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)

7-Hydroxystaurosporine (UCN-01) is a selective protein kinase C (PKC) inhibitor and is being developed as a novel anticancer agent. Because of reports that PKC may be involved in the pathogenesis of some forms of thyroid cancers, we examined four thyroid carcinoma lines (FRO, KAT5, NPA, and WRO). These cells were found to have different susceptibility to UCN-01 treatment, and there appeared to be a correlation between UCN-01-induced death and expression levels of endogenous Bcl-2. KAT5 cells, which normally express a low amount of Bcl-2, exhibited significantly higher sensitivity to UCN-01-induced death than the other cell lines. Of interest, susceptibility did not relate to PKC activity or its inhibition by UCN-01. In order to investigate the role of Bcl-2 in UCN-01-induced death, KAT5 cells were transfected to overexpress Bcl-2. KAT5/Bcl-2 cells were capable of conferring resistance to UCN-01-induced death. Furthermore, upregulating of Bcl-2 by 1alpha,25-dihydroxyvitamin D3 (VD3) could protect primary thyroid cell from death induced by UCN-01. Both in situ TUNEL staining and the flow cytometric analysis of cytokeratin-18 (CK18) cleavage confirmed that UCN-01 was indeed inducing apoptosis, and that this effect was inhibited by increased expression of Bcl-2. These results suggest that the Bcl-2 can block the UCN-01-activated cell death pathway and that the expression of Bcl-2 is inversely related to thyroid carcinoma cell susceptibility to UCN-01. Therefore, the analysis of the expression of apoptosis suppressors provides a basis for the use of UCN-01 in the treatment of thyroid cancer.
Thyroid 2001 Aug
PMID:Susceptibility of thyroid cancer cells to 7-hydroxystaurosporine-induced apoptosis correlates with Bcl-2 protein level. 1152 64

The effect of the phorbol esther phorbol myristate acetate (PMA) on iodide uptake was studied in primary cultures of calf thyroid cells. PMA caused a dose- and time-dependent inhibition of thyrotropin (TSH), forskolin, and db-cAMP stimulation, indicating an effect distal to both TSH receptor and cAMP generation. No action was found on iodide efflux, indicating a selective inhibition of iodide uptake. This inhibition was observed even after 5 minutes of incubation, thus excluding a possible genomic action. Bisindolmaleimide (BS), a specific inhibitor of the protein kinase C (PKC) pathway, reverted the effect of PMA. A similar degree of inhibition of the Na+/K+ adenosine triphosphatase (ATPase) and iodide uptake by PMA was found, thus suggesting a link between both parameters. These results indicate that the PKC pathway inhibits thyroid iodide uptake by an action distal to cAMP generation and probably because of a decrease in Na+/K+-ATPase activity.
Thyroid 2001 Sep
PMID:The protein kinase C pathway inhibits iodide uptake by calf thyroid cells via sodium potassium-adenosine triphosphatase. 1157 49

Thyroid hormone action on brain development is essentially exerted through regulation of the expression rate of a number of genes some of which have been identified in the past 10 years. In the present work we describe the thyroid hormone regulation of a novel Ras homolog which we have named Rhes (Ras homolog enriched in striatum). The rhes cDNA was previously isolated in subtractive hybridization experiments aimed at identifying cDNA clones corresponding to genes expressed preferentially in the rat striatum. The sequence was found to encode a small GTP-binding protein of the Ras family with highest homology to the dexamethasone-inducible Dexras1. Here we show that rhes mRNA and protein in the striatum are strongly dependent on the thyroidal status. Developmentally, Rhes was regulated such that in normal rats there was an increased rhes mRNA content in the striatum after postnatal day 5 (P5). Rhes concentration in hypothyroid rats was similar to that of normal rats at P5, but the subsequent age-dependent increase was blunted. The administration of a single T3 dose to hypothyroid rats normalized rhes mRNA concentration in 8 h, whereas it took 24 h, or more, to normalize the expression of rc3, another T3-dependent brain gene, involved in PKC signaling. Double in situ hybridization using rhes and rc3 riboprobes showed that the bulk of rhes signal was located in cells expressing rc3. Given the relevance of small GTPases in signal transduction it is very likely that control of rhes, in addition to rc3, is of relevance to explain the actions of thyroid hormone in the striatum, a region of the brain especially vulnerable in neurological cretinism.
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PMID:Thyroid hormone regulation of rhes, a novel Ras homolog gene expressed in the striatum. 1159 59

Type 1 and 2 iodothyronine deiodinases (D1 and D2) catalyze thyroxine (T4) activation. In human thyroid, unlike rodents', both D1 and D2 are expressed. We have investigated the effects of thyrotropin (TSH), dibutyryl cyclic adenosine monophosphate [(Bu)2cAMP] (an activator of protein kinase A [PKA]), 12-O-tetradecanoylphorbor 13-actate (TPA) (an activator of protein kinase C [PKC]), T4, and triiodothyronine (T3) on the D2 mRNA levels and activity in cultured human thyroid cells. D2 mRNA levels were increased by TSH and (Bu)2cAMP, and the increment was faster and greater than that of D1 mRNA levels. The increment of the maximum velocity (Vmax) value for D2 by (Bu)2cAMP stimulation was similar to that of D2 mRNA levels, suggesting that (Bu)2cAMP enhances D2 activity mainly at the pretranslational level. Cycloheximide, a protein synthesis inhibitor, partially inhibited the increase of D2 mRNA levels by (BU)2cAMP, suggesting that de novo protein synthesis-dependent pathways are involved. TPA suppressed the D2 mRNA levels in the presence of (Bu)2cAMP. However, T3 and T4 did not significantly change the D2 mRNA levels and activity. In conclusion, D2 expression in human thyroid cells is more rapidly and strongly upregulated by the PKA pathway than D1 expression, and is downregulated by the PKC pathway.
Thyroid 2001 Oct
PMID:Type 2 iodothyronine deiodinase expression is upregulated by the protein kinase A-dependent pathway and is downregulated by the protein kinase C-dependent pathway in cultured human thyroid cells. 1171 36

We have previously shown that long-term thyroxine administration can protect the heart against ischemia. In the present study, we investigated whether thyroxine-induced cardioprotection can mimic the pattern of protection that is afforded by a well-established cardioprotective means such as ischemic preconditioning. In a Langendorff-perfused rat heart preparation, after an initial stabilization, normal and thyroxine-treated hearts were subjected to 20 minutes of zero-flow global ischemia followed by 45 minutes of reperfusion. In thyroxine-treated hearts, phospho-p38 mitogen-activated protein kinase (MAPK) was found to be less at the end of the ischemic period, whereas ischemic contracture was accelerated and postischemic recovery was increased in comparison to normal hearts. In addition, normal hearts were subjected to a four-cycle preconditioning protocol before ischemia. Phospho-p38 MAPK was found to be less at the end of the ischemic period in preconditioned hearts, whereas ischemic contracture was accelerated and postischemic functional recovery was increased in those hearts in comparison to nonpreconditioned hearts. An increase in basal expression and phosphorylation of PKCdelta was also found to occur after long-term thyroxine administration. We conclude that long-term thyroxine administration can protect the heart from ischemic injury through a pattern of protection that closely resembles that of ischemic preconditioning.
Thyroid 2002 Apr
PMID:Long-term thyroxine administration protects the heart in a pattern similar to ischemic preconditioning. 1203 58

The goal of the present review is to collect information concerning membrane effects induced by lindane intoxication, a y isomer of hexachiorocyclohexane (gamma-HCH) that has been largely used as an insecticide and disinfectant in agriculture and entered also in the composition of some lotions, creams and shampoos used against parasites (lice and scabies). Absorbed through respiratory, digestive or transcutaneous pathways, lindane accumulates within lipid rich tissues. Lindane accumulation depends on the duration of the exposure and affects tissues in the following order: adipose tissues > brain > kidney > muscle > lungs > heart > liver > blood. Whatever the mode of lindane absorption, it accumulates in blood and is distributed throughout the body. It may affect human health by exerting systemic, immunologic, teratogenic, and/or cancerogenic effects. The symptoms of lindane intoxication are different according to the mode of intoxication, acute or chronic. The absorption of high doses of gamma-HCH is particularly toxic for the central nervous system and for the female and male reproduction apparatus in mammals where lindane is considered as an endocrine disruptor. Lindane is highly lipophilic and incorporates into biological membranes according to the following sequence: mitochondria > sarcoplasmic reticulum > myelin > brain microsomes > erythrocytes. Lindane exerts a stimulating action on synaptic transmission and inhibits the chloride current activated by gamma-amino butyric acid (GABA) of many muscular and nervous preparations by interacting with the receptors GABA-chloride channel complex. It seems to affect calcium homeostasis of many tissues. The similarity between lindane and inositol (1, 4, 5) phosphate (IP3) suggested that lindane releases Ca2+ from IP3-sensitive intracellular stores in macrophages and myometrial cells. Ca2+ release from reticulum endoplasmic, mitochondria and other Ca2+ stores has been reported in cat kidney cells. Lindane altered energetic metabolism of hepatic mitochondria and the inositol-phosphate synthesis in neuronal cells. However, lindane does not compete with the IP3 receptor. Lindane produces a Ca2+ influx in mice peritoneal macrophage cells responsible for the Ca2+ induced Ca2+ release produced by phospholipase C via IP3 pathway and resulting in a maintained increase of the free cytosolic Ca2+ concentration. Lindane decreased the membrane erythrocyte and cerebral cell concentration of phosphatidyl inositol PI, PIP and PIP2 in rats repetitively exposed to lindane for 3 or 6 months. Lindane induces oxidative stress; it modifies the activity of the scavenger enzymes. This effect is involved in the inhibition of intercellular gap junctions. Modifications of the electrocardiogram (ECG), sinusal rhythm alteration and negative and dysphasic variations of T wave, similar to those produced by hyperkaliemia, have been reported after lindane absorption. During acute lindane poisoning, the activities of serum transaminases (SGOT, SGTP), and lactate deshydrogenase (LDH) increase. Lindane produces histological alterations of cardiac tissues and a cardio-vascular dystrophy (contracture, degenerescence and necrosis) mainly in the left ventricular wall and a hypertrophy of the left ventricle. Chronic application of residual doses of lindane shortened the action potential duration in rat papillary muscle. These effects were similar to those induced by hyperthyroidism. Lindane increases the triiodothyronine (T3) serum level in hyperthyroid rats. T3 plays an important role in the postnatal development of the rat ventricle by increasing the density of potassium channels which contribute to action potential shortening during the development. Thyroid hormones influence the regulation and the expression of messengers ARN which encode different potassium channels involved in action potential repolarization (Kvl.2; Kvl.4; Kvl.5; Kv2.1; Kv4; HCN2). The thyrotropine-releasing hormone (TRH) modulates the HERG-type rapid delayed potassium channel (IKr) encoded by the human gene ether-a-go-go in rat anterior pituitary cells GH3/B6. This channel is involved in the cardiac long QT syndrome. TRH modifies the current kinetics of human HERG potassium channel co-expressed in Xenopus oocytes with the TRH receptor, whose activity is modulated via the protein kinase C pathway linked to a G protein-coupled receptor and is regulated by changes in the PIP2 concentration in the membrane. IKr channels regulation is also dependent on sexual hormones. In conclusion, lindane affects the excitable membranes and the cardio circulatory system. These alterations (may) represent a potential risk for human health.
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PMID:[Cardiotoxicity of lindane, a gamma isomer of hexachlorocyclohexane]. 1264 5

Soluble tumor necrosis factor (TNF)-alpha receptors have the potential to modulate TNF-alpha activity during autoimmune thyroiditis. In this study we examined cell-surface TNF-alpha receptors and soluble TNF-alpha receptor production by thyrocytes from normal and MRL-lpr(-/-) (diseased) mice, which spontaneously develop autoimmune thyroiditis. We found that murine thyrocytes possess the 55-kd receptor (TNF-R1). Examination of soluble TNF-R1 production revealed that diseased thyrocytes produced sevenfold more soluble TNF-R1 than normal thyrocytes. Furthermore, basal protein kinase C (pKC) activity in diseased thyrocytes was 67% higher than that found in normal murine thyrocytes. The elevated basal pKC activity in diseased thyrocytes was related to their enhanced production of soluble TNF-R1 because inhibition of pKC activity with calphostin C caused soluble TNF-R1 production to decrease significantly. Additionally, soluble TNF-R1 production by murine thyrocytes was not a result of cell-surface receptor shedding but through secretion of a truncated version of TNF-R1. This was evident when cell-surface TNF-R1 levels were unchanged after treatment of diseased thyrocytes with calphostin C. Also, the 28-kd form of TNF-R1, which corresponds to the soluble receptor, was present in the intracellular membranes of the diseased thyrocytes.
Thyroid 2004 Apr
PMID:Thyrocytes isolated from autoimmune-diseased thyroids secrete soluble tumor necrosis factor-R1 that is related to their elevated protein kinase C activity. 1514 58

Over the past few years increasing evidence has suggested the nongenomic effects of thyroid hormone, such as the activation of the signal transduction pathways and the activation of nuclear factor-kappaB by the induction of oxidative stress. The present study was undertaken to investigate the effect of thyroid hormone on human polymorphonuclear leukocytes (PMNLs) which are known as important sources of reactive oxygen species in the circulation. The production of superoxide anion (O2-) and the activity of myeloperoxidase were determined in the presence and absence of several inhibitors of the signalling pathway. L-thyroxine (T4) l-3,5,3'-tri-iodothyronine (T3) and L-3,5-di-iodothyronine (T2) stimulated O2- production in PMNLs in a dose-dependent manner within a few minutes of addition to cells. Thyroid hormone-stimulated O2- production was partially inhibited by pertussis toxin, an inhibitor of GTP-binding G protein, and was completely abolished by the protein kinase C inhibitors calphostin C and Ro-32-0432, and by a calcium chelator (BAPTA; bis-(o-aminophenoxy)ethane-N,N,N',N'-tetra-acetic acid). Thyroid hormone stimulated myeloperoxidase activity and induced 125I- incorporation into PMNLs. Furthermore, thyroid hormone pre-incubation enhanced O2- production for n-formyl-methionyl-leucyl- phenylalanine (FMLP) stimulation. In conclusion, novel nongenomic actions of thyroid hormone, the induction of superoxide anion production and the stimulation of myeloperoxidase activity in PMNLs were demonstrated. The induction of O2- production requires calcium and is mediated by a pertussis toxin-sensitive G protein via stimulation of protein kinase C(s). These results suggest the existence of a membrane-bound binding site for thyroid hormone in PMNLs and a physiological role for thyroid hormone in the cellular defence mechanisms by stimulating free-radical production.
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PMID:Nongenomic effect of thyroid hormone on free-radical production in human polymorphonuclear leukocytes. 1581 33

Extranuclear or nongenomic effects of thyroid hormones do not require interaction with the nuclear receptor, but are probably mediated by specific membrane receptors. This review will focus on the extranuclear effects of thyroid hormones on plasma membrane transport systems in non mammalian cells: chick embryo hepatocytes at two different stages of development, 14 and 19 days. At variance with mammals, the chick embryo develops in a closed compartment, beyond the influence of maternal endocrine factors. Thyroid hormones inhibit the Na+/K+-ATPase but stimulate the Na+/H+ exchanger and amino acid transport System A with different dose-responses: a bell-shaped curve in the case of the exchanger and a classic saturation curve in the case of System A. These effects are mimicked by the analog 3,5-diiodothyronine. Signal transduction is mediated by interplay among kinases, mainly protein kinase C and the MAPK pathway, initially primed by second messengers such as Ca2+, IP3, and DAG as in mammalian cells. Thyroid hormones and 3,5-diiodothyronine stimulate thymidine incorporation and DNA synthesis, associated with the increased levels and activity of cyclins and cyclin-dependent kinases involved in the G1/S transition, and also these effects have their starting point at the plasma membrane. Increasing evidence now demonstrates that thyroid hormones act as growth factors for chick embryo hepatocytes and their extranuclear effects are important for prenatal development and differentiation.
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PMID:Short-term effects of thyroid hormone in prenatal development and cell differentiation. 1586 27

Thyroid hormones play critical roles in differentiation, growth and metabolism, but their participation in immune system regulation has not been completely elucidated. Modulation of in vivo thyroid status was used to carry out an integrative analysis of the role of the hypothalamus-pituitary-thyroid (HPT) axis in T and B lymphocyte activity. The participation of the protein kinase C (PKC) signaling pathway and the release of some cytokines upon antigenic stimulation were analyzed. Lymphocytes from hyperthyroid mice displayed higher T-and B-cell mitogen-induced proliferation, and those from hypothyroid mice displayed lower T- and B-cell mitogen-induced proliferation, compared with euthyroid animals. Reversion of hypothyroid state by triiodothyronine (T3) administration recovered the proliferative responses. No differences were found in lymphoid subset balance. Both total PKC content and mitogen-induced PKC translocation were higher in T and B cells from hyperthyroid mice, and lower in cells from hypothyroid mice, compared with controls. Levels of thyroid-stimulating (TSH) and TSH-releasing (TRH) hormones were not directly related to lymphocyte proliferative responses. After immunization with sheep red blood cells (SRBCs) and re-stimulation, in vitro spleen cells from hyper- or hypothyroid mice showed, respectively, increased or decreased production of interleukin (IL)-2 and interferon (IFN)-gamma cytokines. Additionally, an increase in IL-6 and IFN-gamma levels was found in hyperthyroid cells after in vivo injection and in vitro re-stimulation with lipopolysaccharide (LPS). Our results show for the first time a thyroid hormone-mediated regulation of PKC content and of cytokine production in lymphocytes; this regulation could be involved in the altered responsiveness to mitogen-induced proliferation of T and B cells. The results also confirm the important role that these hormones play in regulating lymphocyte reactivity.
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PMID:Integrative study of hypothalamus-pituitary-thyroid-immune system interaction: thyroid hormone-mediated modulation of lymphocyte activity through the protein kinase C signaling pathway. 1661 80


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