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)

Cultured neonatal rat cardiac myocytes have been used extensively to study cellular and molecular mechanisms of cardiac hypertrophy. However, there are only a few studies in cultured mouse myocytes despite the increasing use of genetically engineered mouse models of cardiac hypertrophy. Therefore, we characterized hypertrophic responses in low-density, serum-free cultures of neonatal mouse cardiac myocytes and compared them with rat myocytes. In mouse myocyte cultures, triiodothyronine (T3), norepinephrine (NE) through a beta-adrenergic receptor, and leukemia inhibitory factor induced hypertrophy by a 20% to 30% increase in [(3)H]phenylalanine-labeled protein content. T3 and NE also increased alpha-myosin heavy chain (MyHC) mRNA and reduced beta-MyHC. In contrast, hypertrophic stimuli in rat myocytes, including alpha(1)-adrenergic agonists, endothelin-1, prostaglandin F(2alpha), interleukin 1beta, and phorbol 12-myristate 13-acetate (PMA), had no effect on mouse myocyte protein content. In further contrast with the rat, none of these agents increased atrial natriuretic factor or beta-MyHC mRNAs. Acute PMA signaling was intact by extracellular signal-regulated kinase (ERK1/2) and immediate-early gene (fos/jun) activation. Remarkably, mouse but not rat myocytes had hypertrophy in the absence of added growth factors, with increases in cell area, protein content, and the mRNAs for atrial natriuretic factor and beta-MyHC. We conclude that mouse myocytes have a unique autonomous hypertrophy. On this background, T3, NE, and leukemia inhibitory factor activate hypertrophy with different mRNA phenotypes, but certain Gq- and protein kinase C-coupled agonists do not.
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PMID:Autonomous and growth factor-induced hypertrophy in cultured neonatal mouse cardiac myocytes. Comparison with rat. 1105 82

The signaling pathways regulating blood vessel growth and development are not well understood. In the present report, an in vitro model was used to identify signaling pathways regulating capillary formation in embryonic endothelial cells. Basic fibroblast growth factor (bFGF) plus leukemia inhibitory factor (LIF) optimally stimulate the formation of capillary-like structures of the embryonic endothelial cell line IEM. LIF stimulation of IEM cells leads to activation of the Stat3 as well as the (P41/43)mitogen-activated protein kinase ((P41/43)MAPK) cascade, while bFGF does not activate Stat3 but does induce the (P41/43)MAPK cascade. Inhibition of Stat3 DNA-binding activity by expression of a dominant inhibitory Stat3 mutant increases the capillary outgrowth of the IEM cells induced by LIF. Increased Stat3 activity by overexpression of the wild-type Stat3 greatly reduced capillary outgrowth. In contrast, inhibition of the (P41/43)MAPK cascade using a MEK-1 inhibitor dramatically inhibits the LIF-induced capillary outgrowth. Moreover, the increased formation of capillary-like structures of the IEM cells mediated by Stat3 inhibition does not overcome the requirement for activation of the (P41/43)MAPK pathway for capillary outgrowth. Stat3 activity correlates with the LIF-induced expression of the negative feedback regulators of the Janus (JAK) family of tyrosine kinases, SOCS-1 and SOCS-3. These results provide evidence that Stat3 acts as a negative regulator of capillary outgrowth, possibly by increasing SOCS-1 or SOCS-3 expression. The contradictory signals stimulated by LIF could be necessary to control the intensity of the response leading to capillary outgrowth in vivo.
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PMID:LIF transduces contradictory signals on capillary outgrowth through induction of stat3 and (P41/43)MAP kinase. 1106 77

The chimeric receptors were prepared by exchanging the cytoplasmic region between leukemia inhibitory factor (LIF) receptor alpha subunit (gp190) and the other subunit-gp130 (190/130,130/190) and separately transduced into leukemia line HL-60 (to have the wild type subunit). The purpose is to investigate which subunit for activating MAPK p42/44 in leukemia cell while the cytoplasmic region homodimerization (190cyt-190cyt, 130cyt-130cyt) was induced by LIF. The results showed that MAPK p42/44 expression level after LIF stimulation 5 h was lower in the transformants with pED 130/190 (190cyt- 190cyt) (p < 0.01) and higher in the transformants with pED 190/130 (130cyt- 130cyt) (p < 0.05) than those in the parent cells. Meanwhile, MAPK p42/44 phosphorylation (Thr202/Tyr204) was ascended and the highest at 10 min in the 190/130 and descended in the 130/190. It suggests that gp130 activate MAPK p42/44 and gp190 indirectly regulate its expression and function. In order to analyses the relation of the subunit oligomerization and MAPK p42/44 we also prepared the recombination of the extracellular and transmembrane region of Fas and the cytoplasmic region of each LIFR subunit (Fas/190, Fas/130). After transduction into HL-60 with lipofection and induction by anti-Fas IgG, we found that MAPK p42/44 expression levels were lower in the Fas/190 than in the Fas/130 and parent cells (p < 0.01) and no difference between the Fas/130 and the wild type receptor. However, phospho-MAPK p42/44 were increased in the Fas/130 than the parent cells. It suggests that the oligomerization of the cytoplasmic regions of gp130 be potential to normally initiate MAPK p42/44 for the signal of HL-60 proliferation. We also determine that the separated oligomerization FasDD (no dimerization) can initiate the corresponding signal molecules, then regulate MAPK p42/44 expression and phosphorylation in leukemia cells.
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PMID:Involving of the cytoplasmic region of leukemia inhibitory factor receptor alpha subunit, IL-6 related signal transducer-gp130 or fas death domain for MAPK p42/44 activation in HL-60 cell with LIF or anti-Fas IgG. 1126 54

Mouse embryonic stem (ES) cells remain "pluripotent" in vitro in the continuous presence of leukemia inhibitory factor (LIF). In the absence of LIF, ES cells are irreversibly committed to differentiate into various lineages. In this study we have set up an in vitro assay based on the anti-apoptotic activity of LIF to distinguish pluripotent from "differentiation-committed" ES cells. We have examined the phosphorylation profiles of known (STAT3 and ERKs) and identified new (ribosomal S6 kinases (RSKs) and cAMP-responsive element-binding protein (CREB)) LIF-regulated targets in ES and in ES-derived neuronal cells. We have demonstrated that although STAT3, a crucial player in the maintenance of ES cell pluripotency, is induced by LIF in all cell types tested, the LIF-dependent activation of RSKs is restricted to ES cells. We have shown that LIF-induced phosphorylation of RSKs in ES cells is dependent on ERKs, whereas STAT3 phosphorylation is not mediated by any known MAPK activities. Our results also demonstrate that the LIF-dependent phosphorylation of CREB is partially under the control of the RSK2 kinase.
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PMID:The ribosomal S6 kinases, cAMP-responsive element-binding, and STAT3 proteins are regulated by different leukemia inhibitory factor signaling pathways in mouse embryonic stem cells. 1158 Dec 63

The gp130 cytokine receptor activates a cardiomyocyte survival pathway during the transition to heart failure following the biomechanical stress of pressure overload. Although gp130 activation is observed transiently during transverse aortic constriction (TAC), its mechanism of inactivation is largely unknown in cardiomyocytes. We show here that suppressor of cytokine signaling 3 (SOCS3), an intrinsic inhibitor of JAK, shows biphasic induction in response to TAC. The induction of SOCS3 was closely correlated with STAT3 phosphorylation, as well as the activation of an embryonic gene program, suggesting that cardiac gp130-JAK signaling is precisely controlled by this endogenous suppressor. In addition to its cytoprotective action, gp130-dependent signaling induces cardiomyocyte hypertrophy. Adenovirus-mediated gene transfer of SOCS3 to ventricular cardiomyocytes completely suppressed both hypertrophy and antiapoptotic phenotypes induced by leukemia inhibitory factor (LIF). To our knowledge, this is the first clear evidence that these two separate cardiomyocyte phenotypes induced by gp130 activation lie downstream of JAK. Three independent signaling pathways, STAT3, MEK1-ERK1/2, and AKT activation, that are coinduced by LIF stimulation were completely suppressed by SOCS3 overexpression. We conclude that SOCS3 is a mechanical stress-inducible gene in cardiac muscle cells and that it directly modulates stress-induced gp130 cytokine receptor signaling as the key molecular switch for a negative feedback circuit for both myocyte hypertrophy and survival.
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PMID:Suppressor of cytokine signaling-3 is a biomechanical stress-inducible gene that suppresses gp130-mediated cardiac myocyte hypertrophy and survival pathways. 1171 37

Neurons in vivo are exposed to a variety of different growth factors and cytokines. A principal signalling pathway for ciliary neurotrophic factor (CNTF)-like cytokines is the Janus kinase (Jak)/signal transducer and activator of transcription (STAT) system of kinases and transcription factors. In the human cell line (SH-SY5Y), STAT1 and STAT3 activation by CNTF-like cytokines showed tyrosine phosphorylation peaking at 0.5 h and inactivating within 2 h. Tyrosine phosphorylation of the receptor-associated tyrosine kinases Jak1 and Jak2 showed a similar time course of activation and inactivation in response to CNTF. The STAT1 response to the non-CNTF-like cytokine, interferon-gamma (IFN-gamma) did not inactivate. Inactivation to CNTF was not due to a decrease in CNTF receptor subunit gp130 or in levels of Jak1 or Jak2. STAT inactivation was inhibited by the protein kinase blocker H7 and a tyrosine phosphatase blocker, but not by inhibitors of protein kinase C, mitogen-activated protein kinase (MAPK) kinase, mTOR-P70/S6 kinase or phosphatidyl inositol-3-kinase (PI-3 kinase). Surprisingly, CNTF caused only a minor increase in levels of suppressors of cytokine signalling, SOCS-1 and SOCS-3. CNTF pretreatment desensitized the cells to the CNTF-like cytokines, leukemia inhibitory factor and oncostatin-M but not to IFN-gamma. These results reveal a complex level of regulation of shared signalling pathways for cytokines that is dependent on both the type of cell and cytokine.
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PMID:Activation and inactivation of signal transducers and activators of transcription by ciliary neurotrophic factor in neuroblastoma cells. 1188 86

IL-6 is a pleiotropic cytokine with a wide range of biological activities in immune regulation, hematopoiesis, inflammation, and oncogenesis. Its activities are shared by IL-6-related cytokines such as leukemia inhibitory factor and oncostatin M. The pleiotropy and redundancy of IL-6 functions have been identified by using a unique receptor system comprising two functional proteins: an IL-6 receptor (IL-6R) and gp130, the common signal transducer of cytokines related to IL-6. Signal transduction through gp130 is mediated by two pathways: the JAK-STAT (Janus family tyrosine kinase-signal transducer and activator of transcription) pathway and the Ras mitogen-activated protein kinase pathway. The negative regulators of IL-6 signaling have also been identified, although the physiological roles of the molecules are not yet fully understood. The pathological roles of IL-6 have also been clarified in various disease conditions, such as inflammatory, autoimmune, and malignant diseases. On the basis of the findings, a new therapeutic approach to block the IL-6 signal using humanized anti-IL-6R antibody for rheumatoid arthritis, Castleman's disease, and multiple myeloma has been attempted.
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PMID:The paradigm of IL-6: from basic science to medicine. 1211 Jan 43

Sustained activation of the Ras/Raf/MEK/extracellular signal-regulated kinase (ERK) pathway can lead to cell cycle arrest in many cell types. We have found, with human medullary thyroid cancer (MTC) cells, that activated Ras or c-Raf-1 can induce growth arrest by producing and secreting an autocrine-paracrine factor. This protein was purified from cell culture medium conditioned by Raf-activated MTC cells and was identified by mass spectrometry as leukemia inhibitory factor (LIF). LIF expression upon Raf activation and subsequent activation of JAK-STAT3 was also observed in small cell lung carcinoma cells, suggesting that this autocrine-paracrine signaling may be a common response to Ras/Raf activation. LIF was sufficient to induce growth arrest and differentiation of MTC cells. This effect was mediated through the gp130/JAK/STAT3 pathway, since anti-gp130 blocking antibody or dominant-negative STAT3 blocked the effects of LIF. Thus, LIF expression provides a novel mechanism allowing Ras/Raf signaling to activate the JAK-STAT3 pathway. In addition to this cell-extrinsic growth inhibitory pathway, we find that the Ras/Raf/MEK/ERK pathway induces an intracellular growth inhibitory signal, independent of the LIF/JAK/STAT3 pathway. Therefore, activation of the Ras/Raf/MEK/ERK pathway can lead to growth arrest and differentiation via at least two different signaling pathways. This use of multiple pathways may be important for "fail-safe" induction and maintenance of cell cycle arrest.
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PMID:The Ras/Raf/MEK/extracellular signal-regulated kinase pathway induces autocrine-paracrine growth inhibition via the leukemia inhibitory factor/JAK/STAT pathway. 1250 53

A number of trophoblast products, including human chorionic gonadotropin (hCG), can increase the formation of human placental syncytium through the differentiation of mononuclear cytotrophoblasts. The present study investigated the central role of hCG in this process by using antisense receptor phosphorothioate oligodeoxynucleotides (ODNs). Culturing cytotrophoblasts with the hCG/LH receptor antisense, but not sense, ODN resulted in a significant decrease in receptor protein levels and inhibited spontaneous as well as exogenous hCG induced increase in differentiation. The hCG/LH receptor antisense ODN also inhibited epidermal growth factor (EGF), TGF-alpha, leukemia inhibitory factor (LIF), but not 8-bromo-cAMP, induced increases in differentiation, suggesting that hCG is required for EGF, TGF-alpha and LIF, but not for the cAMP actions. Although antisense EGF receptor and LIF receptor ODNs inhibited EGF and LIF induced increase in differentiation, respectively, they were ineffective against hCG, suggesting that they use separate pathways, but they both converge on a common pathway requiring the hCG actions. Mechanism of action studies revealed that EGF treatment activates its receptors and MAPK, both of which are required for EGF to increase the differentiation, cAMP levels and activate protein kinase A. In summary, our results demonstrate that hCG is an autocrine and paracrine regulator that is required for EGF, TGF-alpha, and LIF, but not for cAMP to increase human placental syncytium formation. Direct activation of protein kinase A seems to bypass the hCG pathway, perhaps by targeting genes associated with the differentiation.
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PMID:The central role of human chorionic gonadotropin in the formation of human placental syncytium. 1258 87

Cholinergic differentiation factors (CDFs) suppress noradrenergic properties and induce cholinergic properties in sympathetic neurons. The CDFs leukemia inhibitory factor (LIF) and ciliary neurotrophic factor (CNTF) bind to a LIFR.gp130 receptor complex to activate Jak/signal transducers and activators of transcription and Ras/mitogen-activated protein kinases signaling pathways. Little is known about how these differentiation factors suppress noradrenergic properties. We used sympathetic neurons and SK-N-BE(2)M17 neuroblastoma cells to investigate CDF down-regulation of the norepinephrine synthetic enzyme dopamine-beta-hydroxylase (DBH). LIF and CNTF activated extracellular signal-regulated kinases (ERKs) 1 and 2 but not p38 or Jun N-terminal kinases in both cell types. Preventing ERK activation with PD98059 blocked CNTF suppression of DBH protein in sympathetic neurons but did not prevent the loss of DBH mRNA. CNTF decreased transcription of a DBH promoter-luciferase reporter construct in SK-N-BE(2)M17 cells, and this was also ERK-independent. Cytokine inhibition of DBH promoter activity did not require a silencer element but was prevented by overexpression of the transcriptional activator Phox2a. Inhibiting ERK activation increased basal DBH transcription in SK-N-BE(2)M17 cells, and DBH mRNA in sympathetic neurons. Transfection of Phox2a into PD98059-treated M17 cells resulted in a synergistic increase in DBH promoter activity compared with Phox2a or PD98059 alone. These data suggest that CDFs down-regulate DBH protein via an ERK-dependent pathway but inhibit DBH gene expression through an ERK-independent pathway. They further suggest that ERK activity inhibits basal DBH gene expression.
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PMID:Cytokine suppression of dopamine-beta-hydroxylase by extracellular signal-regulated kinase-dependent and -independent pathways. 1260 84


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