Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The long bones of the developing skeleton, such as those of the limb, arise from the process of endochondral ossification, where cartilage serves as the initial anlage element and is later replaced by bone. One of the earliest events of embryonic limb development is cellular condensation, whereby pre-cartilage mesenchymal cells aggregate as a result of specific cell-cell interactions, a requisite step in the chondrogenic pathway. In this review an extensive examination of historical and recent literature pertaining to limb development and mesenchymal condensation has been undertaken. Topics reviewed include limb initiation and axial induction, mesenchymal condensation and its regulation by various adhesion molecules, and regulation of chondrocyte differentiation and limb patterning. The complexity of limb development is exemplified by the involvement of multiple growth factors and morphogens such as Wnts, transforming growth factor-beta and fibroblast growth factors, as well as condensation events mediated by both cell-cell (neural cadherin and neural cell adhesion molecule) and cell-matrix adhesion (fibronectin, proteoglycans and collagens), as well as numerous intracellular signaling pathways transduced by integrins, mitogen activated protein kinases, protein kinase C, lipid metabolites and cyclic adenosine monophosphate. Furthermore, information pertaining to limb patterning and the functional importance of Hox genes and various other signaling molecules such as radical fringe, engrailed, Sox-9, and the Hedgehog family is reviewed. The exquisite three-dimensional structure of the vertebrate limb represents the culmination of these highly orchestrated and strictly regulated events. Understanding the development of cartilage should provide insights into mechanisms underlying the biology of both normal and pathologic (e.g. osteoarthritis) adult cartilage.
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PMID:Cellular interactions and signaling in cartilage development. 1096 38

The hexosamine biosynthetic pathway has been hypothesized to be involved in the development of insulin resistance and diabetic vascular complications. In particular, it was demonstrated that hyperglycemia-induced production of transforming growth factor-beta (TGF-beta1), a prosclerotic cytokine causally involved in the development of diabetic nephropathy. Several lines of evidence indicate that TGF-beta1 induction is mediated by the hexosamine pathway. In cultured mesangial cells, high glucose levels induce TGF-beta1 production. This effect is eliminated by inhibition of glutamine: fructose-6-phosphate-amidotransferase (GFAT), the rate-limiting enzyme of this pathway. Furthermore, stable overexpression of GFAT increased levels of TGF-beta1 protein, mRNA, and promoter activity. Inasmuch as stimulation or inhibition of GFAT increased or decreased high glucose-stimulated activity of protein kinase C (PKC), respectively, the observed effects appear to be transduced by PKC. In similar experiments, involvement of the hexosamine pathway in hyperglycemia-induced production of cytokines (TGF-alpha and basic fibroblast growth factor [bFGF]) was demonstrated in vascular smooth muscle cells. These studies also revealed a rapid increase in GFAT activity by treatment with agents that elevated levels of cyclic adenosine 3',5' monophosphate (cAMP), thus indicating that GFAT activity is tightly regulated by cAMP-dependent phosphorylation. Using immunohistochemistry and in situ hybridization, high expression of GFAT was found in human adipocytes, skeletal muscle, vascular smooth muscle cells, and renal tubular epithelial cells. whereas glomerular cells remained essentially unstained. However, significant staining occurred in glomerular cells of patients with diabetic nephropathy. Current data indicate that the flux through the hexosamine pathway, regulated by GFAT, may be causally involved in the development of diabetic vascular disease, particularly diabetic nephropathy.
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PMID:Role of the hexosamine biosynthetic pathway in diabetic nephropathy. 1099 85

Amadori-glycated albumin in diabetic nephropathy: Pathophysiologic connections. Nonenzymatic glycation of proteins represents a major mechanism by which hyperglycemia leads to diabetic renal disease. Recent research has shown that Amadori-modified albumin, the principal glycated protein in plasma, elicits pathobiologic effects in cultured renal cells that are identical to those of high ambient glucose. When added to the incubation media of glomerular mesangial and endothelial cells, glycated albumin stimulates protein kinase C (PKC) activity, increases transforming growth factor-beta (TGF-beta) bioactivity, and induces gene overexpression and enhanced production of extracellular matrix proteins. These cellular events, whereby PKC-mediated TGF-beta activation leads to increased matrix expression, are inextricably linked, and they form the central tenets of a pathophysiologic connection between glycated proteins and diabetic nephropathy. In vivo studies further corroborate the role of glycated proteins in the pathogenesis of diabetic nephropathy. Reduction or neutralization of glycated albumin in the db/db mouse model of type 2 diabetes significantly ameliorates the proteinuria, renal insufficiency, mesangial expansion, and overexpression of matrix proteins. In human type 1 diabetes, the plasma-glycated albumin concentration is independently associated with the presence of nephropathy. Abrogating the biologic effects of increased glycated albumin has novel therapeutic potential in the management of renal complications in diabetes.
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PMID:Amadori-glycated albumin in diabetic nephropathy: pathophysiologic connections. 1099 89

The transforming growth factor-beta (TGF beta) polypeptides control a variety of cellular processes including organogenesis and cellular proliferation and differentiation. In the developing lung, TGF beta(1) treatment inhibits airway branching and expression of the genes for surfactant proteins (SP). Many effects of TGF beta are mediated at the level of gene transcription but there is limited information regarding signaling pathways and target transcription factors. In this study with human pulmonary adenocarcinoma H441 cells, we investigated TGF beta(1) effects on SP-B, a protein which is essential for normal function of pulmonary surfactant. TGF beta(1) (10 ng/ml) reduced SP-B mRNA content in a time-dependent fashion, and transient transfection studies localized responsiveness to the region of the SP-B promoter (-112/-72 bp) containing binding sites for thyroid transcription factor-1 (TTF-1) and hepatocyte nuclear factor 3 (HNF3), transcription factors that are important enhancers of SP gene expression. Using electrophoretic mobility shift assay and immunofluorescence, we demonstrated rapid accumulation of these transcription factors in the cytoplasm and subsequent loss from the nucleus on TGF beta(1) treatment of both adenocarcinoma cells and cultured human fetal lung. TGF beta(1) treatment caused intracellular translocation of protein kinase C and effects of TGF beta(1) were mostly abrogated in the presence of the protein kinase inhibitor calphostin C. We conclude that TGF beta(1), acting via protein phosphorylation, blocks nuclear translocation of TTF-1 and HNF3 which results in down-regulation of the SP-B gene and presumably other pulmonary genes which are transactivated by these factors.
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PMID:Transforming growth factor-beta(1) regulation of surfactant protein B gene expression is mediated by protein kinase-dependent intracellular translocation of thyroid transcription factor-1 and hepatocyte nuclear factor 3. 1100 79

Heparin-binding epidermal growth factor-like growth factor (HB-EGF), a member of the epidermal growth factor family of growth factors, is synthesized as a membrane-an-chored precursor (proHB-EGF) that is capable of stimulating adjacent cells in a juxtacrine manner. ProHB-EGF is cleaved in a protein kinase C-dependent process, to yield the soluble form. It was observed that HB-EGF acts as a morphogen for the collecting duct system in developing kidneys. HB-EGF protein was expressed in the ureteric bud of embryonic kidneys. Cultured mouse ureteric bud cells (UBC) produced HB-EGF via protein kinase C activation. After stimulation with phorbol ester (12-O-tetradecanoylphorbol-13-acetate) or recombinant soluble HB-EGF, UBC cultured in three-dimensional collagen gels formed short tubules with varied abundant branches. When proHB-EGF-transfected UBC were stimulated with 12-O-tetradecanoylphorbol-13-acetate and cultured in collagen gels, they exhibited linear growth, forming long tubular structures with few branches at the time of appearance of proHB-EGF on the cell surface. The structures exhibited a strong resemblance to the early branching ureteric bud of embryonic kidneys. When UBC were cultured in the presence of transforming growth factor-beta and soluble HB-EGF, they formed long tubules and few branches, similar to the structures observed in proHB-EGF-transfected UBC. These cells exhibited apical-basolateral polarization and expression of the water channel aquaporin-2. These findings indicate that soluble HB-EGF and proHB-EGF induce branching tubulogenesis in UBC in different ways. Juxtacrine activation by proHB-EGF or the synergic action of soluble HB-EGF with transforming growth factor-beta is important for well balanced morphogenesis of the collecting duct system.
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PMID:Induction of collecting duct morphogenesis in vitro by heparin-binding epidermal growth factor-like growth factor. 1131 55

Bone morphogenetic protein-2 (BMP-2), a member of the transforming growth factor-beta (TGF-beta) family, regulates osteoblast differentiation and bone formation. Here we show a novel function of BMP-2 in human osteoblasts and identify a signaling pathway involved in this function. BMP-2 promotes apoptosis in primary human calvaria osteoblasts and in immortalized human neonatal calvaria osteoblasts, as shown by terminal deoxynucleotidyl transferase-mediated nick end labeling analysis. In contrast, TGF-beta 2 inhibits apoptosis in human osteoblasts. Studies of the mechanisms of action showed that BMP-2 increases the Bax/Bcl-2 ratio, whereas TG beta-2 has a negative effect. Moreover, BMP-2 increases the release of mitochondrial cytochrome c to the cytosol. Consistent with these results, BMP-2 increases caspase-9 and caspase-3, -6, and -7 activity, and an anti-caspase-9 agent suppresses BMP-2-induced apoptosis. Overexpression of dominant-negative Smad1 effectively blocks BMP-2-induced expression of the osteoblast transcription factor Runx2 but not the activation of caspases or apoptosis induced by BMP-2, indicating that the Smad1 signaling pathway is not involved in the BMP-2-induced apoptosis. The proapoptotic effect of BMP-2 is PKC-dependent, because BMP-2 increases PKC activity, and the selective PKC inhibitor calphostin C blocks the BMP-2-induced increased Bax/Bcl-2, caspase activity, and apoptosis. In contrast, the cAMP-dependent protein kinase A inhibitor H89, the p38 MAPK inhibitor SB203580, and the MEK inhibitor PD-98059 have no effect. The results show that BMP-2 uses a Smad-independent, PKC-dependent pathway to promote apoptosis via a Bax/Bcl-2 and cytochrome c-caspase-9-caspase-3, -6, -7 cascade in human osteoblasts.
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PMID:Bone morphogenetic protein-2 promotes osteoblast apoptosis through a Smad-independent, protein kinase C-dependent signaling pathway. 1139 80

Deposition of hyaluronan has been implicated in the pathogenesis of diabetic glomerulosclerosis. We hypothesized the involvement of hyaluronan in diabetic tubulointerstitial fibrosis. We investigated high-glucose effect on hyaluronan production by rat renal interstitial fibroblasts (normal rat kidney [NRK] cells) and examined the role of hyaluronan in NRK cell proliferation. The involvement of protein kinase C (PKC) and transforming growth factor-beta (TGF-beta) in this response was also examined. After 24 hours of incubation in medium containing 25.6 mmol/L glucose, production of hyaluronan by NRK cells was significantly increased compared with medium containing 5.6 mmol/L glucose (P <.01). L-glucose and mannitol had no effect on hyaluronan production. High glucose enhanced basal in situ PKC activity (P <.01), and both an activator of PKC (phorbol 12-myristate 13-acetate; [PMA]) and TGF-beta 1 were able to increase hyaluronan production by NRK cells (P <.01). The effect of high glucose on hyaluronan production was diminished by coincubating cells with PKC inhibitors (staurosporine [Stp] or calphostin C [CpC]) or with an anti-TGF-beta neutralizing antibody. Stimulation of hyaluronan production by PMA was also normalized by anti TGFbeta neutralizing antibody, but the effect of TGF-beta1 was not affected by inhibition of PKC. Finally, incubating quiescent NRK cells with 50 or 100 ng/mL hyaluronan for 24 hours significantly increased NRK cell number (P <.01). In conclusion, high glucose stimulates hyaluronan production through the PKC/TGF-beta cascade. Increased hyaluronan promotes NRK cell proliferation. These results suggest that hyaluronan may play a role in the pathogenesis of interstitial fibrosis in diabetic kidney disease.
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PMID:High glucose stimulates hyaluronan production by renal interstitial fibroblasts through the protein kinase C and transforming growth factor-beta cascade. 1143 83

The biological effect of transforming growth factor-beta (TGF-beta) is cell type-specific and complex. The precise role of TGF-beta is not clear in vivo. To elucidate the regulation mechanism of endogenous TGF-beta on hepatoma progression, we modified the MH129F mouse hepatoma cell with a retroviral vector encoding the extracellular region of type II TGF-beta receptor (TRII). Soluble TRII (TRIIs) blocked TGF-beta binding to TRII on the membrane of hepatoma cells. Growth of MH129F cells was inhibited by TGF-beta1 treatment; however, soluble TRII-overexpressing cells (MH129F/TRIIs) did not show any change in proliferation after TGF-beta1 treatment. MH129F/TRIIs cells also increased vascular endothelial growth factor (VEGF) expression, endothelial cell migration, and tube formation. Implantation of MH129F/TRIIs cells into C3H/He mice showed the significantly enhanced tumor formation. According to Western blot and protein kinase C assay, the expression of VEGF, KDR/flk-1 receptor, and endothelial nitric-oxide synthase was enhanced, and the phosphorylation activity of protein kinase C was increased up to 3.7-fold in MH129F/TRIIs tumors. Finally, a PECAM-1-stained intratumoral vessel was shown to be 4.2-fold higher in the MH129F/TRIIs tumor. These results indicate that VEGF expression is up-regulated by a blockade of endogenous TGF-beta signaling in TGF-beta-sensitive hepatoma cells and then stimulates angiogenesis and tumorigenicity. Therefore, we suggest that endogenous TGF-beta is a major regulator of the VEGF/flk-1-mediated angiogenesis pathway in hepatoma progression.
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PMID:Induction of angiogenesis by expression of soluble type II transforming growth factor-beta receptor in mouse hepatoma. 1145 44

Growth factor-like molecules have been found in various invertebrate species. In particular, we have reported the presence of platelet-derived growth factor (PDGF)-AB and transforming growth factor-beta (TGF-beta)1 immunoreactive molecules in molluscs, insects and annelids. Moreover, PDGF-AB and TGF-beta1 affect the main immune functions, such as phagocytosis, chemotaxis and cell motility. Changes in cell shape are induced via interactions of growth factors with their respective specific receptors. The extracellular signals are transduced by the activation of classical signal transduction pathways, such as those involving PKA and PKC, and pivotal transcription regulators, i.e. the Fos, Jun and SMAD proteins. The two growth factors intervene in stress responses by activating the CRH-ACTH-biogenic amine axis. Exogenous administration of PDGF-AB and TGF-beta1 in a molluscan wound provokes an accelerated migration of immunocytes and fibroblasts to the injured area, stimulating granulation tissue formation and wound re-epithelialization. These findings suggest that these molecules are ancestral and that their function is well conserved and crucial in the maintenance of invertebrate homeostasis.
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PMID:Platelet-derived growth factor and transforming growth factor-beta in invertebrate immune and neuroendocrine interactions: another sign of conservation in evolution. 1148 27

Myofibroblasts are ultrastructurally and metabolically distinctive fibroblasts that express smooth muscle (SM)-alpha actin and are associated with various fibrotic lesions. The present study was undertaken to investigate the myofibroblast phenotype that appears after activation of normal lung fibroblasts by thrombin. We demonstrate that thrombin induces smooth muscle-alpha actin expression and rapid collagen gel contraction by normal lung fibroblasts via the proteolytically activated receptor-1 and independent of transforming growth factor-beta pathway. Using antisense oligonucleotides we demonstrate that a decreased level of PKCepsilon abolishes SM-alpha actin expression and collagen gel contraction induced by thrombin in normal lung fibroblasts. Inhibition of PKCepsilon translocation also abolishes thrombin-induced collagen gel contraction, SM-alpha actin increase, and its organization by normal lung fibroblasts, suggesting that activation of PKCepsilon is required for these effects. In normal lung fibroblasts PKCepsilon binds to SM-alpha actin after thrombin treatment, but in activated fibroblasts derived from scleroderma lung they associate even in untreated cells. This suggests that SM-alpha actin may serve as a substrate for PKCepsilon in lung fibroblasts when activated by thrombin. We propose that thrombin differentiates normal lung fibroblasts to a myofibroblast phenotype via a PKC-dependent pathway. Thrombin-induced differentiation of normal lung fibroblasts to a myofibroblast phenotype resembles the phenotype observed in scleroderma lung fibroblasts. Therefore, we conclude that chronic exposure to thrombin after microvascular injury leads to activation of normal lung fibroblasts and to the appearance of a myofibroblast phenotype in vivo. Our study provides novel, compelling evidence that thrombin is an important mediator of the interstitial lung fibrosis associated with scleroderma.
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PMID:Thrombin differentiates normal lung fibroblasts to a myofibroblast phenotype via the proteolytically activated receptor-1 and a protein kinase C-dependent pathway. 1157 91


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