Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A potentially important cross-talk characteristic of transforming growth factor-beta (TGF-beta) is to inhibit platelet-derived growth factor-induced intracellular calcium rise (Baffy, G., Sharma, K., Shi, W., Ziyadeh, F. N., and Williamson, J. R. (1995) Biochem. Biophys. Res. Commun. 210, 378-383) in murine mesangial cells. The present study examined the possible basis for this effect by evaluating the regulation of the type I inositol 1,4,5-trisphosphate receptor (IP3R) by TGF-beta. TGF-beta1 down-regulates IP3R protein expression by >90% with maximal and half-maximal effects after 8 and 2 h, respectively. TGF-beta1 also decreased IP3R mRNA expression by 59% after 1 h. Phosphorylation of the IP3R was also demonstrated as early as 15 min after TGF-beta1 exposure. Back phosphorylation assays of IP3R from TGF-beta1-treated mesangial cells with protein kinase A (PKA), indicated that TGF-beta1-induced phosphorylation of the IP3R occurs at similar sites as for PKA. In vitro kinase assays using the known IP3R peptide substrates for PKA, RPSGRRESLTSFGNP and ARRDSVLAAS, demonstrated that TGF-beta1 induces phosphorylation of both peptides (158 and 123% of control values, respectively). TGF-beta1-induced phosphorylation was prevented by the addition of the PKA inhibitor peptide in the in vitro kinase assay. It is proposed that TGF-beta-mediated effects on the IP3R may be an important characteristic of its ability to modulate the response of cells to factors that employ IP3R-mediated calcium release.
 ...
PMID:Transforming growth factor-beta1 inhibits type I inositol 1,4,5-trisphosphate receptor expression and enhances its phosphorylation in mesangial cells. 916 22

Growth factors, especially basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), and transforming growth factor-beta (TGF-beta) are known to play key roles in the pathogenesis of mesangial proliferative glomerulonephritis. TNP-470 (AGM-1470), a potent anti-angiogenic compound, has anti-growth factor properties and inhibits the activation of cyclin-dependent kinase (cdk) 2 and phosphorylation of RB protein. We investigated whether TNP-470 could suppress growth factor induced mesangial cell proliferation in vitro and experimental model of mesangial proliferative glomerulonephritis in vivo. TNP-470 inhibited potently PDGF- and bFGF-stimulated proliferation of rat mesangial cells in vitro (IC50 = 50 pg/ml). In anti-Thy 1.1 glomerulonephritis, high dose use of TNP-470 (20 mg/kg/day) markedly suppressed mesangial cell proliferation and mesangial matrix expansion on day 6; however, mesangiolysis remained. Low dose use of TNP-470 (10 mg/kg/day) moderately inhibited mesangial cell proliferation and mesangial matrix synthesis, and induced appropriate glomerular healing on day 14 in anti-Thy 1.1 glomerulonephritis. Thus, TNP-470 potently inhibits growth factor-induced proliferation of mesangial cells in vitro, and mesangial cell proliferation and extracellular matrix expansion in anti-Thy 1.1 glomerulonephritis in vivo. These results suggest a novel therapeutic potential of TNP-470 in mesangial proliferative glomerulonephritis.
 ...
PMID:Anti-angiogenic compound (TNP-470) inhibits mesangial cell proliferation in vitro and in vivo. 918 73

Activins, members of the transforming growth factor-beta family, have been implicated in the regulation of growth and differentiation of various types of cells. We have recently found that activin A induces apoptotic cell death of plasmacytic cells including B cell hybridoma cells and myeloma cells. In the present study, we demonstrated that activin A caused cell-cycle arrest in the G1 phase before appearance of apoptotic cells in mouse B cell hybridoma cells. Phosphorylation of retinoblastoma protein (Rb) and in vitro Rb kinase activity of cyclin-dependent kinase (CDK)4 was inhibited in activin A-treated cells. Analysis of expression of genes regulating Rb phosphorylation revealed that activin A suppressed cyclin D2, the sole D-type cyclin gene expressed in the hybridoma cells, and activated p21CIP1/WAF1 but had no effect on expression of cyclin-dependent kinases (CDK2, CDK4, CDK6) and other CDK inhibitors (p27KIP1, p16INK4a, p15INK4b). Modulation of cyclin D2 and p21CIP1/WAF1 expression resulted in a decrease in level of cyclin D2-CDK4 complex and an increase in level of CDK4 complexed with p21CIP1/WAF1. Moreover, overexpression of cyclin D2 partially abrogated inhibition of Rb phosphorylation and G1 arrest in the hybridoma cells.
 ...
PMID:Activin A induction of cell-cycle arrest involves modulation of cyclin D2 and p21CIP1/WAF1 in plasmacytic cells. 921 52

CGP 42112, a high-affinity ligand for angiotensin II AT2 receptors, binds to rat macrophage/microglia lacking AT2 receptors. Here we report that CGP-42112 binds to human monocytes and exerts specific effects. Binding studies revealed a single site, highly specific for CGP-42112, not displaceable by angiotensin II, angiotensin fragments, tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-4, IL-10, transforming growth factor-beta, or lipopolysaccharide (LPS). Incubation of purified human monocytes in serum-free medium with CGP-42112 enhanced, in a dose-dependent manner, cell attachment to fibronectin and collagen-coated dishes as well as matrix metalloproteinase-9 secretion. CGP-42112 did not promote cytokine secretion. In contrast, when added in the presence of low doses of LPS, CGP-42112 reduced the LPS-stimulated secretion of TNF-alpha, IL-1 alpha, IL-1 beta, and IL-6 without affecting IL-10 and decreased the LPS-stimulated matrix metalloproteinase-9 activity. Additionally, CGP-42112 inhibited the increase in protein kinase A activity produced by LPS. Our results indicate that CGP-42112 may modulate monocyte activation through binding to a novel receptor.
 ...
PMID:CGP-42112 partially activates human monocytes and reduces their stimulation by lipopolysaccharides. 931 2

This review summarizes recent studies on the cell cycle profile of hematopoietic cell differentiation and its regulatory mechanisms. Hematopoiesis involves self-renewal of stem cells, expansion of lineage-committed progenitors, and maturation into the terminal elements. The cell cycle status of each process is tightly regulated according to function: stem cells are in a quiescent state for self renewal, the immature progenitor population actively cycles for expansion, and terminally-differentiated cells are arrested in G0/G1 to efficiently express various genes. Recent investigations have defined critical components implicated in cell cycle regulation during hematopoietic cell differentiation. Inhibition of pRB phosphorylation and E2F activity, probably through the effects of negative growth factors, such as transforming growth factor-beta and the interferons, is found to be important for cell cycle arrest of stem cells. De-repression of these elements by cyclin-dependent kinases (CDKs), which can be activated by colony stimulating factors, is associated with the expansion of immature progenitor cells. Suppression of pRB phosphorylation and E2F activity is once again accompanied by terminal differentiation. Among hematopoietic cells, megakaryocytes are known to have a distinct mode of cell cycle processes, namely endomitosis, and become hyperploid. Induction of CDK inhibitor p21 and the presence of a megakaryocyte-specific licensing factor are proposed to be the underlying mechanisms of polyploidization. Further advancement in this field should help resolve many clinical problems caused by the disruption of cell cycle control of hematopoietic cells.
 ...
PMID:Cell cycle control during hematopoietic cell differentiation. 943 35

We recently demonstrated that transforming growth factor-beta (TGF-beta) stimulates phosphorylation of the type I inositol 1,4, 5-trisphosphate receptor (Sharma, K., Wang, L., Zhu, Y., Bokkala, S., and Joseph, S. (1997) J. Biol. Chem. 272, 14617-14623), possibly via protein kinase A (PKA) activation in murine mesangial cells. In the present study, we evaluated whether TGF-beta stimulates PKA activation. Utilizing a specific PKA kinase assay, we found that TGF-beta increases PKA activity by 3-fold within 15 min of TGF-beta1 treatment, and the enhanced kinase activity was completely reversed by the inhibitory peptide for PKA (PKI; 1 microM). In mesangial cells transfected with a PKI expression vector, enhanced PKA activity could not be demonstrated with TGF-beta1 treatment. TGF-beta1 was also found to stimulate translocation of the alpha-catalytic subunit of PKA to the nucleus by Western analysis of nuclear protein as well as by confocal microscopy. TGF-beta1-mediated phosphorylation of cAMP response element-binding protein was completely reversed by H-89 (3 microM), a specific inhibitor of PKA. Stimulation of fibronectin mRNA by TGF-beta1 was also attenuated in cells overexpressing PKI. We thus conclude that TGF-beta stimulates the PKA signaling pathway in mesangial cells and that PKA activation contributes to TGF-beta stimulation of cAMP response element-binding protein phosphorylation and fibronectin expression.
 ...
PMID:Transforming growth factor-beta1 stimulates protein kinase A in mesangial cells. 952 67

This review focuses on the cell cycle of hematopoietic stem cell and its regulatory mechanisms. Owing to recent advances in cell culture techniques and analyzing tools, hematopoietic stem cells can be purified from bone marrow, peripheral blood, and umbilical cord blood by using specific surface markers such as Sca-1 (murine) and CD34 (human). Stem cell compartment includes primitive stem cells with self-renewal capacity, multipotential progenitor cells, and lineage-committed progenitors. The cell cycle profile of each population corresponds to their functional status: the most primitive stem cells are dormant (in G0 phase), the majority of self-renewing stem cells are in G1 phase and slowly cycling, and committed progenitors are rapidly cycling for effective expansion. Recent investigations have defined critical components implicated in cell cycle regulation of mammalian cells, and those at work for hematopoietic stem cells are also becoming clear. It has been reported that cell cycle arrest of stem cells is mediated through inhibition of pRB phosphorylation and E2F activity, as well as induction of cyclin-dependent kinase (cdk) inhibitors. Negative growth factors such as transforming growth factor-beta, macrophage inflammatory protein-1, and the interferons may play a role in these events. De-repression of these elements by cdk/cyclin complexes, which are activated by colony stimulating factors, is associated with the expansion of immature progenitor cells. Further advancement in this field should help resolve many of the clinical problems caused by the disruption of cell cycle regulation of hematopoietic stem cells.
 ...
PMID:Cell cycle regulation of hematopoietic stem cells. 977 2

Diabetes mellitus is a complex disease characterised by chronic hyperglycaemia responsible for complications affecting the kidneys, eyes, peripheral nerves and micro- and macrovascular systems. Von Willebrand factor (vWf), a multimeric glycoprotein mainly synthesised by endothelial cells, is involved in platelet adhesion and aggregation and acts as the carrier of coagulation factor VIII in plasma. Increased levels of vWf, reflecting activation of or damage to endothelial cells, have been described in association with atherosclerosis and diabetes. vWf appears to be a predictive marker of diabetic nephropathy and neuropathy, although not of retinopathy, which suggests that endothelial dysfunction precedes the onset of diabetic microangiopathy. This dysfunction could be especially involved in the pathogenesis of renal abnormalities of diabetes. vWf is not a predictive marker of macroangiopathy when diabetes is associated with atherosclerotic risk factors. In the presence of chronic diabetic complications, vWf levels are not associated with any grade of retinopathy but increase with the severity of nephropathy and would appear to be a risk factor for macrovascular mortality in these patients. The endothelial dysfunction of diabetes can generate atherosclerotic lesions responsible for damage to the arterial wall, atheroma and formation of platelet microaggregates. Concomitant with high vWf levels, other possible mechanisms of endothelial damage include reduced synthesis or release of nitric oxide, hyperglycaemic pseudohypoxia and protein kinase-C activation, increased synthesis of proteins bearing advanced glycosylation end-products or transforming growth factor-beta (TGF-beta) activation of coagulation and inhibition of fibrinolysis. At present, it is not known whether high vWf levels are inherent to the physiopathology of diabetes, nor whether diabetes induces endothelial dysfunction through other pathways. However, since angiopathy resulting from endothelial dysfunction is the main cause of morbidity and mortality in diabetic patients, appropriate therapy is necessary to reduce these complications. Glycaemic control seems to be insufficient to normalise plasma vWf, whereas a decrease can be obtained by ingestion of diets rich in oleic acid or by treatment with statins. Inhibition of the binding of vWf to the GPlba receptor by synthetic peptides, aurin tricarboxylic acid or monoclonal antibodies has been proposed to prevent the thrombosis induced by high levels of plasma vWf. Thus, vWf probably represents an interesting target for the inhibition of thrombosis in diabetes.
 ...
PMID:Von Willebrand factor in diabetic angiopathy. 980 43

Several recent studies have provided clear evidence that angiotensin-converting enzyme (ACE)-inhibitors slow the progression of renal disease. These effects are mainly independent from a comitant reduction in systemic blood pressure. Thus, angiotensin II (Ang II) exerts other effects on the kidney which are involved in the loss of renal function. Ang II induces proliferation of cultured mesangial and glomerular endothelial cells. Our group was the first to demonstrate that Ang II stimulates hypertrophy of cultured proximal tubular cells. Ang II stimulates bioactivation and expression of transforming growth factor-beta (TGF-beta) in tubular MCT cells. This Ang II-mediated expression of TGF-beta is due to an increase in transcriptional activity. A neutralizing anti-TGF-beta antibody attenuates the Ang II-induced increase in protein synthesis in MCT cells suggesting that the hypertrophy is mediated by synthesis and activation of endogenous TGF-beta. Proximal tubular cells undergoing Ang II-mediated hypertrophy are arrested in the G1-phase of the cell cycle and express typical G1-phase-associated genes. Induction of such G1-phase-associated early growth response genes have been also described in vivo after infusion of Ang II into the renal artery. This G1-phase arrest depends on the induction of the cyclin-dependent kinase (CdK) inhibitor p27Kip1. p27Kip1 expression is stimulated after incubation of LLC-PK1 cells with Ang II or TGF-beta and binds to cyclin D1-CdK4 complexes, inhibits their kinase activity, and hampers G1-phase exit. Ang II stimulates transcription of collagen type IV in MCT cells. In addition to the classical a1 (IV) chain, a3 (IV) collagen, which has normally a restricted localization in the kidney, is also induced. This stimulation is mediated by endogenous synthesis and autocrine action of TGF-beta because a neutralizing anti-TGF-beta antibody as well as TGF-beta antisense oligonucleotides attenuate Ang II-induced collagen type IV transcription and synthesis. In addition, Ang II exerts immunomodulatory effects on the kidney through the induction of chemokines such as MCP-1 and RANTES. In conclusion, Ang II has emerged as a multifunctional acting as a growth factor and a profibrogenic cytokine, and even having inflammatory properties.
 ...
PMID:Angiotensin II is involved in the progression of renal disease: importance of non-hemodynamic mechanisms. 985 83

To assess the regulation of stem factor factor (SCF) gene expression during spermatogenesis, we tested the effects of hormones (FSH, testosterone, and 17beta-estradiol) and some growth factors [transforming growth factor-beta (TGF beta), TGF alpha, tumor necrosis factor-alpha, and activin] on SCF gene expression by using a transillumination-assisted microdisection technique, a seminiferous tubule culture system, and Northern hybridization. Our results showed that FSH (10 ng/ml) increased steady state levels of SCF messenger RNA (mRNA) in a stage-specific and time-dependent manner. 8-Bromo-cAMP could increase the SCF mRNA level in a similar way as FSH, whereas phorbol 12-myristate 13-acetate had no effect. Actinomycin D could abolish the stimulatory effect of FSH, whereas cyclohexamide could not. The half-life of SCF mRNA was apparently prolonged after FSH stimulation (FSH-treated tubules, 15.6 +/- 1.2 h; controls, 8.6 +/- 2.7 h). Nuclear run-on assay revealed 5- and 10-fold increases in the transcription rate after FSH stimulation for 8 and 30 h, respectively. Neither testosterone nor estradiol had significant effects on SCF gene expression in our tissue culture system. Activin, TGF beta, TGF alpha, and tumor necrosis factor-alpha had no effect on SCF gene expression in vitro. In conclusion, SCF gene expression in the rat seminiferous tubule is regulated by FSH through the cAMP/protein kinase A pathway. FSH regulates SCF gene expression at both transcriptional and posttranscriptional levels involving the increase in transcription rate and prolongation of half-life of SCF mRNA, but is independent of de novo protein synthesis.
 ...
PMID:Stage-specific regulation of stem cell factor gene expression in the rat seminiferous epithelium. 1006 79


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>