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)

The effect of phorbol diester tumour promoters on the release of growth hormone (GH) and prolactin (Prl) was studied in rat pituitary cells cultured in monolayer. 12-O-tetradecanoyl phorbol-13-acetate (TPA), the most potent phorbol ester, stimulated GH accumulation in the cultured medium in a dose-dependent manner. TPA also stimulated Prl accumulation. A time course study indicated that TPA mainly stimulates release of GH. The maximal stimulation of GH release by TPA (100 ng/ml) was 3-4-fold over control. Phorbol-12,13-dibutyrate (PDB), another tumour-promoting phorbol ester, stimulated GH release to an extent similar to that of TPA, while a biologically inactive compound, phorbol-12,13-diacetate (PDA), had no effect. TPA-stimulated GH release was not affected by the presence of indomethacin, an inhibitor of prostaglandin (PG) synthesis, indicating that PG is not involved in the process of TPA-stimulated GH release. Co++, a competitive antagonist of Ca++, at 2.0 mM completely suppressed the GH release induced by TPA, and this inhibition was partially reversed by the addition of 2.0 mM Ca++. Verapamil, a Ca++ channel blocker, reduced TPA-stimulated GH release, and trifluoperazine, an inhibitor of Ca-calmodulin formation, had a similar effect. Somatostatin (SRIF) also inhibited the GH release by TPA. These observations are compatible with the idea that Ca++ may be involved in the process of TPA-stimulated GH release. Since TPA has been reported to activate a Ca++- and phospholipid-dependent protein kinase (protein kinase C), it is possible that TPA stimulate GH release by activating the enzyme. Further studies are required to clarify this point.
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PMID:Effect of phorbol esters on the release of growth hormone and prolactin from rat pituitary cells cultured in monolayer. 614 63

The addition of epidermal growth factor (EGF) to cultured rat pituitary cells (GH3) leads to increased synthesis of prolactin and to partial inhibition of cell proliferation. Monoclonal antibodies generated against EGF receptor from human epidermoid carcinoma (A-431) cells were used to characterize the EGF receptor kinase system of GH3 cells and to investigate the role of the hormone-receptor complex in the expression of the prolactin gene in these cells. The EGF receptor of GH3 cells is a 170,000-dalton protein associated with a protein kinase. It is similar but not identical to the EGF receptor identified in other tissues. The immunoprecipitated membrane receptor is phosphorylated on both serine and tyrosine residues. The monoclonal antibody denoted 2G2-IgM binds to EGF receptor on GH3 cells. Like EGF, the monoclonal antibody induced the synthesis of prolactin and morphological changes in these cells. Hence, EGF receptor in GH3 cells, when properly triggered, contains all of the biological attributes necessary for the induction of EGF-induced gene expression and morphological changes in GH3 cells.
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PMID:Monoclonal antibodies against epidermal growth factor receptor induce prolactin synthesis in cultured rat pituitary cells (GH3). 619 56

Thyrotropin-releasing hormone (TRH) is a tripeptide that rapidly enhances prolactin secretion in clonal, hormone-responsive GH3 rat pituitary cells. In an effort to identify postreceptor mechanisms for TRH, protein phosphorylation studies have been conducted. Our previous studies (Drust, D.S., Sutton, C.A., and Martin, T. F. J. (1982) J. Biol. Chem. 257, 3306-3312; Drust, D.S., and Martin, T. F. J. (1982) J. Biol. Chem. 257, 7566-7573) showed that TRH rapidly (less than 15 s) increased the phosphorylation of at least six cytosolic proteins (41K (Mr = 41,000), several 59K, 65K, 82K, and 97K) and, with a 5- to 10-min latency, increased the phosphorylation of a seventh (80K). Cyclic AMP did not appear to mediate TRH-stimulation of protein phosphorylation; in contrast, Ca2+ translocation and Ca2+-dependent protein phosphorylation accounted for hormone-induced changes in 97K (and possibly 41K) phosphorylation. The studies reported here indicate that lipid (diacylglycerol) accumulation and protein kinase C activation mediate TRH-stimulated phosphorylation of the additional five cytosolic proteins (two 59K, 65K, 80K, and 82K). This conclusion is based on the findings that: 1) phospholipase C treatment, which produces diacylglycerol, mimicked several TRH effects; 2) bombesin, another peptide that induces inositol phosphatide turnover, mimicked several TRH effects; 3) phorbol esters, which were shown to activate GH3 cell protein kinase C directly, produced TRH-like effects; 4) partially purified GH3 cell cytosolic protein kinase C was activated by diacylglycerol; and 5) 59K and 82K proteins were endogenous in vitro substrates for a cytosolic lipid-stimulated protein kinase. We conclude that rapid TRH effects in promoting inositol phosphatide turnover in GH3 cells may be linked to the activation of protein phosphorylation mediated by protein kinase C. These, and previously reported studies, indicate a role for Ca2+ and lipids (diacylglycerol) as dual intracellular messengers for TRH.
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PMID:Thyrotropin-releasing hormone rapidly activates protein phosphorylation in GH3 pituitary cells by a lipid-linked, protein kinase C-mediated pathway. 623 63

The present experiments were designed to study whether exogenous LH could elicit acute cyclic AMP-mediated activation of cyclic AMP-dependent protein kinase and phosphorylation of cellular protein in intact porcine granulosa cells. Incubation of porcine granulosa cells (from 3 to 5 mm diameter follicles) with 2 microgram luteinizing hormone/ml (LH) caused a significant rise of cellular cyclic AMP content within 2 min of the addition of LH. The increase was dose-dependent and occurred between doses of 0.2 and 2.0 microgram LH/ml. Luteinizing hormone also caused a time- and dose-dependent dissociation of the type II cyclic AMP-dependent protein kinase isozyme in porcine granulosa cells. Luteinizing hormone (0.05--2 microgram/ml) significantly dissociated the cyclic AMP-dependent protein kinase between 2 and 30 min after stimulation. The protein kinase dissociation was a specific effect of LH and was not elicited by either adrenocorticotrophic hormone or prolactin. During the period of LH-induced protein kinase activation, several soluble granulosa cell proteins, ranging in molecular weights from about 43 000 to 99 000, became phosphorylated in a time-dpeendent and hormone-specific manner. The results suggest that cyclic AMP-mediated activation of granulosa cell type II cyclic AMP-dependent protein kinase may be a prerequisite in the short-term molecular action of LH leading to LH-specific phosphorylation of several soluble granulosa cell proteins of an as yet unidentified function.
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PMID:Activation induced by luteinizing hormone of type II protein kinase dependent on cyclic adenosine monophosphate and phosphorylation of soluble proteins in porcine granulosa cells. 624 56

The objective of this work was to identify the natural substrates of cyclic AMP-dependent protein kinase in pituitary cells. Studies were performed using 2 systems: intact pituitary cells stimulated with dibutyryl cyclic AMP (DBC) after preincubation with [gamma-32P]. Phosphorylation of proteins was analyzed by two-dimensional gel electrophoresis, followed by autoradiography. In intact cells, the only clear and reproducible effect of DBC stimulation is increased phosphorylation of 3 proteins (termed A, B, and C), each with a molecular weight of about 20 000 dalton. The time-course and dose-dependence of phosphorylation of A, B and C are generally similar to that for DBC-induced hormone secretion, which is consistent with a role for these proteins in the secretory mechanism. When [gamma-32P]ATP is added to cell extracts, proteins A, B, and C are not measurably phosphorylated, either in the absence or presence of cyclic AMP. This observation suggests that proteins A, B and C may not be directly phosphorylated by cyclic AMP-dependent protein kinase, but may be phosphorylated indirectly by a second kinase. On the other hand, growth hormone and prolactin are readily phosphorylated in cell extracts by cyclic AMP-dependent protein kinase (although they are not phosphorylated in vivo). This finding makes clear the need for caution in interpreting results from broke cell systems.
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PMID:Dibutyryl cyclic AMP-induced phosphorylation of specific proteins in adenohypophysial cells. 626

Benzodiazepines reduce basal and stimulated rat prolactin (PRL) serum levels in vivo. We investigated whether the inhibition of PRL secretion by the benzodiazepine receptor agonist, diazepam, occurs directly at the pituitary. At nanomolar concentrations diazepam did not affect PRL secretion, whereas at micromolar concentrations, diazepam dose-dependently inhibited basal and secretagogue-stimulated PRL release from hemipituitary glands and from primary cultures of rat anterior pituitary cells. The inhibitory effect of the highest concentration of diazepam (100 microM) was abolished when the pituitary tissue was incubated with the benzodiazepine receptor antagonist Ro 15-1788. Although nanomolar concentrations of diazepam alone did not affect PRL release, they did enhance the PRL inhibitory effect of muscimol, a gamma-amino butyric acid (GABA) receptor agonist. Neither diazepam nor muscimol affected cellular adenosine 3',5'-monophosphate (cAMP) content. Since these effects do not appear to occur through an inhibition of the cAMP generating system, diazepam may inhibit PRL release via a cAMP-independent pathway. We suggest that diazepam inhibits PRL secretion either by enhancing the GABAergic inhibition of PRL release, or by inhibiting, at micromolar concentrations, a benzodiazepine-sensitive Ca2+-calmodulin dependent protein kinase.
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PMID:The benzodiazepine agonist diazepam inhibits basal and secretagogue-stimulated prolactin release in vitro. 632 Sep 63

Twenty-nine patients with advanced prostatic adenocarcinoma were evaluated clinically, biochemically and radiologically and randomly assigned either to orchiectomy or to medical treatment. The latter consisted of the chronic administration of an LHRH agonistic analogue by parenteral and/or intranasal routes. Plasma testosterone levels fell to castrate values and remained so for as long as the follow-up lasted (24 months); estrogen levels fell as well. No change in basal cortisol, thyroxine or prolactin levels was noticed. A decrease in prostate size and improvement in prostatism occurred in all. Bone pain and radiology conventionally or by isotopic scanning, did not parallel the improvement seen in the primary disease locus. Similarly, the changes in alkaline phosphatase were minimal when compared to that of prostatic acid phosphatase. Both enzymes increased prior to or concurrently with relapse of the disease. The longest remission and survival was seen in patients with low enzyme levels, non diffuse bone metastases and high degree of tumor differentiation. Chronic use of agonistic analogues of LHRH induces effective castration in men with prostatic carcinoma and can replace orchiectomy or estrogen administration. The quantitative analysis of androgen receptors (AR) in subcellular fractions of tumor cells; the use of techniques to enhance the number of AR in the cytosol; and the determination of the type II/I regulatory subunit of protein kinase may be used to identify hormone independent clones and spare patients of unnecessary procedures.
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PMID:Advanced prostatic adenocarcinoma: biological aspects and effects of androgen deprivation achieved by castration or agonistic analogues of LHRH. 644 76

We have investigated the ability of a constitutively active Gq-alpha mutant, Q209L-alpha q, to regulate target gene expression. Transient expression in GH3 pituitary cells of a rat proximal prolactin promoter-chloramphenicol acetyltransferase construct (-187)PRL-CAT, was stimulated by co-expression of Q209L alpha q, but not by wild-type alpha q. Q209L-alpha q stimulated expression of constructs driven by promoters for either rat prolactin or growth hormone, but not of a control construct driven by the thymidine kinase promoter. Thus, transcriptional effects of alpha q are specific both for the activated state of this G-alpha subunit and the promoter examined. Since both the prolactin and growth hormone promoters are activated by the pituitary cell-specific transcription factor Pit-1, we examined whether a Pit-1 binding site could direct a response to Q209L-alpha q. Two copies of prolactin promoter Pit-1 binding site 1P conferred upon a heterologous metallothionein promoter a response to Q209L-alpha q, implying an involvement of this site in the transcriptional action of Q209L-alpha q on the prolactin promoter. The phorbol ester activator of protein kinase C, 12-O-tetradecanoylphorbol-13-acetate, stimulated (-187)PRL-CAT activity, but opposed the action of Q209L-alpha q on activity of this PRL-CAT construct. Q209L-alpha q stimulation of (-187)PRL-CAT activity was inhibited by co-expression of a dominant negative Raf mutant, Raf-C4, but not by a point mutant of Raf-C4 with reduced inhibitory properties. These results imply that activated alpha q subunits can stimulate prolactin promoter activity via a pathway that involves a Pit-1 DNA binding site(s), is opposed by protein kinase C, and is mediated by a pathway in which Raf-1 kinase plays a role.
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PMID:Constitutively active Gq-alpha stimulates prolactin promoter activity via a pathway involving Raf activity. 748 29

Milk production during lactation is a consequence of the suckling stimulus and the presence of glucocorticoids, prolactin, and insulin. After weaning the glucocorticoid hormone level drops, secretory mammary epithelial cells die by programmed cell death and the gland is prepared for a new pregnancy. We studied the role of steroid hormones and prolactin on the mammary gland structure, milk protein synthesis, and on programmed cell death. Slow-release plastic pellets containing individual hormones were implanted into a single mammary gland at lactation. At the same time the pups were removed and the consequences of the release of hormones were investigated histologically and biochemically. We found a local inhibition of involution in the vicinity of deoxycorticosterone- and progesterone-release pellets while prolactin-release pellets were ineffective. Dexamethasone, a very stable and potent glucocorticoid hormone analogue, inhibited involution and programmed cell death in all the mammary glands. It led to an accumulation of milk in the glands and was accompanied by an induction of protein kinase A, AP-1 DNA binding activity and elevated c-fos, junB, and junD mRNA levels. Several potential target genes of AP-1 such as stromelysin-1, c-jun, and SGP-2 that are induced during normal involution were strongly inhibited in dexamethasone-treated animals. Our results suggest that the cross-talk between steroid hormone receptors and AP-1 previously described in cells in culture leads to an impairment of AP-1 activity and to an inhibition of involution in the mammary gland implying that programmed cell death in the postlactational mammary gland depends on functional AP-1.
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PMID:Glucocorticoid and progesterone inhibit involution and programmed cell death in the mouse mammary gland. 749 Feb 85

Chinese hamster ovary (CHO-K1) cells were stably transfected with prolactin (PRL) receptor cDNA. These cells (CHO-E32) expressed the long form of functional PRL receptor. Using microfluorimetric and patch-clamp techniques, we have investigated the effects of PRL on intracellular Ca2+ concentration ([Ca2+]i) and membrane ion conductances. Exposure of CHO-E32 cells to 5 nM PRL resulted in an increase in [Ca2+]i. Two types of response were observed: 1) a stimulation of Ca2+ entry and 2) an intracellular Ca2+ mobilization. As PRL inhibited voltage-activated Ca2+ current, the PRL-induced Ca2+ increase does not involve voltage-activated Ca2+ channels. PRL also increased a charybdotoxin-sensitive Ca(2+)-dependent K+ conductance. Simultaneous measurements showed that PRL hyperpolarized the membrane potential before increasing intracellular Ca2+ levels. In voltage clamp, hyperpolarizing voltage steps were associated with increased Ca2+ concentrations, whereas depolarizing voltage steps decreased [Ca2+]i. Cell-free patch-clamp experiments showed that PRL directly stimulates K+ channel activity. Our results suggest the existence of a regulatory complex involving a protein kinase tightly associated with the Ca(2+)-activated K+ channels and that PRL stimulates these channels by means of the activation of protein kinase. The resulting hyperpolarization stimulates Ca2+ entry, probably through voltage-insensitive nonspecific channels.
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PMID:Early effects of PRL on ion conductances in CHO cells expressing PRL receptor. 752 Nov 30


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