphorylation of extracellular signal-regulated protein kinase 1/2 in PDGF-BB-stimulated VSMCs. It also suppressed the levels of proliferative cell nuclear antigen (PCNA) in VSMCs both time- and dose-dependently. These results indicate that labedipinedilol-A may inhibit cell proliferation by attenuating activation of the ERK 1/2 pathway, which is regulated by PKC and Ca, suggesting that it may have great potential in the prevention of progressive atherosclerosis.
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PMID:Inhibition of mitogen-mediated proliferation of rat vascular smooth muscle cells by labedipinedilol-A through PKC and ERK 1/2 pathway. 1550 90

Theophylline has been used in the management of bronchial asthma and chronic obstructive pulmonary disease for over 50 years. It has not only a bronchodilating effect, but also an anti-inflammatory one conducive to the inhibition of airway remodeling, including subepithelial fibrosis. To date however, whether theophylline has a direct inhibitory effect on airway fibrosis has not been established. To clarify this question, we examined whether theophylline affected the function of lung fibroblasts. Theophylline suppressed TGF-beta-induced type I collagen (COL1) mRNA expression in lung fibroblasts and also inhibited fibroblast proliferation stimulated by FBS and TGF-beta-induced alpha-SMA protein. A cAMP analog also inhibited TGF-beta-induced COL1 mRNA expression in lung fibroblasts. A PKA inhibitor reduced the inhibitory effect of theophylline on TGF-beta-induced COL1 mRNA expression. These results indicate that theophylline exerts anti-fibrotic effects, at least partly, through the cAMP-PKA pathway.
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PMID:Anti-fibrotic effects of theophylline on lung fibroblasts. 1643 Aug 59

A recent clinical trial (Chwalisz K, Larsen L, Mattia-Goldberg C, Edmonds A, Elger W, Winkel CA. Fertil Steril 87: 1399-1412, 2007) has demonstrated that the selective progesterone receptor modulator asoprisnil efficiently causes the shrinkage of uterine leiomyoma. The present study was conducted to examine whether asoprisnil elicits endoplasmic reticulum (ER) stress-induced apoptosis in cultured human uterine leiomyoma cells. After subculture in phenol red-free DMEM supplemented with 10% FBS for 120 h, cultured cells were stepped down to serum-free conditions with or without graded concentrations of asoprisnil. ER stress-associated and apoptosis-related proteins were assessed by reverse transcription-PCR analysis or Western blot analysis. RNA interference of growth-arrest- and DNA-damage-inducible gene 153 (GADD153) was performed using small interfering RNA. Terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick end labeling (TUNEL)-positive rates were assessed by TUNEL assay. Compared with untreated control cultures, treatment with 10(-7) M asoprisnil significantly (P < 0.05) increased the protein contents of ubiquitin at 2 h and phospho-double-stranded RNA-activated protein kinase-like ER kinase, phospho-eukaryotic initiation factor 2alpha, activating transcription factor 4, and glucose-regulated protein 78 kDa at 4 h, followed by the significant (P < 0.05) increase in GADD153 protein content at 6 h and cleaved poly(adenosine 5'-diphosphate ribose)polymerase (PARP) at 8 h. RNA interference of GADD153 suppressed protein contents of asoprisnil-induced cleaved PARP, Bax, Bak, GADD34, and tribbles-related protein 3 (TRB3) and TUNEL-positive rate but attenuated asoprisnil-induced reduction in Bcl-2 protein content in cultured leiomyoma cells. These results suggest that asoprisnil elicits ER stress-induced apoptosis in cultured leiomyoma cells and that GADD153 plays a role in asoprisnil-induced apoptosis by modulating the Bcl-2 family of proteins, GADD34, and TRB3.
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PMID:Selective progesterone receptor modulator asoprisnil induces endoplasmic reticulum stress in cultured human uterine leiomyoma cells. 1765 52

Epothilone D (Epo-D) is a paclitaxel-like microtubule-stabilizing agent that was isolated from the myxobacterium Sorangium cellulosum. Although Epo-D can inhibit proliferation in multiple tumor cell lines, the effect of Epo-D on neointimal hyperplasia after angioplasty has not been reported. The aim of the present study was to investigate the effects of Epo-D on neointimal hyperplasia using an in vivo rat carotid artery injury model. We demonstrated that local Epo-D treatment significantly reduced neointimal hyperplasia after in vivo rat carotid artery injury, and Epo-D potently inhibited DNA synthesis, cell cycle progression and cell proliferation after FBS- and PDGF-BB-stimulation; PDGF-BB has been identified as the most potent growth factor for stimulating the proliferation of activated rat aortic smooth muscle cells (RASMCs). To clarify the specific effects of Epo-D on cell cycle machinery, we examined its effects on cyclin-dependent kinase (CDK)2, CDK4, cyclin E, p27, and retinoblastoma (Rb) proteins as cell cycle-related proteins in cellular lysates from PDGF-BB-stimulated RASMCs. Epo-D treatment significantly decreased the level of CDK2 protein, but did not change the levels of CDK4 and cyclin E proteins. Furthermore, Epo-D inhibited the phosphorylation of Rb, a key regulator of the G1 to S phase transition in the cell cycle. These findings suggest that Epo-D may regulate the cell cycle G1-checkpoint proteins as its major molecular mechanism for inhibiting neointimal hyperplasia after in vivo rat carotid artery injury.
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PMID:Epothilone D, a microtubule-stabilizing compound, inhibits neointimal hyperplasia after rat carotid artery injury by cell cycle arrest via regulation of G1-checkpoint proteins. 1770 65

Beta-catenin plays a dual role in cellular signaling by stabilizing cadherin-mediated cell-cell contact and by regulating gene transcription associated with cell cycle progression. Nonetheless, its presence and function in airway smooth muscle have not been determined. We hypothesized a central role for beta-catenin in mitogenic signaling in airway smooth muscle in response to growth factor stimulation. Immunocytochemical and biochemical analysis revealed that human airway smooth muscle cells indeed express abundant beta-catenin, which was localized primarily to the plasma membrane in quiescent cells. Treatment of airway smooth muscle cells with PDGF or FBS induced sustained phosphorylation of glycogen synthase kinase-3 (GSK-3), a negative regulator in its unphosphorylated form that promotes beta-catenin degradation. GSK-3 phosphorylation was also increased in airway smooth muscle cells with a proliferative phenotype compared with quiescent airway smooth muscle cells with a mature phenotype. Parallel with the increase in GSK-3 phosphorylation, growth factor treatment induced an increased expression and nuclear presence of beta-catenin and activated promitogenic signaling in airway smooth muscle, including the phosphorylation of retinoblastoma protein, DNA synthesis ([(3)H]thymidine incorporation), and cell proliferation. Importantly, small interfering RNA knockdown of beta-catenin strongly reduced retinoblastoma protein phosphorylation, [(3)H]thymidine incorporation, and cell proliferation induced by PDGF and FBS. Collectively, these data reveal the existence of a GSK-3/beta-catenin signaling axis in airway smooth muscle that is regulated by growth factors and of central importance to mitogenic signaling.
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PMID:GSK-3/beta-catenin signaling axis in airway smooth muscle: role in mitogenic signaling. 1839 Aug 27


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