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)

In synergistic combination 0.75 mmol/kg diet of N-(4-hydroxyphenyl) retinamide and 32 mmol/kg diet of glucarate inhibits the growth of primary rat mammary tumors, but are equally effective as single agents at 1.5 and 128 mmol/kg diet, respectively. Dose-response studies suggest that like retinoids, glucarate acts directly on tumor cells, rather than having an adjuvant effect. Although synergism is maintained down to at least 0.38 mmol/kg diet of the retinoid, experiments using Vitamin A-deficient diets indicates 128 mmol/kg glucarate acts independent of retinoid. Both alone and in combination, glucarate and retinoid inhibited the growth of human mammary tumor cells grown in the athymic mouse, the growth of rat mammary tumors in germfree rats and the hormone-independent MTW 9a/R rat mammary tumor. Like retinoids, glucarate suppresses protein kinase C and induces transforming growth factor-beta, in the mammary tumor cells.
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PMID:Mechanism of growth inhibition of mammary carcinomas by glucarate and the glucarate: retinoid combination. 829 19

Platelet-derived growth factor (PDGF) is a potent mitogen consisting of heterodimers of two distinct but homologous polypeptide chains, denoted A and B. PDGF-like homodimers of the A- and B-chains have been isolated, as well as two distinct receptor types (alpha and beta), which discriminate among the PDGF isoforms. The PDGF A- and B-chains are encoded by distinct genes located on human chromosomes 7 and 22, respectively. Although PDGF has been implicated as an important participant in development, tissue repair, and numerous pathologic states including tumorigenesis, atherosclerosis and inflammation, the mechanisms which determine the rate of its synthesis are only beginning to be understood. Basal expression of the PDGF A- and B-chain genes has been characterized in a number of cell types and is directed in part by elements in the respective proximal promoter-regulatory regions of the two genes. In addition, the first intron of PDGF-B has been shown to contain both positive and negative regulatory elements. Transcription of the PDGF subunit genes is inducible by a wide variety of mitogenic growth factors, cytokines and other agonists. These agents produce a rapid increase in steady-state concentrations of PDGF A- and B-chain mRNAs, peaking within 4-8 h of stimulation. The inductive effects of protein kinase C-activating phorbol 12-myristate 13-acetate (PMA), thrombin and transforming growth factor-beta (TGF-beta) are mediated through increases in the transcription rates of both genes. In addition, cAMP blocks the increases in transcription of the B-chain gene induced by thrombin and TGF-beta. Studies have demonstrated the importance of sequences immediately upstream of the B-chain transcription start site for induction in response to PMA-initiated megakaryocyte differentiation, an effect which is dependent on protein synthesis. However, cis-acting elements which mediate more rapid transcriptional induction seen in endothelial cells and astrocytes have yet to be identified in the proximal 5'-flanking sequences of either the A- or B-chain genes, suggesting that such events may be mediated by elements located outside of this region.
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PMID:Transcriptional control of the platelet-derived growth factor subunit genes. 834 77

The effect(s) of transforming growth factor-beta (TGF-beta) on Pi transport was investigated in confluent opossum kidney (OK) epithelial cells. TGF-beta induced a time- and concentration-dependent decrease in the initial rate of sodium-dependent Pi, but not alanine, transport. This selective inhibitory effect on Pi transport was largely reversible and was not associated with a rise in adenosine 3',5'-cyclic monophosphate production. The reduction in Pi uptake was also independent of changes in extracellular calcium concentrations and prostaglandin synthesis. TGF-beta-mediated Pi transport inhibition appeared to involve neither pertussis toxin-sensitive G protein(s) nor augmented protein kinase C activity. However, the probable role of a serine/threonine protein kinase in signal transduction was supported by the considerable attenuation of TGF-beta effect by H-7. Furthermore, the TGF-beta-induced Pi transport reduction was blunted by cycloheximide and abolished by actinomycin D. In conclusion, TGF-beta selectively inhibits the activity of the sodium-dependent Pi transport system present in the apical membrane of renal epithelial cells. This action appears to be exerted via an unprecedented inhibitory pathway that might involve a serine/threonine protein kinase and alterations in the transcriptional and translational processes.
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PMID:Transforming growth factor-beta inhibits phosphate transport in renal epithelial cells. 847 75

The effect of transforming growth factor-beta (TGF-beta) on the endogenous protein phosphorylation caused by phorbol 12-myristate 13-acetate (PMA), a potent activator of protein kinase C (PKC), was examined in primary cultured mouse epidermal cells. PMA markedly stimulates phosphorylation of endogenous proteins, i.e. KP-1 and KP-2, through Ca(2+)-dependent conventional PKC (cPKC), and KP-10 through Ca(2+)-independent novel PKC (nPKC) in intact epidermal cells. TGF-beta strongly suppressed the PMA-stimulated phosphorylation of these three proteins. Rate of dephosphorylation of these phosphorylated proteins was not affected by TGF-beta. Treatment of epidermal cells with TGF-beta decreased cPKC activity both in cytosolic and particulate fractions, but not nPKC activity. These results indicate that TGF-beta suppresses cPKC- and nPKC-mediated endogenous protein phosphorylation in intact epidermal cells, but the mechanisms of suppression are different.
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PMID:Suppressive effect of transforming growth factor-beta on the phosphorylation of endogenous substrates by conventional and novel protein kinase C in primary cultured mouse epidermal cells. 850 30

EGF has been reported to promote oocyte maturation in several species, although the mechanism of action is not yet known. The present study is designed to determine the pathway used by EGF to enhance porcine oocyte maturation. Oocytes were aspirated from 2-5 mm follicles and cultured with various treatments in Medium-199 at 37 degrees C, 100% relative humidity, and 5% CO2 for 48 hr for the maturation study and 3 hr for intracellular cAMP measurement. Although treatment with 100 IU/ml hCG stimulated both intracellular cAMP formation and oocyte maturation, 10 ng/ml EGF stimulated oocyte maturation only. Dibutyryl cAMP (dbcAMP) inhibited oocyte maturation at 10(-5), 10(-4), and 10(-3) M concentration s in the control medium. However, in the presence of 10 ng/ml EGF, dbcAMP inhibited oocyte maturation only at a concentration of 10(-3) M. Increasing concentrations of EGF (i.e., 25 and 50 ng/ml) were ineffective in overcoming the inhibitory effect of dbcAMP at 10(-3) M. In contrast, EGF reversed the decreased maturation rate caused by transforming growth factor-beta. Phorbol myristate acetate (PMA), a tumor-promoting phorbol ester, enhanced the spontaneous maturation rate; 4 alpha-phorbol dideconoate, an inactive phorbol ester, did not show this effect. PMA- and EGF-stimulated porcine oocyte maturation is reversed by calphostin-C, a PKC inhibitor. In conclusion, EGF's promotional activity on porcine oocyte maturation is independent of the cAMP pathway and probably mediated by the PKC pathway.
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PMID:Mechanism of action of epidermal growth factor-induced porcine oocyte maturation. 857 45

Mesangial cell growth and accumulation of extracellular matrix proteins constitute key features of progressive glomerular injury. Endothelin-1 (ET-1) and angiotensin II (Ang II), two potent vasoconstrictor agents, evoke a number of similar responses in mesangial cells. In rat mesangial cells, we compared ET-1 and Ang II effects on matrix protein production and cell proliferation as well as the potential interaction between the two hormones. When cells in 0.5% fetal calf serum were incubated for 24 hours with various concentrations of ET-1 or Ang II, both peptides stimulated, in a dose-dependent manner, fibronectin and type IV collagen mRNA expression, fibronectin synthesis, and mitogenesis. Incubation with specific receptor antagonists of both hormones demonstrated that endothelin subtype A (ETA) and angiotensin type 1 (AT1) receptors were involved. Preincubation of cells with two different protein kinase C inhibitors or with a neutralizing anti-transforming growth factor-beta antibody, but not an unrelated IgG, diminished the peptide-induced fibronectin synthesis. A dual interrelation seems to exist between ET-1 and Ang II. Thus, the AT1 receptor antagonist losartan and the angiotensin-converting enzyme inhibitors quinaprilat and captopril diminished the ET-1-mediated effects, whereas, the ETA receptor antagonist BQ-123 diminished the Ang II-induced fibronectin synthesis and mesangial cell proliferation. Our results suggest that ET-1 and Ang II stimulate matrix protein synthesis and mesangial cell mitogenesis through ETA and AT1 receptors, respectively, by complicated mechanisms, implicating protein kinase C activation, synthesis of transforming growth factor-beta, and release of one peptide by the other. These data could be important for a better understanding of the participation of vasoactive substances in the pathogenesis of glomerulosclerosis.
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PMID:Effects and interactions of endothelin-1 and angiotensin II on matrix protein expression and synthesis and mesangial cell growth. 861 64

In the present study, we examined the effect of the thromboxane/prostaglandin endoperoxide analogue U46619 on proliferation and hypertrophy in cultured rat vascular smooth muscle cells and the roles of protein kinase C and transforming growth factor-beta (TGF-beta) in the mediation of the hypertrophic response to U46619. Since an increase in basic fibroblast growth factor (bFGF) was previously shown to mediate the hypertrophic response to U46619, we also assessed the relationship between bFGF and TGF-beta in the expression of U46619 actions. U46619 increased [35S]methionine incorporation into protein and protein content of vascular smooth muscle cells but had no effect on cell number. A role for TGF-beta was supported by the following observations: (1) exogenous human TGF-beta 1 increased protein synthesis; (2) antibody to TGF-beta blocked both TGF-beta- and U46619-induced increases in protein content; (3) U46619 increased active and total TGF-beta bioactivities; and (4) the actions of U46619 on protein content and TGF-beta bioactivity were blocked by the thromboxane/prostaglandin endoperoxide receptor antagonist SQ 29,548. Previous observations had demonstrated a role for bFGF in the expression of U46619 actions on protein synthesis. Results of the present study suggest that TGF-beta and bFGF interact in mediating the protein synthetic response to U46619. First, the concentration of exogenous TGF-beta (10 pmol/L) alone required to produce a protein synthetic response equivalent to that induced by U46619 was much higher than the concentration of endogenous active TGF-beta that accumulated in the media in response to U46619 (0.7 pmol/L). Second, bFGF (20 ng/mL) increased total TGF-beta bioactivity and stimulated protein synthesis. The hyper-trophic response to bFGF was blocked by anti-TGF-beta. The ability of U46619 and bFGF to increase protein synthesis and protein content in vascular smooth muscle cells was associated with TGF-beta-induced suppression of proliferation, as evidenced by the ability of antibody to TGF-beta to enhance U46619- and bFGF-induced increases in [3H]thymidine incorporation into DNA. Results of the present study also supported a role for protein kinase C in the expression of U46619 and bFGF actions. U46619 increased protein kinase C activity in the particulate fraction of vascular smooth muscle cells. Moreover, the protein kinase C inhibitors GF109203X and staurosporine blocked U46619- and bFGF-induced increases in protein synthesis as well as active and total TGF-beta bioactivities. By contrast, the protein kinase C inhibitors did not prevent the increases in protein synthesis induced by exogenous TGF-beta. The results demonstrate that thromboxane/prostaglandin endoperoxide signals increased TGF-beta bioactivity via protein kinase C. Increases in both bFGF and TGF-beta are required for an optimal hypertrophic response to U46619. The hypertrophic response to TGF-beta occurs through a protein kinase C-independent pathway.
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PMID:Thromboxane/prostaglandin endoperoxide-induced hypertrophy of rat vascular smooth muscle cells is signaled by protein kinase C-dependent increases in transforming growth factor-beta. 870 77

The anabolic effect of parathyroid hormone (PTH) on bone is partly due to a stimulation of osteoblast proliferation. The PTH signal is transduced by the pathways of adenylyl cyclase (AC)/protein kinase (PK) A and phospholipase C/PKC/Ca++. There is still uncertainty about the relative contribution of the two pathways to the proliferative effects of the hormone. In our study, PTH(1-34), AC/PKA agonists, and phorbol 12-myristate-13-acetate (PMA, a PKC activator) stimulated cell proliferation in cultured mouse calvariae. In isolated osteoblasts, only PMA stimulated proliferation, whereas AC/PKA agonists and PTH(1-34) inhibited it. As already known, PTH in the presence of supramaximal concentrations of transforming growth factor-beta (TGF-beta) stimulated osteoblast growth; under these same conditions, AC/PKA agonists reproduced the stimulatory effect of PTH(1-34), whereas PMA became inhibitory. PTH(1-31), which stimulates AC without affecting PKC, acted similarly to the fully active PTH(1-34) in both calvaria and isolated osteoblasts. On the contrary, midregion fragments that activate only PKC stimulated calvaria cell proliferation faintly in comparison with PTH(1-34); no effect was seen in osteoblasts, either with or without TGF-beta. Our study shows that the effects of PTH on proliferation can be mimicked by agonists of the AC/cAMP pathway. Although PMA is indeed able to stimulate cell growth in tissue explants, its effects on isolated osteoblasts markedly diverge from those of PTH. We conclude that activation of the AC/PKA pathway is the main component of the proliferative effects of PTH.
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PMID:Effects of parathyroid hormone and agonists of the adenylyl cyclase and protein kinase C pathways on bone cell proliferation. 871 38

The regulation of de novo synthesis of thyroid hormones in primary cultures of human thyroid cells has been examined and correlated with the regulation of the synthesis of the insulin-like growth factor-binding proteins (IGFBPs). In the serum-free culture medium, insulin and TSH (0.01-0.3U/L)were found to be obligatory additives for iodide uptake and organification. In the presence of TSH, cells reorganized into 3D follicles, which stored thyroglobulin. High concentrations of TSH ( > 1U/L), epidermal growth factor, protein kinase C activation with phorbol esters, and transforming growth factor beta 1 all were strongly inhibitory to iodide metabolism and thyroid hormone synthesis. Conditioned medium from the thyroid cell cultures contained at least 5 125I-IGF-labeled bands IGFBPs, including the two glycosylation variants of IGFBP-3. TSH, at concentrations optimal for iodide uptake, inhibited the secretion of all these binding proteins. These effects were mimicked by forskolin and the cell-permeable analog of cAMP, dibutyryl cAMP. The changes in IGFBP proteins were reflected by marked reductions in the steady-state levels of the messenger RNAs of IGFBP-3 and IGFBP-5. This reduction was less pronounced for IGFBP-4. In contrast, protein kinase C activation with phorbol esters and transforming growth factor beta, and high TSH concentrations enhanced IGFBP secretion. Steady-state levels of IGFBP-3 and IGFBP-5 messenger RNAs were elevated after treatment with transforming growth factor-beta and high TSH concentrations. This Study shows that enhanced production of IGFBPs is correlated with inhibition of thyroid function and that TSH, through cAMP, is one factor capable of inhibiting IGFBP production.
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PMID:Functional human thyroid cells and their insulin-like growth factor-binding proteins: regulation by thyrotropin, cyclic 3',5' adenosine monophosphate, and growth factors. 876 74

Twitcher (twi/twi) is a murine model of globoid cell leukodystrophy in humans caused by a genetic deficiency in activity of galactosylceramidase. Our previous study demonstrated that the rate of Schwann cell proliferation in twi/twi was considerably lower than that of the control (+/+) in vitro. We hypothesize that the lower mitotic rate in twi/twi results from the metabolic perturbation of Schawann cells caused by an accumulation of the toxic metabolite of galactosylceramidase, psychosine, a potent inhibitor of protein kinase C (PKC). Mouse Schwann cells are known to be stimulated to divide by growth factors in media containing fetal bovine serum. The stimulation by glial growth factor (GGF) or platelet-derived growth factor-BB (PDGF-BB) is though to be through the PKC pathway, but not by the basic fibroblast growth factor (bFGF) or transforming growth factor-beta (TGF-beta). Thus, we tested responses of twi/twi and +/+ Schwann cells to these growth factors. Schwann cells were isolated from the dorsal root ganglia at 30 days of age and the experiments were carried out at 21 days in vitro. In media containing PDGF-BB or bovine pituitary extract (BPE), the mitotic rate of twi/twi Schwann cells was 76% or 69% of the +/+ value, respectively, while significant differences were detected between twi/twi and +/+ in cultures containing TGF-beta or bFGF. When phorbol 12,13-dibutyrylate, a specific activator of PKC, was added to the media containing PDGF-BB or BPE, the mitotic rate of twi/twi Schwann cells improved up to 90% of +/+ cells. Staurosporine, an inhibitor of PKC. suppressed the proliferation of both twi/twi and +/+ Schwann cells. However, proliferation of twi/twi Schwann cells was suppressed by one-tenth of the concentration required for +/+ Schwann cells. These results are consistent with an accumulation of psychosine, an inhibitor of PKC, and suggest that the signal transduction system through PKC is impaired in the twi/twi Schwann cells.
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PMID:Impairment of protein kinase C activity in twitcher Schwann cells in vitro. 877 76


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