Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A monoclonal antibody prepared by immunization of mice with a rat pituitary granule fraction stained a single band on a Western blot of pituitary homogenate (bovine, ovine, porcine, or rat) with an apparent mol wt of 78,000 (7.5% acrylamide gel in sodium dodecyl sulfate) and pI 5.0-5.1 (isoelectric focusing). Subcellular fractionation studies of rat pituitaries indicated that the determinant of the monoclonal antibody was markedly enriched in the secretory granule fraction, an observation that was independently confirmed by immunohistochemistry of intact cells. Immunohistochemistry also indicated that this determinant was selectively located in gonadotropes and thyrotropes. On Western blots, this band comigrated with adrenal secretogranin-II (SII; chromogranin-C), had the same N-terminal sequence (six amino acids), and was heat stable (95 C; 10 min). The pituitary protein containing the determinant for the monoclonal antibody could be precipitated by a polyclonal antibody prepared by immunization of rabbits with the C-terminal sequence of adrenal SII (triodecapeptide). Conversely, the monoclonal antibody precipitated the protein containing the determinant for the polyclonal antibody. While both the monoclonal and polyclonal antisera recognized the pituitary molecule, only the polyclonal antibody recognized SII from the adrenal. A RIA was established and used to assess the release pattern of this molecule from pituitary cell cultures. Release was stimulated by GnRH and blocked by a GnRH antagonist. Release was Ca2+ dependent and stimulated by either phorbol myristyl acetate (a protein kinase-C activator) or NaF (a G-protein activator). GHRH and TRH were not as effective secretogogues as GnRH. The observations that a unique form of SII is present in the pituitary gonadotrope and secreted in response to a specific endocrine stimulus present the possibility that this substance has an endocrine function. Further, the tissue specificity of the determinant suggest that it may be useful for the specific diagnosis and monitoring of pituitary tumors.
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PMID:SIIp: a unique secretogranin/chromogranin of the pituitary released in response to gonadotropin-releasing hormone. 157 11

Interleukin 6 (IL-6) production was shown to be stimulated by vasoactive intestinal peptide via cAMP dependent signal transduction pathway in the pituitary. We were interested in whether other hypothalamic neuropeptides, which activate adenylate cyclase in the pituitary, also stimulate pituitary IL-6 production. Whereas vasoactive intestinal peptide was effective in stimulating pituitary IL-6 production only at concentrations of 10(-6) M or higher, pituitary adenylate cyclase activating polypeptide with 38 residues (PACAP38) and calcitonin gene-related peptide (CGRP) at concentrations from 10(-10) to 10(-9) M significantly stimulated IL-6 production. Similar effective concentrations of each peptide were required for activating adenylate cyclase, as measured by extracellular cAMP accumulation. H89, a specific inhibitor of cAMP dependent protein kinase (protein kinase A), inhibited IL-6 production stimulated by PACAP38, CGRP, and (Bu)2cAMP. However, H89 failed to inhibit the IL-6 production stimulated by lipopolysaccharide, a ligand which enhanced IL-6 production in the absence of cAMP accumulation. Two other peptides which are known to activate pituitary adenylate cyclase, corticotropin-releasing factor and GRF failed to stimulate IL-6 production in pituitary cells. Using discontinuous Percoll gradients to fractionate the pituitary cells, the greatest PACAP38-stimulated IL-6 secretion was observed in the low density fraction 1 (F1). This fraction also contained the highest percentage of folliculo-stellate (FS) cells, one of the nonhormone secreting pituitary cells. However, the largest PACAP38-induced accumulation of cAMP was observed in F4. These results suggest that the production of IL-6 stimulated by PACAP and CGRP is mediated by the adenylate cyclase/protein kinase A signal transduction system. FS cells appear to be the most likely target cell type for PACAP-induced IL-6 production. However, IL-6 producing FS cells may not be an exclusive target for PACAP in the pituitary.
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PMID:Neuropeptide regulation of interleukin-6 production from the pituitary: stimulation by pituitary adenylate cyclase activating polypeptide and calcitonin gene-related peptide. 165 84

Somatostatin (SRIF) reduces growth hormone releasing hormone (GRF)-stimulated growth hormone (GH) release from avian and mammalian adenohypophyseal cells. The present studies examined the intracellular mechanisms mediating SRIF inhibition of GRF-stimulated GH release from chicken pituitary cells. Increases (P less than 0.05) in GH release were observed in the presence of (1) GRF; (2) the adenylyl cyclase stimulator, forskolin; (3) a cAMP analog, 8-bromo-cAMP; (4) the phosphodiesterase inhibitor 3-isobutyl-l-methyl-xanthine (IBMX) combined with GRF; (5) a tumor-promoting phorbol ester and protein kinase C activator, phorbol 12-myristate, 13-acetate (PMA); (6) a diacylglycerol analog, 1,2-dioctanoyl-glycerol (DiC8); and (7) a calcium ionophore, A23187, alone and in combination with PMA. Somatostatin (10 ng/ml) reduced the release of GH stimulated by GRF, forskolin, and 8-bromo cAMP and the GRF-provoked release of GH in the presence of IBMX (P less than 0.05). Somatostatin, however, did not influence GH release in the presence of the protein kinase C activators, PMA or DiC8, or the calcium ionophore A23187. These data suggest that SRIF inhibits GRF-provoked GH release by reducing the ability of the cAMP-protein kinase A but not of the calcium or protein kinase C intracellular message pathways to stimulate GH release.
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PMID:Possible involvement of adenylyl cyclase-cAMP-protein kinase a pathway in somatostatin inhibition of growth hormone release from chicken pituitary cells. 170 26

These studies examined the cellular basis for the inhibitory effects of triiodothyronine (T3) on growth hormone-releasing factor (GRF)-evoked growth hormone (GH) release from chicken anterior pituitary cells in vitro. A primary monolayer culture of anterior pituitaries from 4- to 8-week-old White Leghorn cockerels was performed as previously described by this laboratory. Following a 72-hr preincubation period, cells were washed and incubated (2 hr) with either secretagogues or media alone (control). T3 (20 ng/ml) or vehicle was added to cells during both the preincubation (48-72 hr) and incubation (2 hr period. Triiodothyronine reduced (P less than 0.05) GH release (ng/ml) in response to (1) GRF; (2) the adenylyl cyclase stimulator, forskolin; (3) the cAMP analog and protein kinase A activator, 8-bromo cAMP; and (4) the phorbol ester and protein kinase C activator, phorbol 12-myristate 13-acetate. Triiodothyronine reduced (P less than 0.05) the intracellular content of GH and total GH (released GH and intracellular GH) irrespectively of whether secretagogues were also present. When GH release was expressed as a percentage of total GH [released GH/(intracellular GH + released GH)], percentage GH released in response to GRF, or the protein kinase A, protein kinase C, or calcium pathway activators was not as great in T3-treated versus non-T3-treated cells. These data indicate that T3 inhibits GRF-evoked GH release by reducing the availability of intracellular stores of GH and by also inhibiting second messenger-stimulated GH release pathways.
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PMID:Triiodothyronine (T3) inhibition of growth hormone secretion by chicken pituitary cells in vitro. 172 15

Most of the transcriptional effects of cyclic AMP are mediated by the cAMP response element binding protein (CREB). After activation of cAMP-dependent protein kinase A, the catalytic subunits of this enzyme apparently mediate the phosphorylation and activation of CREB. As cAMP serves as a mitogenic signal for anterior pituitary somatotrophic cells, we investigated whether CREB similarly regulates proliferation of these cells. We prepared transgenic mice expressing a transcriptionally inactive mutant of CREB (CREBM1), which cannot be phosphorylated, in cells of the anterior pituitary. If CREB activity is required for proliferation, the overexpressed mutant protein would effectively compete with wild-type CREB activity and thereby block the response to cAMP. As predicted, the CREBM1 transgenic mice exhibited a dwarf phenotype with atrophied pituitary glands markedly deficient in somatotroph but not other cell types. We conclude that transcriptional activation of CREB is necessary for the normal development of a highly restricted cell type, and that environmental cues, possibly provided by the hypothalamic growth hormone-releasing factor, are necessary for population of the pituitary by somatotrophic cells.
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PMID:Somatotroph hypoplasia and dwarfism in transgenic mice expressing a non-phosphorylatable CREB mutant. 182 63

A clonal cell line (44-2C) which synthesizes and secretes somatostatin, neurotensin, calcitonin (CT), and CT gene-related peptide and transiently expresses c-fos was used to characterize the mechanism of action of basic fibroblast growth factor (bFGF). bFGF had two modes of action: 1) short term incubation of 44-2C cells with bFGF increased the cellular content of neurotensin, somatostatin, and CT; and 2) bFGF enhanced the response of the cells to rat hypothalamic GRF-mediated cAMP efflux. The long term action of bFGF was manifested by the permissive effect of the molecule. bFGF had a sustained effect on RNA synthesis, and pretreatment with bFGF for 24 h altered the time course of response of the cells to rat GRF. In this cell line the cellular action of bFGF was not mediated via protein kinase-C action. bFGF was not mitogenic in 44-2C cells. bFGF stimulated uridine incorporation without affecting thymidine incorporation. Results obtained with actinomycin-D and alpha-amanitin suggest that the above effects of bFGF can be correlated with increased RNA stability produced by bFGF.
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PMID:Fibroblast growth factor stabilizes ribonucleic acid and regulates differentiated functions in a multipeptide-secreting neuroendocrine cell line. 244 40

The regulation of GRF secretion was studied using a fetal rat hypothalamic cell culture system. The cells were subjected to short term release experiments on days 10-18 after plating, and GRF secretion was assessed by RIA. The identity of GRF immunoreactivity in the incubation medium was confirmed by reverse phase liquid chromatographic analysis. Depolarization of the cells with 56 mM K+ evoked a 4-fold increase in basal GRF release. When cultures were pretreated for 6 days with the adenylate cyclase activator forskolin, basal GRF release was augmented in subsequent release experiments to levels 2-fold greater than those in the control cultures. In nonpretreated cultures, forskolin (1-100 microM) and the protein kinase C activator phorbol 12-myristate 13-acetate (10 nM-1 microM), stimulated basal GRF release in a dose-dependent fashion. The Ca2+ channel blocker verapamil (100 microM) significantly inhibited the GRF response to both forskolin and phorbol 12-myristate 13-acetate. The gamma-aminobutyric acid (GABA) agonist muscimol (0.1-10 microM) inhibited forskolin-stimulated, but not K+ stimulated, GRF release in a dose-dependent manner. This inhibition was reversed by the GABA antagonists bicuculline and picrotoxinin. Muscimol (10 microM) slightly suppressed basal GRF release. The present findings suggest that GRF secretion can be evoked by agents known to increase intracellular cAMP levels or activate protein kinase-C. They also support a role for GABA in the inhibitory control of GRF secretion.
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PMID:Growth hormone-releasing factor secretion from fetal hypothalamic cell cultures is modulated by forskolin, phorbol esters, and muscimol. 253

To examine the role of protein kinase-C in the mediation of GH release we used acutely dispersed purified somatotrophs in static incubation and acutely dispersed adenohypophyses in perifusion. In static incubation, activation of protein kinase-C by phorbol 12-myristate 13-acetate (PMA) and 1,2-dioctanoyl-rac-glycerol (diC8) resulted in an increase in GH release and a concurrent concentration-dependent increase in cAMP accumulation. The GH response to diC8 in perifusion was reversible and repeatable. On the other hand, the GH response to PMA was not repeatable. The lack of repeatability is most likely due to the depletion of protein kinase-C by prolonged treatment with PMA. This assumption is strengthened by the observation that 1 h of perifusion with PMA left the somatotrophs refractory to a subsequent application of diC8. When graded pulses of GRF were applied during treatment with PMA, the GH response to GRF was not altered. Somatostatin reduced (in static incubation) or blocked (in perifusion) the release of GH induced by diC8 and PMA, but the accumulation of cAMP was not affected. We conclude that 1) activation of protein kinase-C in normal somatotrophs results in GH release which may not be completely independent of the cAMP pathway; 2) activation of protein kinase-C is not essential for GRF-induced GH release; and 3) SRIF acts at a site distal to or independent of cAMP to inhibit GH release induced by activators of protein kinase-C.
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PMID:Protein kinase C is not essential for growth hormone (GH)-releasing factor-induced GH release from rat somatotrophs. 256 18

Desensitization of rat pituitary somatotrophs to human growth hormone-releasing factor (hGHRF) was investigated using cultured rat anterior pituitary cells. Growth hormone (GH) release decreased but the production of cAMP was still induced in response to subsequently added 10(-9) M hGHRF from cells pretreated with hGHRF at concentrations ranging from 10(-11) to 10(-7) M for 4 h. Desensitization to 10(-9) M hGHRF was also observed in cells pretreated with 10(-9) M hGHRF for 4 h in the presence of 2 mM EGTA, 10 ng/ml nifedipine or 10(-9) M somatostatin-28, which decreased GH release during pretreatment. Forskolin and A23187, at concentrations of 10(-6) M and 10(-4) M, respectively, stimulated GH release from cells pretreated with hGHRF to the same extent as that from the control cells. These results, therefore, suggest that desensitization to GHRF occurs regardless of the presence of releasable GH pool and that some changes such as uncoupling of GHRF receptors with adenylate cyclase and decreased sensitivity to cAMP of cAMP-dependent protein kinase of the secretory mechanism of GH, in addition to the decrease in releasable GH pool and down regulation of GHRF receptors, may be involved in the desensitization mechanism.
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PMID:Desensitization of rat pituitary somatotrophs to growth hormone-releasing factor occurs in vitro. 289 86

Molt 4b lymphoblasts have previously been shown to possess a single class of pharmacologically specific, high affinity receptors for vasoactive intestinal polypeptide (VIP). This study further explores the molecular basis for modulation of human lymphocyte function by VIP. Dose-dependent stimulation of adenylate cyclase was observed in Molt lymphoblasts over the range of 0.1 nM to 1 microM VIP. VIP-mediated by guanine nucleotide. Accumulation of intracellular cAMP was observed in the presence of either VIP or the diterpene, forskolin. The effects of these two agonists were synergistic. Two neuropeptides that share sequence homology with VIP were also studied; both peptide histidine isoleucine (PHI) and human pancreatic growth hormone releasing factor (1-44 GHRF) competed for 125I-VIP binding to Molt cells. PHI stimulated intracellular cAMP accumulation and demonstrated synergism with forskolin, whereas GHRF had no effect on cAMP. Photoaffinity labeling of 100,000 X G soluble proteins with 8-N3-[32P]cAMP followed by SDS gel electrophoresis demonstrated the presence of cAMP-dependent protein kinases I and II. Cyclic AMP-dependent protein kinase II predominated in the soluble fraction and was the only isozyme observed in particulate fractions. Protein phosphorylation was studied in Molt 4b cells preincubated with [32P]PO43- followed by addition of media alone, 1 microM peptide, or 10 microM forskolin. Cells were lysed and subjected to two-dimensional electrophoresis. Increased phosphorylation of a specific 41,000 Mr protein was observed after addition of forskolin, VIP, or PHI. A much lower concentration of VIP (1 nM) also caused a significant net increase in phosphorylation, which was of a lower magnitude. In contrast, no net effect on protein phosphorylation was seen with GHRF. These data demonstrate the presence of a functional VIP receptor that is linked to the G protein-adenylate cyclase complex. The demonstration of cAMP-dependent protein kinase and of VIP- and PHI-mediated protein phosphorylation in Molt 4b lymphoblasts provides evidence on a molecular level for neuropeptide modulation of human lymphocyte function.
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PMID:Cyclic AMP-dependent protein kinase in Molt 4b lymphoblasts: identification by photoaffinity labeling and activation in intact cells by vasoactive intestinal polypeptide (VIP) and peptide histidine isoleucine (PHI). 298 3


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