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 previous studies, rat adrenal zona glomerulosa (ZG) cells were demonstrated to release interleukin-6 (IL-6). In the current study, cultures of ZG cells and bioassays for tumor necrosis factor (TNF) and IL-6 were used to determine if ZG cells release TNF and to define more fully the factors that regulate ZG IL-6 release. ZG cells released IL-6 and TNF, and this release was stimulated by lipopolysaccharide, interleukin-1 alpha, interleukin-1 beta, a protein kinase C activator, and a calcium ionophore without affecting intracellular adenosine 3', 5'-cyclic monophosphate (cAMP) content. In contrast, adrenocorticotropic hormone (ACTH) increased the intracellular cAMP content, increased basal and secretagogue-stimulated IL-6 release but decreased basal and secretagogue-stimulated TNF release. The effects of ACTH on IL-6 and TNF release may be mediated by increases in intracellular cAMP because ACTH and dibutyryl cAMP modified IL-6 and TNF release in an identical manner. Therefore, IL-6 and TNF release from ZG cells can be differentially regulated. Because IL-6 and TNF modify adrenal steroid release, the adrenal production of these cytokines may have a role in the stress response.
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PMID:Differential release of tumor necrosis factor and IL-6 from adrenal zona glomerulosa cells in vitro. 784 Jan 68

A mouse genomic clone named HGMP01B has been isolated by homology screening with a probe representing part of the human melanocortin 3 receptor gene. HGMP01B was found to encode a 325 amino acid protein with all the landmarks of G-protein-coupled receptors and belonging to the growing melanocortin receptor family. This receptor displays four potential sites for N-linked glycosylation and five potential sites of phosphorylation by protein kinase C. The HGMP01B gene was found to be expressed in many tissues, including skin, adrenal gland, skeletal muscle, bone marrow, spleen, thymus, gonads, uterus, and brain. A stable Chinese hamster ovary (CHO) cell line expressing approximately 10,000 receptors per cell was established. This cell line displayed a saturable binding capacity for the radioiodinated alpha-melanocyte-stimulating hormone (alpha-MSH) analog [Nle4,D-Phe7]-alpha-MSH (NDP-MSH) with an apparent Kd of 1.47 +/- 0.15 nM. Binding of the labeled ligand was competed for by all melanocortin peptides, except beta-endorphin or corticotropin-like intermediate lobe peptide (CLIP). NDP-MSH was the most powerful competitor, followed by alpha-MSH, adrenocorticotropic hormone (ACTH), beta-MSH, the gamma-MSHs, and ACTH 4-10. Functional assays confirmed that HGMP01B, like other melanocortin receptors, stimulated adenylyl cyclase. The potency order obtained in these cyclic adenosine monophosphate (cAMP) accumulation assays was consistent with that of the binding studies. HGMP01B therefore appears as a fifth melanocortin receptor (MC5), responding mainly to alpha-MSH (EC50 = 1.07 +/- 0.13 nM) and endowed with a pharmacological profile similar to that of the melanocyte MSH (MC1) receptor, but characterized by a broad tissue distribution.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Molecular cloning of a mouse melanocortin 5 receptor gene widely expressed in peripheral tissues. 816 9

Although both angiotensin II (Ang II) and potassium ion (K+) induce marked elevations of cytosolic free calcium concentration, [Ca2+]c, in adrenal zona glomerulosa cells-an effect which is thought to trigger aldosterone synthesis-Ang II is also known to reduce the sustained [Ca2+]c rise induced by K+. We have examined whether this effect of Ang II on the calcium messenger system is reflected at the level of the final biological response, aldosterone synthesis. In superfused isolated rat glomerulosa cells, K+ (8 mM) induced a sustained, 60-fold increase in aldosterone production. In contrast, the maximal response to Ang II (10 nM) amounted to only 10 times the basal production. When added subsequent to K+ stimulation, Ang II provoked an immediate and dramatic drop in aldosterone synthesis, to levels obtained with Ang II alone. Under conditions of maximal K+ stimulation, this effect depended upon Ang II concentration, while the well-known synergistic effect was observed with submaximal concentrations of both agonists. The inhibitory effect of Ang II could be reproduced with dioctanoylglycerol, a selective activator of protein kinase C. By contrast, the aldosterone response to adrenocorticotropic hormone (ACTH) was not affected by Ang II. At submaximal concentrations of ACTH, the steroidogenic effect of Ang II was even additive to that of ACTH. Thus, we have shown that, under conditions of maximal stimulation, Ang II exerts a profound inhibition of steroidogenesis in K(+)-stimulated rat adrenal glomerulosa cells. This counter-regulatory mechanism may ensure adequate levels of aldosterone production in vivo.
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PMID:Demonstration of an angiotensin II-induced negative feedback effect on aldosterone synthesis in isolated rat adrenal zona glomerulosa cells. 879 59

Incubation of rat adrenal glomerulosa cells with low concentrations (up to 50 nM) of the protein kinase (PKC) inhibitor staurosporine (ST) inhibited aldosterone (ALDO) and cyclic AMP (cAMP) production stimulated by adrenocorticotropic hormone (ACTH) and cholera toxin. Only higher concentrations (1.6 microM) of staurosporine inhibited dibutyryl-cAMP- and forskolin-induced stimulation of aldosterone production. cAMP levels were increased only with low concentrations of the PKC inhibitor. This latter increase was avoided by treatment with a maximal concentration of isobutylmethylxanthine (MIX). Our results suggest that: (1) second messengers other than cAMP are involved in ACTH action; (2) staurosporine inhibits different kinases involved in ACTH action in a dose-dependent manner; (3) the protein kinase inhibited by high concentrations of staurosporine appears to be the cAMP-dependent kinase, PKA; and (4) the protein kinase inhibited by low concentrations of staurosporine remains to be identified. This latter species is suggested as being involved in mediating ACTH-induced activation of Gs.
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PMID:Effects of staurosporine on ACTH-mediated stimulation of aldosterone production. 891 88

Both urocortin (UCN) and corticotropin-releasing hormone (CRH) are known to stimulate secretion of adrenocorticotropic hormone (ACTH) by corticotroph cells via type-1 corticotropin-releasing hormone receptor (CRHR-1). We extensively examined UCN effects on the anterior pituitary (AP), particularly on proopiomelanocortin (POMC) mRNA and CRHR-1 mRNA as well as ACTH secretion in vivo. Moreover, signal transduction with UCN exposure was assessed in AP cell cultures in comparison with transduction following CRH exposure. Intravenously administered of UCN (5 microg/kg) increased ACTH and corticosterone secretion. Similarly, intravenous administration of UCN increased POMC mRNA and decreased CRHR-1 mRNA in the AP. These UCN effects were more potent and long-lasting than those of CRH. The prominent effect of UCN on ACTH secretion in vivo was confirmed in AP cell cultures, where application of UCN stimulated ACTH release approximately 7 times more strongly than CRH. The effect of UCN on ACTH release was enhanced by phorbol esters which activate protein kinase C, but was reduced by the selective cAMP-dependent protein kinase inhibitor, H-89. These results suggest that, as with CRH, UCN stimulates ACTH production and/or release through cAMP-dependent mechanisms, and that protein kinase C-dependent mechanism has a synergistic effect upon UCN-induced ACTH release. The more potent effects of UCN relative to CRH may be attributable to UCN's higher affinity for CRHR-1.
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PMID:Effect of urocortin on ACTH secretion from rat anterior pituitary in vitro and in vivo: comparison with corticotropin-releasing hormone. 973 15

Angiotensin II (AngII) is thought to stimulate aldosterone secretion from bovine adrenal glomerulosa cells in part via activation of protein kinase C (PKC), while adrenocorticotropic hormone (ACTH) functions through increases in intracellular cAMP levels and calcium influx. Rather than using invasive homogenization techniques as in previous studies, we chose to monitor PKC activity in intact glomerulosa cells in situ by measuring the phosphorylation of the endogenous PKC substrate, myristoylated alanine-rich C-kinase substrate (MARCKS). AngII enhanced MARCKS phosphorylation in a rapid, sustained manner; whereas ACTH induced a rapid and sustained inhibition of MARCKS phosphorylation. Studies using pharmacological agents to mimic various signals indicated that the AngII-induced MARCKS phosphorylation was due to PKC activation, and the ACTH-elicited decrease was mediated by increases in calcium influx rather than cAMP production. We propose that changes in the phosphorylation state of MARCKS, an actin-binding protein, may contribute to cytoskeletal rearrangements involved in steroidogenesis.
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PMID:Effects of angiotensin II and adrenocorticotropic hormone on myristoylated alanine-rich C-kinase substrate phosphorylation in glomerulosa cells. 1050 94

Secretin, glucagon, gastric inhibitory polypeptide (GIP), and parathyroid hormone (PTH) belong, together with vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase (AC)-activating polypeptide, to a family of peptides (the VIP-secretin-glucagon family), which also includes growth hormone-releasing hormone and exendins. All the members of this peptide family possess a remarkable amino-acid sequence homology, and bind to G-protein-coupled receptors, whose signaling mechanism primarily involves AC/protein kinase A and phospholipase C/protein kinase C cascades. VIP and pituitary AC-activating polypeptide play a role in the regulation of the hypothalamus-pituitary-adrenal (HPA) axis, and in this review we survey findings that also other members of the VIP-secretin-glucagon family may have the same function. Secretin and secretin receptors are expressed in the hypothalamus and pituitary gland, and secretin inhibits adrenocorticotropic hormone (ACTH) release. No evidence is available for the presence of secretin receptors in adrenal glands, but secretin selectively depresses the glucocorticoid response to ACTH of dispersed zona fasciculata-reticularis (ZF/R) cells. Glucagon and glucagon-like peptide-1 are contained in the hypothalamus, and all the components of the HPA axis are provided with glucagon and glucagons-like-1 receptors. These peptides exert a short-term inhibitory effect on stress-induced pituitary ACTH release and depress the ZF/R cell response to ACTH by inhibiting the AC/protein kinase A cascade; they also stimulate hypothalamic arginine-vasopressin release. GIP receptors are present in the ZF/R of the normal adrenals, and are particularly abundant in some types of adrenocortical adenomas and hyperplasias. GIP, through the activation of the AC/protein kinase A cascade, evokes a sizeable glucocorticoid secretagogue effect, leading to the identification of a food/GIP-dependent Cushing's syndrome. PTH and PTH-related protein are expressed in the hypothalamus and pituitary gland, and PTH and PTH-related protein receptors in all the components of the HPA axis. Both peptides enhance ACTH and arginine-vasopressin release, as well as stimulate aldosterone and glucocorticoid secretion of dispersed zona glomerulosa and ZF/R cells, respectively. The involvement of growth hormone-releasing hormone and exendins in the functional regulation of the HPA axis has not yet been extensively investigated.
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PMID:Secretin, glucagon, gastric inhibitory polypeptide, parathyroid hormone, and related peptides in the regulation of the hypothalamus- pituitary-adrenal axis. 1076 61

The steroidogenic acute regulatory (StAR) protein mediates cholesterol transport within the mitochondria, and its phosphorylation is believed to be required for steroidogenesis. Increased extracellular potassium concentrations (K(+)), angiotensin II (AngII), and adrenocorticotropic hormone (ACTH) induce aldosterone secretion from bovine adrenal glomerulosa cells. We hypothesized that, although these agonists act via different signaling pathways, StAR phosphorylation should be common to their action. We studied the effects of K(+), AngII, and ACTH, at concentrations that yield comparable secretory responses, on StAR phosphorylation. All three agents induced significant increases in StAR phosphorylation although the response to ACTH was less than that of AngII and K(+). In cells stimulated with the protein kinase C (PKC) agonist 12-tetradecanoylphorbol 13-acetate (TPA), the Ca(2+) channel agonist BAY K8644, and the adenylate cyclase agonist forskolin, TPA caused a small but statistically significant increase in StAR phosphorylation while BAY K8644 and forskolin had no significant effect. Interestingly, the combination of TPA and BAY K8644 produced a larger increase in StAR phosphorylation than the agents alone. We conclude that in cultured bovine adrenal glomerulosa cells the PKC signaling pathway is most effective at inducing StAR phosphorylation but that there is no simple correlation between this event and aldosterone production.
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PMID:Differential effects of agonists of aldosterone secretion on steroidogenic acute regulatory phosphorylation. 1122 80

Our previous studies have identified a role for annexin 1 (ANXA1), a protein produced by the pituitary folliculostellate cells, as a paracrine/juxtacrine mediator of the acute regulatory effects of glucocorticoids on the release of adrenocorticotropic hormone and other pituitary hormones. In the present study, we focused on the secretion of thyroid stimulating hormone (TSH) and luteinizing hormone (LH) and used a battery of ANXA1-derived peptides to identify the key domains in the ANXA1 molecule that are critical to the inhibition of peptide release. In addition, as ANXA1 is a substrate for protein kinase C (PKC) and tyrosine kinase, we examined the roles of these kinases in the manifestation of the ANXA1-dependent inhibitory actions of dexamethasone on TSH and LH release. Dexamethasone suppressed the forskolin-induced release of TSH and LH from rat anterior pituitary tissue in vitro. Its effects were mimicked by human recombinant ANXA1 (hrANXA1) and a truncated protein, ANXA1(1-188). ANXA1(Ac2-26), also suppressed stimulated peptide release but it lacked both the potency and the efficacy of the parent protein. Shorter N-terminal ANXA1 sequences were without effect. The PKC inhibitor PKC(19-36) abolished the inhibitory actions of dexamethasone on the forskolin-evoked release of TSH and LH; it also attenuated the inhibitory actions of ANXA1(Ac2-26). Similar effects were produced by annexin 5 (ANXA5) which sequesters PKC in other systems. By contrast, the tyrosine kinase inhibitors, p60v-src (137-157) and genistein, had no effect on the secretion of TSH or LH alone or in the presence of forskolin and/or dexamethasone. Dexamethasone caused the translocation of a tyrosine-phosphorylated species of ANXA1 to the surface of pituitary cells. The total amount of ANXA1 exported from the cells in response to the steroid was unaffected by tyrosine kinase blockade. However, the degree of tyrosine-phosphorylation of the exported protein was markedly reduced by genistein. These results suggest that (i) the ANXA1-dependent inhibitory actions of dexamethasone on the release of TSH and LH require PKC and sequences in the N-terminal domain of ANXA1, but are independent of tyrosine kinase, and (ii) while dexamethasone induces the cellular exportation of a tyrosine-phosphorylated species of ANXA1, tyrosine phosphorylation per se is not critical to the steroid-induced passage of ANXA1 across the membrane.
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PMID:Kinase-dependent regulation of the secretion of thyrotrophin and luteinizing hormone by glucocorticoids and annexin 1 peptides. 1296 39

Epidermal growth factor (EGF) regulates pituitary development, hormone synthesis, and cell proliferation. Although ErbB receptor family members are expressed in pituitary tumors, the effects of EGF signaling on pituitary tumors are not known. Immunoprecipitation and Western blot confirmed EGF receptor (EGFR) and p185(c-neu) protein expression in GH3 lacto-somatotroph but not in adrenocorticotropic hormone-secreting AtT20 pituitary tumor cells. EGF (5 nmol/L) selectively enhanced baseline ( approximately 4-fold) and serum-induced (>6-fold) prolactin (PRL) mRNA levels, whereas gefitinib, an EGFR antagonist, suppressed serum-induced cell proliferation and Pttg1 expression, blocked PRL gene expression, and reversed EGF-mediated somatotroph-lactotroph phenotype switching. Downstream EGFR signaling by ERK, but not phosphoinositide-3-kinase or protein kinase C, mediated the gefitinib response. Tumors in athymic mice implanted s.c. with GH3 cells resulted in weight gain accompanied by increased serum PRL, growth hormone, and insulin growth factor 1. Gefitinib decreased tumor volumes and peripheral hormone levels by approximately 30% and restored normal mouse body weight patterns. Mice treated with gefitinib exhibited decreased tumor tissue ERK1/2 phosphorylation and down-regulated tumor PRL and Pttg1 mRNA abundance. These results show that EGFR inhibition controls tumor growth and PRL secretion in experimental lacto-somatotroph tumors. EGFR inhibitors could therefore be useful for the control of PRL secretion and tumor load in prolactinomas resistant to dopaminergic treatment, or for those prolactinomas undergoing rare malignant transformation.
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PMID:Rat prolactinoma cell growth regulation by epidermal growth factor receptor ligands. 1867 63


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