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:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Regulation of the mitogen-activated protein (MAP) kinase by thyrotropin-releasing hormone (TRH) in GH3 rat pituitary tumor cells was investigated. Both TRH and epidermal growth factor (EGF) acutely activated this enzyme, via tyrosine and serine/threonine phosphorylation. Down-regulation of cellular protein kinase C (PKC) only partly inhibited the phosphorylation of MAP kinase by TRH, suggesting both PKC-dependent and -independent pathways. Both TRH and EGF similarly increased the phosphorylation of raf-1, by a PKC-independent mechanism. Both TRH and EGF stimulated the formation of a ras-GTP complex. This activation of ras by growth factors is thought to involve the tyrosine phosphorylation of Shc. EGF stimulated the tyrosine phosphorylation of three Shc proteins and their subsequent association with its receptor. TRH stimulated the tyrosine phosphorylation of the 52-kDa Shc protein, although neither phorbol esters nor the calcium ionophore A23187 had any effect, indicating that this effect of TRH was not dependent on PKC. Both TRH and EGF induced the association of tyrosine phosphorylated Shc proteins with a fusion protein containing SH2 and SH3 domains of Grb2, another important component in ras activation. These results provide evidence that MAP kinase is acutely activated by TRH through a PKC-dependent pathway as well as a second pathway possibly involving tyrosine phosphorylation.
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PMID:Thyrotropin-releasing hormone stimulates MAP kinase activity in GH3 cells by divergent pathways. Evidence of a role for early tyrosine phosphorylation. 750 19

We recently reported the existence of two separate pathways for thyrotropin-releasing hormone (TRH)-induced mitogen-activated protein (MAP) kinase activation in GH3 pituitary tumor cells. To test the role of MAP kinase in TRH action, we examined the effect of dopamine (DA) on TRH-induced MAP kinase in primary cultures of rat anterior pituitary cells. 1 microM of DA attenuated 1 microM TRH-induced MAP kinase activity and phosphorylation. 100 ng/ml of islet-activating protein (IAP) blocked these inhibitory effects of DA. These results suggest that crosstalk exists between the DA signaling pathway and the TRH-stimulated MAP kinase activating pathway in rat anterior pituitary cells.
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PMID:Dopamine inhibits TRH-induced MAP kinase activation in dispersed rat anterior pituitary cells. 800 97

Corticotropin-releasing hormone (CRH) plays an important role in regulating the development and function of hypothalamic-pituitary-adrenal axis. The mechanisms by which CRH regulates tissue-specific growth, differentiation and gene expression remain to be established. In the present study, we show that CRH differentially regulates MAP kinase activity in normal ovine anterior pituitary cells and mouse corticotrope AtT20 cells. Incubation of ovine normal anterior pituitary cells with CRH increased MAP kinase activity, an effect mimicked by cAMP and inhibited by the protein kinase A inhibitor H89. In contrast, incubation of mouse pituitary tumor AtT20 cells with CRH inhibited MAP kinase activity, an effect also mimicked by forskolin and inhibited by H89. This decrease in MAP kinase activity occurred with a time course similar to the increase seen in normal anterior pituitary cells. Furthermore, both effects of CRH on MAP kinase activity were inhibited by atrial natriuretic peptide (ANP). ANP also reversed the inhibition of DNA synthesis induced by CRH in AtT20 cells. Thus, CRH may differentially regulate cell growth in sheep normal anterior pituitary and mouse tumor corticotropes by modulating MAP kinase activity through a mechanism dependent on cAMP production and subject to regulation by ANP.
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PMID:Differential regulation of MAP kinase activity by corticotropin-releasing hormone in normal and neoplastic corticotropes. 992 8

Regulation of the mitogen-activated protein kinase (MAPK) family by prolactin-releasing peptide (PrRP) in both GH3 rat pituitary tumor cells and primary cultures of rat anterior pituitary cells was investigated. PrRP rapidly and transiently activated extracellular signal-regulated protein kinase (ERK) in both types of cells. Both pertussis toxin, which inactivates G(i)/G(o) proteins, and exogenous expression of a peptide derived from the carboxyl terminus of the beta-adrenergic receptor kinase I, which specifically blocks signaling mediated by the betagamma subunits of G proteins, completely blocked the PrRP-induced ERK activation, suggesting the involvement of G(i)/G(o) proteins in the PrRP-induced ERK activation. Down-regulation of cellular protein kinase C did not significantly inhibit the PrRP-induced ERK activation, suggesting that a protein kinase C-independent pathway is mainly involved. PrRP-induced ERK activation was not dependent on either extracellular Ca(2+) or intracellular Ca(2+). However, the ERK cascade was not the only route by which PrRP communicated with the nucleus. JNK was also shown to be significantly activated in response to PrRP. JNK activation in response to PrRP was slower than ERK activation. Moreover, to determine whether a MAPK family cascade regulates rat prolactin (rPRL) promoter activity, we transfected the intact rPRL promoter ligated to the firefly luciferase reporter gene into GH3 cells. PrRP activated the rPRL promoter activity in a time-dependent manner. Co-transfection with a catalytically inactive form of a MAPK construct or a dominant negative JNK, partially but significantly inhibited the induction of the rPRL promoter by PrRP. Furthermore, co-transfection with a dominant negative Ets completely abolished the response of the rPRL promoter to PrRP. These results suggest that PrRP differentially activates ERK and JNK, and both cascades are necessary to elicit rPRL promoter activity in an Ets-dependent mechanism.
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PMID:Prolactin-releasing peptide activation of the prolactin promoter is differentially mediated by extracellular signal-regulated protein kinase and c-Jun N-terminal protein kinase. 1065 64

Pituitary tumor-transforming gene (PTTG) is a recently characterized oncogene that can act as a transcriptional activator. In this study, we have characterized the transactivation domain of PTTG. Transient transfection of fusion constructs containing GAL4 DNA-binding domain and different parts of PTTG indicated the transactivation domain of PTTG is located between amino acids 119 and 164. Mitogen-activated protein (MAP) kinase cascade is important in the regulation of cell growth, apoptosis, and differentiation. Therefore, we have explored the possibility that this kinase cascade plays a role in regulating PTTG transactivation function. Activation of the MAP kinase cascade by epidermal growth factor or an expression vector for a constitutively active form of the MAP kinase kinase (MEK1) led to stimulation of PTTG transactivation activity. We showed that PTTG is phosphorylated in vitro on Ser(162) by MAP kinase and that this phosphorylation site plays an essential role in PTTG transactivation function. We demonstrated that PTTG interacts directly with MEK1 through a putative SH3 domain-binding site located between amino acids 51 and 54 and that this interaction is crucial for PTTG transactivation function. In addition, we showed that activation of MAP kinase phosphorylation cascade resulted in nuclear translocation of PTTG. Together, our data establish that a growth factor-stimulated MAP kinase plays an important role in modulating PTTG function.
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PMID:Activation of mitogen-activated protein kinase cascade regulates pituitary tumor-transforming gene transactivation function. 1090 23

Introduction of somatostatin analogs has greatly contributed to improving the prognosis of acromegaly. Although the majority of patients are effectively treated by these agents, resistance occurs in a subset of patients. So far, resistance to somatostatin has never been associated with mutations of the somatostatin receptor subtypes (sst2 and sst5) that inhibit GH secretion. Molecular analysis of genomic DNA from pituitary tumor and peripheral blood obtained from an acromegalic resistant to octreotide showed a somatic activating mutation of Gsalpha (Arg201Cys), no mutation in sst2, and one polymorphism (Pro109Ser) and one germ line mutation (Arg240Trp) in sst5. Wild-type (WT) and mutant sst5 PCR products were cloned and transfected into Chinese hamster ovary K1 cells. In Chinese hamster ovary K1 cells stably expressing mutant sst5, somatostatin-28 was less potent in inhibiting cyclic AMP levels than in WT cells. Proliferation of mutant cells exceeded that of WT by 50%. Moreover, somatostatin reduced cell growth and MAPK activity in WT but not in mutant cells in which the peptide even increased MAPK activity. We suggest that this mutation that abrogates the antiproliferative action of somatostatin and activates mitogenic pathways may be involved in the resistance to somatostatin treatment.
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PMID:Mutation of somatostatin receptor type 5 in an acromegalic patient resistant to somatostatin analog treatment. 1150 16

Fibroblast growth factors play a critical role in cell growth, development, and differentiation and are also implicated in the formation and progression of tumors in a variety of tissues including pituitary. We have previously shown that fibroblast growth factor activation of the rat PRL promoter in GH4T2 pituitary tumor cells is mediated via MAP kinase in a Ras/Raf-1-independent manner. Herein we show using biochemical, molecular, and pharmacological approaches that PKCdelta is a critical component of the fibroblast growth factor signaling pathway. PKC inhibitors, or down-regulation of PKC, rendered the rat PRL promoter refractory to subsequent stimulation by fibroblast growth factors, implying a role for PKC in fibroblast growth factor signal transduction. FGFs caused specific translocation of PKCdelta from cytosolic to membrane fractions, consistent with enzyme activation. In contrast, other PKCs expressed in GH4T2 cells (alpha, betaI, betaII, and epsilon) did not translocate in response to fibroblast growth factors. The PKCdelta subtype-selective inhibitor, rottlerin, or expression of a dominant negative PKCdelta adenoviral construct also blocked fibroblast growth factor induction of rat PRL promoter activity, confirming a role for the novel PKCdelta isoform. PKC inhibitors selective for the conventional alpha and beta isoforms or dominant negative PKCalpha adenoviral expression constructs had no effect. Induction of the endogenous PRL gene was also blocked by adenoviral dominant negative PKCdelta expression but not by an analogous dominant negative PKCalpha construct. Finally, rottlerin significantly attenuated FGF-induced MAP kinase phosphorylation. Together, these results indicate that MAP kinase-dependent fibroblast growth factor stimulation of the rat PRL promoter in pituitary cells is mediated by PKCdelta.
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PMID:Fibroblast growth factor activation of the rat PRL promoter is mediated by PKCdelta. 1151

17alpha-E(2), a weak estrogen exhibited both agonistic and antagonistic effects, and caused a time- and dose-dependent induction of VEGF-A mRNA expression in GH3 rat pituitary tumor cells. This effect was unaffected by the presence of the pure estrogen receptor antagonist ICI 182,780 but was specifically blocked by a protein synthesis inhibitor puromycin. Inhibition of phosphatidylinositol-3 kinase (PI3K) activity by wortmannin decreased the effect of 17alpha-E(2) on VEGF-A mRNA expression. This inhibitor also blocked the increase in phosphorylation of Akt induced by exposure to 17alpha-E(2). In contrast, exposure to the MAP kinase inhibitor, U0126, had no impact on 17alpha-E(2)-induced VEGF-A mRNA expression. Taken together, these studies indicate that like potent estrogens 17alpha-E(2) up-regulates VEGF-A mRNA expression in estrogen responsive GH3 rat pituitary tumor cells, but this induction is not mediated through a classical estrogen receptor pathway. PI3K-Akt signaling pathway is required for the induction of VEGF-A mRNA in GH3 cells by 17alpha-E(2).
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PMID:17alpha-estradiol-induced VEGF-A expression in rat pituitary tumor cells is mediated through ER independent but PI3K-Akt dependent signaling pathway. 1248 May 45

Carney complex (CNC) is caused by PRKAR1A-inactivating mutations. PRKAR1A encodes the regulatory subunit type I-alpha (RIalpha) of the cAMP-dependent kinase (PKA) holoenzyme; how RIalpha insufficiency leads to tumorigenesis remains unclear. In many cells PKA inhibits the extracellular receptor kinase (ERK1/2) cascade of the mitogen-activated protein kinase (MAPK) pathway leading to inhibition of cell proliferation. We investigated whether the PKA-mediated inhibitory effect on ERK1/2 is affected in CNC cells that carry germline PRKAR1A mutations. PKA activity both at baseline and after stimulation with cAMP was augmented in cells carrying mutations. Quantitative message analysis showed that the main PKA subunits expressed were type I (RIalpha and RIbeta) but RIalpha was decreased in mutant cells. Immunoblot assays of ERK1/2 phosphorylation by the cell- and pathway-specific stimulant lysophosphatidic acid (LPA) showed activation of this pathway in a time- and concentration-dependent manner that was prevented by a specific inhibitor. There was a greater rate of growth in mutant cells; forskolin and isoproterenol inhibited LPA-induced ERK1/2 phosphorylation in normal but not in mutant cells. Forskolin inhibited LPA-induced cell proliferation and metabolism in normal cells, but stimulated these parameters in mutant cells. These data were also replicated in a pituitary tumor cell line carrying the most common PRKAR1A mutation (c.578del TG), and an in vitro construct of mutant PRKAR1A that was recently shown to lead to augmented PKA-mediated phosphorylation. We conclude that PKA activity in CNC cells is increased and that its stimulation by forskolin or isoproterenol increases LPA-induced ERK1/2 phosphorylation, cell metabolism and proliferation. Reversal of PKA-mediated inhibition of this MAPK pathway in CNC cells may contribute to tumorigenesis in this condition.
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PMID:Protein kinase-A activity in PRKAR1A-mutant cells, and regulation of mitogen-activated protein kinases ERK1/2. 1281 76

Fibroblast growth factors (FGFs) play a critical role in pituitary development and in pituitary tumor formation and progression. We have previously characterized FGF signal transduction and regulation of the tissue-specific rat prolactin (rPRL) promoter in GH4 pituitary cells. FGF induction of rPRL transcription is independent of Ras, but mediated by a protein kinase C-delta (PKCdelta)-dependent activation of MAPK (ERK). Here we demonstrate a functional role for the Rho family monomeric G protein, Rac1, in FGF regulation of PRL gene expression via an atypical signaling pathway. Expression of dominant negative Rac, but not RhoA or Cdc42, selectively inhibited FGF-induced rPRL promoter activity. Moreover, expression of dominant negative Rac also attenuated FGF-2 and FGF-4 stimulation of MAPK (ERK). However, in contrast to other Rac-dependent signaling pathways, FGF activation of rPRL promoter activity was independent of the c-Jun N-terminal kinase (JNK) and phosphoinositide 3-kinase/Akt cascades. FGFs failed to activate JNK1 or JNK2, and expression of dominant negative JNK or Akt constructs did not block FGF-induced PRL transcription. Consistent with the role of PKCdelta in FGF regulation of PRL gene expression, activation of the rPRL promoter was blocked by an inhibitor of phospholipase Cgamma (PLCgamma) activity. FGF treatment also induced rapid tyrosine phosphorylation of PLCgamma in a Rac-dependent manner. These results suggest that FGF-2 and FGF-4 activate PRL gene expression via a novel Rac1, PLCgamma, PKCdelta, and ERK cascade, independent of phosphoinositol-3-kinase and JNK.
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PMID:Fibroblast growth factors regulate prolactin transcription via an atypical Rac-dependent signaling pathway. 1284 10


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