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)

It is well known that GH-PRL secreting GH3 cells express constitutive neuronal nitric oxide synthase (nNOS) and produce nitric oxide (NO*). In addition, these cells possess plasma membrane prolactin (PRL) receptors which can be responsible for an autocrine 'short-loop' feedback. The aim of the present study was to investigate whether the activation of PRL receptors modulates the expression of the different spliced forms of nNOS gene, and the transductional mechanisms involved in this action. In GH3 cells, both exon 2-containing nNOSalpha and exon 2-lacking nNOSbeta were time-dependently expressed, whereas the other two isoforms eNOS and iNOS were not. The antibodies directed against the residues 53-68 of the external domain common to both the long and short form of rat PRL receptors, and the selective D2 agonist cabergoline (1 nm) reduced both basal and exogenous PRL-induced expressions of nNOSalpha and nNOSbeta, but to a greater extent for the beta splicing form. In line with these results, oPRL (1 and 10 microm) added to the incubation medium increased to a greater extent the expression of nNOSbeta form than of the nNOSalpha. The receptor and non-receptor protein tyrosine kinase (PTK) inhibitors, genistein (10 microm), the Src-specific tyrosine kinase inhibitor PP2 (100 microm), the MAPK inhibitor PD 098059 (50 nm) and the two PI3'-K inhibitors, wortmannin (300 nm) and LY-294002 (25 microm) prevented both basal and exogenous PRL-induced expression of nNOSalpha and nNOSbeta isoforms. In addition, exogenous PRL induced a phosphorylation of protein kinase B (PKB) (Akt) that was prevented both by the two MAPK inhibitors PD 098059 and U 0126, and by the PI3'-K inhibitors wortmannin and LY-294002. Up-regulation of the expression of the two splicing forms of nNOS elicited by PRL-receptor activation was mirrored by the increased synthesis of NO*. In conclusion, PRL receptor activation up-regulated the expression of both nNOSalpha and nNOSbeta proteins via a PTK, PI3'-K, MAPK and PKB signalling transduction components. This action may represent the molecular mechanism by which PRL exerts the 'short-loop' feedback on its own secretion.
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PMID:Involvement of PI3'-K, mitogen-activated protein kinase and protein kinase B in the up-regulation of the expression of nNOSalpha and nNOSbeta splicing variants induced by PRL-receptor activation in GH3 cells. 1261 37

Previous findings from our laboratory have shown that pituitary calcitonin-like peptide (pit-CT) is synthesized and released by gonadotrophs and inhibits prolactin (PRL) release, synthesis, and lactotroph proliferation. To investigate further the regulation of PRL gene transcription by CT, we examined the effect of CT on rat PRL (rPRL) promoter activity in rat pituitary GGH3 cells. GGH3 cells were transiently transfected with rPRL promoter- luciferase and control plasmids. Thirty-six hours later, the cells were treated with CT or other agents and their effect on luciferase activity was examined. The effect of CT and/or thyrotropin-releasing hormone (TRH) on p42/44 mitogen-activated protein kinase (MAPK) activity was also investigated. CT inhibited basal rPRL promoter activity in a dose-dependent fashion, with an approximate IC(50) of 3 nM. The maximal inhibition occurred 1 h after the CT addition, and the peptide was equipotent in inhibiting 600 and 2500 rPRL promoter constructs. CT also inhibited TRH-, Bay K 8644-, and ionomycin-induced rPRL promoter activity. CT mimicked the actions of MEK inhibitors U0126 and PD 980089. However, CT could not inhibit rPRL promoter activity in GGH3 cells expressing constitutively active ERK1 or ERK2. CT markedly attenuated phospho-MAPK immunoreactivity in untreated as well as TRH-treated GGH3 cells. These results suggest that CT inhibits rPRL promoter activity by antagonizing Ca(2+) and ERK1/2-mediated signaling events. They also demonstrate that CT is a potent inhibitor of early events associated with PRL gene activation and may play an important role in regulation of lactotroph function.
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PMID:Calcitonin inhibits prolactin promoter activity in rat pituitary GGH3 cells: evidence for involvement of p42/44 mitogen-activated protein kinase in calcitonin action. 1266 64

Nitric oxide (NO) enhances prolactin-stimulated DNA synthesis and inhibits prolactin-induced differentiation in mouse mammary epithelium. The molecular pathways used by NO were determined by employing specific inhibitors of the transducers utilized by NO. Inhibitors of the Jun N-terminal kinase (JNK) blocked the effect of NO on DNA synthesis, although this appeared to involve a protein kinase G (PKG)-independent pathway. In contrast, inhibitors of the extracellular signal-regulated kinase (ERK) prevented NO from suppressing alpha-lactalbumin accumulation and this effect was PKG-dependent. NO can also elevate cAMP through the inhibition of phosphodiesterase 3 and cAMP mimicks the actions of NO on both DNA synthesis and differentiation. However, suppression of cAMP levels did not prevent the effects of NO. Therefore, NO uses two separate pathways to affect mammary epithelium: it stimulates growth via JNK and inhibits differentiation through ERK.
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PMID:The mechanisms by which nitric oxide affects mammary epithelial growth and differentiation. 1271 33

The decidualized endometrium plays a role in regulating trophoblast invasion for successful implantation and maintenance of pregnancy. IL-1 beta, a proinflammatory cytokine, has been suggested to play a role in this process. Recently, several lines of evidence indicate the importance of p38 MAPK in various inflammatory responses. We investigated whether endometrial stromal cells (ESC) change their inflammatory responses to IL-1 beta as related to p38 MAPK phosphorylation during the process of decidualization. ESC were decidualized by the treatment with progesterone for 9 d, as determined as such by an increase in the production of prolactin and cAMP by the cells. Whereas IL-1 beta increased the production of IL-6, IL-8, and monocyte chemotactic protein-1, and expression of cyclooxygenase-2 mRNA in ESC cultured without treatment, the stimulatory effects of IL-1 beta were reduced in the decidualized cells. Treatment with SB202190, a p38 MAPK inhibitor, also reduced the stimulatory effects of IL-1 beta in nondecidualized ESC. P38 MAPK phosphorylation was increased by IL-1 beta in nondecidualized ESC, whereas the IL-1 beta-induced increase was suppressed in the decidualized cells. Treatment with 8-bromo-cAMP reduced IL-1 beta-induced phosphorylation of p38 MAPK in nondecidualized ESC. In contrast, treatment with H89, a protein kinase A inhibitor, reversed a reduction in IL-1 beta-induced p38 MAPK phosphorylation in the decidualized cells. In summary, decidualization seems to be a process during which endometrial cells diminish their response to IL-1 beta, a known key factor for implantation, leading to the down-regulation of inflammation-like events, which may be relevant to controlled trophoblast invasion. The altered property of decidualized cells is thought to be caused by attenuation of IL-1 beta-induced p38 MAPK phosphorylation in a way that involves the activation of the cAMP/protein kinase A pathway.
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PMID:Endometrial stromal cells undergoing decidualization down-regulate their properties to produce proinflammatory cytokines in response to interleukin-1 beta via reduced p38 mitogen-activated protein kinase phosphorylation. 1272 80

In previous studies we demonstrated that insulin-like growth factor I (IGF-I) induces pituitary vasoactive intestinal peptide (VIP) gene expression and secretion, and that IGF-I-induced prolactin (PRL) release is mediated by VIP. In this study, we investigate the mitotropic action of IGF-I and VIP on pituitary lactotropes, and their possible interplay in this effect. Cultured male rat pituitary cells were treated with rhIGF-I (10(-7)M) and/or VIP (10(-7)M) for 48 h. 5-Bromo-2'-deoxyuridine (BrdU) (10 microM) was added for labeling proliferation of pituitary cells. BrdU-labeling indices indicative of the proliferation rate of lactotropes were determined by double-labeling immunofluorescence staining for PRL and BrdU. Treatment with either IGF-I or VIP increased BrdU-labeling indices of lactotropes, but there was no further increase upon combined incubation with both factors, suggesting an interaction between the signal transduction pathways of IGF-I and VIP. VIP antiserum partially suppressed IGF-I-induced BrdU-labeling indices of lactotropes. We also investigated the intracellular signal transduction pathways in the action of IGF-I and VIP on the proliferation of lactotropes. Treatment of pituitary cells with an inhibitor of the mitogen-activated protein kinase (MAPK) pathway completely abolished IGF-I-induced lactotrope proliferation, whereas it partially suppressed VIP-induced BrdU-labeling indices. The protein kinase A (PKA) inhibitor, which abolished the mitogenic action of VIP, markedly suppressed IGF-I-induced lactotrope proliferation. These results indicate that both IGF-I and VIP stimulate lactotrope proliferation, and that IGF-I-induced lactotrope proliferation is partially mediated by VIP produced locally. Also, this study suggests that interactions between MAPK and cyclic adenosine 3',5'-monophosphate-PKA signaling pathways are implicated in the lactotrope proliferation induced by IGF-I and VIP.
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PMID:Involvement of vasoactive intestinal peptide on insulin-like growth factor I-induced proliferation of rat pituitary lactotropes in primary culture: evidence for an autocrine and/or paracrine regulatory system. 1280 80

Previous work has shown that naturally phosphorylated prolactin antagonizes the growth-promoting activities of unmodified prolactin (U-PRL) and that this effect is duplicated by a molecular mimic, S179D PRL. At the same time, the S179D PRL is a superagonist with regard to expression of some PRL-regulated genes. We have asked whether the different activities of U-PRL and S179D PRL are the result of differential signaling. HC11 cells (a normal mouse mammary cell line) were grown to confluence, primed with hydrocortisone, and then exposed to the PRLs. A 15 min incubation of PRL-naive cells led to substantial tyrosine phosphorylation of Jak 2 and Stat 5a by U-PRL and an essentially equivalent Jak 2 activation by S179D PRL. The latter, however, was accompanied by reduced tyrosine phosphorylation of Stat 5a. EMSA analysis using a Stat 5 binding site showed both PRLs to cause equivalent binding of nuclear proteins and that most of what bound was complexed through Stat 5a. Phosphoamino acid analysis of Stat 5 showed S179D PRL to double the amount of serine phosphorylation versus that seen with U-PRL. Analysis of the MAP kinase pathway showed U-PRL capable of activation of ERKs 1 and 2 but that signaling via ERKs 1 and 2 was greater with S179D PRL. A 7-day incubation in either PRL increased beta-casein mRNA levels, but S179D PRL caused a 2-fold increase over that seen with U-PRL. The increase, over that seen with U-PRL, was blocked by the MAP kinase inhibitor, PD98059. After 7 days of treatment with S179D PRL, expression of the short PRL receptor was doubled, and signaling showed a greater dependence on the MAP kinase pathway (2.9-fold increase in ERK 1 and 2 activation). We conclude that although both PRLs use both pathways to some extent, U-PRL signals primarily through Jak 2-Stat 5 whereas S179D PRL signals primarily through the MAP kinase pathway especially after prolonged exposure. This is the first demonstration of differential involvement of signaling pathways by different forms of PRL.
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PMID:Different biological effects of unmodified prolactin and a molecular mimic of phosphorylated prolactin involve different signaling pathways. 1280 12

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

Pit-1 and Ets-1 binding to a composite element synergistically activates and targets Ras-mitogen-activated protein kinase signaling to the rat prolactin promoter. These transcriptional responses appear to depend on three molecular features: organization of the Ets-1/Pit-1 composite element, physical interaction of these two factors via the Pit-1 homeodomain (amino acids 199-291) and the Ets-1 regulatory III domain (amino acids 190-257), and assembly of their transcriptional activation domains (TADs). Here we show that the organization of the Ets-1/Pit-1 composite element tolerates significant flexibility with regard to Ras stimulation and synergy. Specifically, the putative monomeric Pit-1 binding site can be substituted with bona fide binding sites for either a Pit-1 monomer or dimer, and these sites tolerated a separation of 28 bp. Additionally, we show that the physical interaction of Ets-1 and Pit-1 is not required for Ras responsiveness or synergy because block mutations of the Pit-1 interaction surface in Ets-1, which reduced Ets-1/Pit-1 binding in vitro, did not significantly affect Ets-1 stimulation of Ras responsiveness or synergy. We also show differential use of distinct TAD subtypes and Pit-1 TAD subregions to mediate either synergy or Ras responsiveness. Specifically, TADs from Gal4, VP16, or Ets-2 regulatory III domain linked to Ets-1 DNA binding domain constructs restored synergy to these TAD/Ets-1 DNA binding domain fusions. Conversely, deletion of the defined Pit-1 TAD (amino acids 2-80) retained synergy, but not Ras responsiveness. Consequently, we further defined the Pit-1 amino-terminal TAD into region 1 (R1, amino acids 2-45) and region 2 (R2, amino acids 46-80). R1 appears to regulate basal and synergistic responses, whereas the Ras response was mapped to R2. In summary, Ras responsiveness and Pit-1/Ets-1 synergy are mediated through the assembly of distinct TADs at a flexible composite element, indicating that different mechanisms underlie these two transcriptional responses and that the Pit-1 R2 subregion represents a novel, tissue-specific Ras-responsive TAD.
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PMID:Ras signaling and transcriptional synergy at a flexible Ets-1/Pit-1 composite DNA element is defined by the assembly of selective activation domains. 1290 43

In pituitary cells, transcriptional regulation of the prolactin (PRL) gene and prolactin secretion are controlled by multiple transduction pathways through the activation of G protein coupled receptors and receptor tyrosine kinases. In the somatolactotrope GH4C1 cell line, we have previously identified crosstalk between the MAPKinase cascade ERK1/2 and the cAMP/protein kinase A pathway after the activation of the VPAC2 receptor by vasoactive intestinal polypeptide (VIP) or pituitary adenylyl cyclase-activating polypeptide (PACAP38). In the present study, we focus on the involvement of the GTPases Ras and Rap1 as downstream components of signal transmission initiated by activation of the VPAC2 receptor. By using pull-down experiments, we show that VIP and PACAP38 preferentially activate Rap1, whereas thyrotropin releasing hormone (TRH) and epidermal growth factor (EGF) mainly activate Ras GTPase. Experiments involving the expression of the dominant-negative mutants of Ras and Rap1 signaling (RasN17 or Rap1N17) indicate that both GTPases Ras and Rap1 are recruited for the ERK activation by VIP and PACAP38, whereas Rap1 is poorly involved in TRH or EGF-induced ERK activation. The use of U0126, a selective inhibitor of MAPKinase kinase, provides evidence that MAPKinase contributes to the regulation of the PRL gene. Moreover, cotransfection of RasN17 or Rap1N17 with the PRL proximal promoter luciferase reporter construct indicates that Rap1 may be responsible for VIP/PACAP-induced activation of the PRL promoter. Interestingly, Ras would be involved as a negative regulator of VIP/PACAP-induced PRL gene activation, in contrast to its stimulatory role in the regulation of the PRL promoter by TRH and EGF.
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PMID:Differential involvement of the Ras and Rap1 small GTPases in vasoactive intestinal and pituitary adenylyl cyclase activating polypeptides control of the prolactin gene. 1455 Dec

Mammary gland development involves complex cycles of proliferation, differentiation, and morphogenesis, regulated by hormones including estrogens, prolactin (PRL), and epidermal growth factor (EGF). The mouse mammary epithelial cell line HC11 has been shown to be valuable for investigations of differentiation of mammary gland. In this study, we show that HC11 cells express estrogen receptor (ER)alpha and ER beta proteins at all developmental stages. We have established two different stable HC11 cell lines; H-estrogen response element (ERE) containing an ERE-reporter and H-Bc containing a beta-casein reporter. Transcription of the ERE-reporter was activated only in proliferating cells in the presence of EGF. When the cells entered the differentiation program, in the absence of EGF, estradiol-induced transcription of the ERE reporter was repressed, and similar results were obtained when MAPK signaling was inhibited in proliferating cells. We propose that these findings are related to changes in ER corepressor levels, regulated by EGF. We also report that the beta-casein reporter was activated in terminally differentiated cells and that this induction was effectively repressed by estradiol treatment. Finally, we show a physical interaction between endogenous ER alpha and signal transducer and activator of transcription 5 in differentiated HC11 cells. In summary, our results show that ER functional activity changes during differentiation of HC11 cells.
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PMID:Estrogen receptor functional activity changes during differentiation of mammary epithelial cells. 1460 98


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