Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aldose reductase (AR) is a ubiquitously expressed protein with pleiotrophic roles as an efficient catalyst for the reduction of toxic lipid aldehydes and mediator of hyperglycemia, cytokine, and growth factor-induced redox-sensitive signals that cause secondary diabetic complications. Although AR inhibition has been shown to be protective against oxidative stress signals, the role of AR in regulating nitric oxide (NO) synthesis and NO-mediated apoptosis has not been elucidated to date. We therefore investigated the role of AR in regulating lipopolysaccharide (LPS)-induced NO synthesis and apoptosis in RAW 264.7 macrophages. Inhibition or RNA interference ablation of AR suppressed LPS-stimulated production of NO and overexpression of iNOS mRNA. Inhibition or ablation of AR also prevented the LPS-induced apoptosis, cell cycle arrest, activation of caspase-3, p38-MAPK, JNK, NF-kappaB, and AP1. In addition, AR inhibition prevented the LPS-induced down-regulation of Bcl-xl and up-regulation of Bax and Bak in macrophages. L-Arginine increased and L-NAME decreased the severity of cell death caused by LPS and AR inhibitors prevented it. Furthermore, inhibition of AR prevents cell death caused by HNE and GS-HNE, but not GS-DHN. Our findings for the first time suggest that AR-catalyzed lipid aldehyde-glutathione conjugates regulate the LPS-induced production of inflammatory marker NO and cytotoxicity in RAW 264.7 cells. Inhibition or ablation of AR activity may be a potential therapeutic target in endotoximia and other inflammatory diseases.
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PMID:Aldose reductase mediates endotoxin-induced production of nitric oxide and cytotoxicity in murine macrophages. 1738 9

Suppressor of cytokine signaling 3 (SOCS3) is expressed by lymphoid cells and can modulate the sensitivity of these cells to cytokine stimulation through inhibition of Janus kinase (JAK)/signal transducers and activators of transcription (STAT) signaling pathways. This study employed a mouse pro-B cell line expressing the human GH receptor (BaF/3-GHR), to elucidate the signal transduction pathways used by GH to elicit SOCS3 expression. GH treatment of these cells caused a rapid, dose-dependent increase in SOCS3 mRNA expression, which was independent of de novo protein synthesis. As expected, GH treatment increased JAK-dependent STAT5 tyrosine phosphorylation, which bound to the proximal STAT response element (pSRE) on the SOCS3 promoter. This process appeared to involve STAT5b, rather than STAT5a. In addition, GH activation of the SOCS3 promoter required a nearby activator protein (AP) 1/cAMP response element (CRE), which bound cAMP response element binding protein, c-Fos, and c-Jun. Moreover, inhibitors of p38 MAPK and c-Jun N-terminal kinase prevented GH-stimulation of SOCS3 mRNA expression in these cells, suggesting a role for these kinases in SOCS3 transcription. Importantly, GH stimulation increased binding of FOXO3a to the SOCS3 promoter at a site overlapping the AP1/CRE response element, and overexpression of FOXO3a in these cells augmented SOCS3 promoter activation. In addition, we show a direct interaction between FOXO3a and STAT5 in these cells, which may provide a link between STAT5 and the AP1 transcription factors on the SOCS3 promoter. We conclude that regulation of SOCS3 expression by GH in a pro-B cell involves not only the pSRE, but also a transcriptionally active complex involving cAMP response element binding protein/c-Fos/c-Jun and FOXO3a. This study has implications for cytokine regulation of SOCS gene expression in lymphoid cells.
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PMID:Regulation of suppressor of cytokine signaling 3 (SOC3) by growth hormone in pro-B cells. 1760 38

The transcriptional cofactor FHL2 interacts with a broad variety of transcription factors and its expression is often deregulated in various types of cancer. Here we analyzed for the first time the molecular function of FHL2 in breast cancer. FHL2 is overexpressed in almost all human mammary carcinoma samples tested but not in normal breast tissues and only low levels of FHL2 expression were present in four premalignant ductal carcinoma in situ (DCIS). Cell cycle analysis revealed an upregulation of endogenous FHL2 towards G2/M in MDA-MB 231 cells and an accelerated G2/M transition when FHL2 expression was suppressed in these cells. In search for G2/M specific target genes regulated by FHL2, we found that expression of the cell cycle inhibitor p21Cip1/Waf1 (hereafter p21) is dependent on FHL2 in MDA-MB 231 breast cancer cells. Downregulation of FHL2 by shRNA abrogated the cell cycle dependent upregulation of p21 as well as the induction of p21 in response to treatment with the DNA damaging agent doxorubicin. FHL2-dependent p21 expression occurs in a p53-independent manner and p21 expression can be downregulated by specific inhibition of mitogen-activated protein kinases (MAPKs), implicating an involvement of MAPK signaling in this regulation. Analysis of FHL2 contribution to the MAPK signaling identified FHL2 as an important downstream effector of MAPKs in breast cancer cells, capable of transactivating endogenous AP1 target genes as well as AP1 dependent reporter genes. Finally, downregulation of FHL2 reduces the ability of MDA-MB 231 cells to form colonies in soft agar, while FHL2 overexpression enhances colony formation of breast cancer cells. Thus, our findings indicate that overexpression of the transcriptional cofactor FHL2 contributes to breast cancer development by mediating transcriptional activation of MAPK target genes known to be involved in cancer progression, such as p21.
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PMID:FHL2 regulates cell cycle-dependent and doxorubicin-induced p21Cip1/Waf1 expression in breast cancer cells. 1768 92

Hypoxia represents a major stress that requires an immediate cellular response in which different signaling pathways participate. Hypoxia induces an increase in the activity of TAK1, an atypical mitogen-activated protein kinase kinase kinase (MAPKKK), which responds to oxidative stress by triggering cascades leading to the activation of c-Jun N-terminal kinase (JNK). JNK activation by hypoxia requires assembly with the JIP1 scaffold protein, which might also interact with other intracellular proteins that are less well known but that might modulate MAPK signaling. We report that TAK1 is able to form a stable complex with JIP1 and thus regulate the activation of JNK, which in turn determines the cellular stress response to hypoxia. This activation of TAK1-JIP1-JNK is suppressed by vaccinia-related kinase 2 (VRK2). VRK2A is able to interact with TAK1 by its C-terminal region, forming stable complexes. The kinase activity of VRK2 is not necessary for this interaction or the downregulation of AP1-dependent transcription. Furthermore, reduction of the endogenous VRK2 level with short hairpin RNA can increase the response induced by hypoxia, suggesting that the intracellular levels of VRK2 can determine the magnitude of this stress response.
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PMID:Vaccinia-related kinase 2 modulates the stress response to hypoxia mediated by TAK1. 1770 93

Marine invertebrates, algae, and microorganisms are prolific producers of novel secondary metabolites. Some of these secondary metabolites have the potential to be developed as chemotherapeutic agents for the treatment of a wide variety of diseases, including cancer. We describe here the mechanism leading to apoptosis of esophageal cancer cell lines in the presence of triprenylated toluquinones and toluhydroquinones originally isolated from the Arminacean nudibranch Leminda millecra. Triprenylated toluquinone-induced and toluhydroquinone-induced cell death is mediated via apoptosis after a cell cycle block. Molecular events include production of reactive oxygen species (ROS), followed by induction and activation of c-Jun (AP1) via c-Jun-NH2-kinase-mediated and extracellular signal-regulated kinase-mediated pathways. Partial resistance to these compounds could be conferred by the ROS scavengers Trolox and butylated hydroxyanisol, a c-Jun-NH2-kinase inhibitor, and inhibition of c-Jun with a dominant negative mutant (TAM67). Interestingly, the levels of ROS produced varied between compounds, but was proportional to the ability of each compound to kill cells. Because cancer cells are often more susceptible to ROS, these compounds present a plausible lead for new antiesophageal cancer treatments and show the potential of the South African marine environment to provide new chemical entities with potential clinical significance.
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PMID:Reactive oxygen species mediated apoptosis of esophageal cancer cells induced by marine triprenyl toluquinones and toluhydroquinones. 1787 50

A mechanistically based mathematical model is used to investigate some of the important factors in priming hepatocytes to enter the G1 phase of the cell cycle. The model considers all of the relevant biochemical mechanisms from signal-receptor binding to the elevation of AP-1 (activation protein transcription factor) levels. Focus is centered on the chain of biochemical events governing the sequential activation of protein kinase C (PKC), mitogen-activated protein kinase (MAPK) and AP-1. Factors such as amplitude and duration of growth factors signals, the kinetics of guanosine diphosphate (GDP) to guanosine triphosphate (GTP) conversion, and the negative feedback control mechanisms governing initial steps in cellular replication were theoretically examined. The results of our theoretical assessments support the finding that specific mutations along the PKC-AP1 pathways can have a critical effect on the rate at which cells enter the division cycle.
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PMID:Replication potential of cells via the protein kinase C-MAPK pathway: application of a mathematical model. 1788 16

The JNK signaling pathway is implicated in the regulation of the AP1 transcription factor and cell proliferation. Here, we examine the role of JNK by using conditional and chemical genetic alleles of the ubiquitously expressed murine genes that encode the isoforms JNK1 and JNK2. Our analysis demonstrates that JNK is not essential for proliferation. However, JNK is required for expression of the cJun and JunD components of the AP1 transcription factor, and JNK-deficient cells exhibit early p53-dependent senescence. These data demonstrate that JNK can act as a negative regulator of the p53 tumor suppressor.
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PMID:Suppression of p53-dependent senescence by the JNK signal transduction pathway. 1789 31

Inhibition of glycogen synthase kinase 3beta (GSK3beta) as a consequence of its phosphorylation by protein kinase B/Akt (PKB/Akt) has been implicated in cardiac myocyte hypertrophy in response to endothelin-1 or phenylephrine. We examined the regulation of GSK3alpha (which we show to constitute a significant proportion of the myocyte GSK3 pool) and GSK3beta in cardiac myocytes. Although endothelin increases phosphorylation of GSK3 and decreases its activity, the response is less than that induced by insulin (which does not promote cardiac myocyte hypertrophy). GSK3 phosphorylation induced by endothelin requires signalling through the extracellular signal-regulated kinase 1/2 (ERK1/2) cascade and not the PKB/Akt pathway, whereas the reverse is true for insulin. Cardiac myocyte hypertrophy involves changes in morphology, and in gene and protein expression. The potent GSK3 inhibitor 1-azakenpaullone increases myocyte area as a consequence of increased cell length whereas phenylephrine increases both length and width. Azakenpaullone or insulin promotes AP1 transcription factor binding to an AP1 consensus oligonucleotide, but this was significantly less than that induced by endothelin and derived principally from increased binding of JunB protein, the expression of which was increased. Azakenpaullone promotes significant changes in gene expression (assessed by Affymetrix microarrays), but the overall response is less than with endothelin and there is little overlap between the genes identified. Thus, although GSK3 may contribute to cardiac myocyte hypertrophy in some respects (and presumably plays an important role in myocyte metabolism), it does not appear to contribute as significantly to the response induced by endothelin as has been maintained.
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PMID:Glycogen synthase kinases 3alpha and 3beta in cardiac myocytes: regulation and consequences of their inhibition. 1799 64

Estrogen-related receptor alpha (ERRalpha), a member of the nuclear receptor superfamily, is closely related to the estrogen receptors (ERalpha and ERbeta). The ERRalpha gene is estrogen-responsive in several mouse tissues and cell lines, and a multiple hormone-response element (MHRE) in the promoter is an important regulatory region for estrogen-induced ERRalpha gene expression. ERRalpha was recently shown to be a negative prognostic factor for breast cancer survival, with its expression being highest in cancer cells lacking functional ERalpha. The contribution of ERRalpha in breast cancer progression remains unknown but may have important clinical implications. In this study, we investigated ERRalpha gene expression and chromatin structural changes under the influence of 17beta-estradiol in both ER-positive MCF-7 and ER-negative SKBR3 breast cancer cells. We mapped the nucleosome positions of the ERRalpha promoter around the MHRE region and found that the MHRE resides within a single nucleosome. Local chromatin structure of the MHRE exhibited increased restriction enzyme hypersensitivity and enhanced histone H3 and H4 acetylation upon estrogen treatment. Interestingly, estrogen-induced chromatin structural changes could be repressed by estrogen antagonist ICI 182 780 in MCF-7 cells yet were enhanced in SKBR3 cells. We demonstrated, using chromatin immunoprecipitation assays, that 17beta-estradiol induces ERRalpha gene expression in MCF-7 cells through active recruitment of co-activators and release of co-repressors when ERRalpha and AP1 bind and ERalpha is tethered to the MHRE. We also found that this estrogen effect requires the MAPK signaling pathway in both cell lines.
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PMID:Estrogen induces estrogen-related receptor alpha gene expression and chromatin structural changes in estrogen receptor (ER)-positive and ER-negative breast cancer cells. 1817 57

The activity of beta-secretase (BACE1), the endo-protease essential for the production of amyloid beta (Abeta) peptides, is increased in brain of late-onset sporadic Alzheimer's disease (AD), and oxidative stress is the potential cause of this event. Oxidative stress up-regulates the expression and the activity of BACE1 in cellular and animal models, through a mechanism that involves the increase of gamma-secretase cleavage on APP and the activation of c-jun N-terminal kinase/activator protein 1 (JNK/AP1) pathway. We further characterized the cellular pathways that control BACE1 expression under oxidative stress. We investigated the involvement of extracellular signal regulated MAP kinase (ERK1/2) pathway in the regulation of BACE1 expression, since it has been recently shown that ERK1/2 is an endogenous regulator of the gamma-secretase activity. We found that ERK1/2 pathway negatively modulates BACE1 expression and activity. Moreover, we observed that conditions that abrogate the gamma-secretase activity favor the activation of signalling pathways that promote cell survival, such as ERK1/2 and the serine/threonine kinase Akt/protein kinase B (Akt). These data suggest that the positive or negative cellular responses to oxidative stress parallel the activities of the beta- and the gamma-secretase. ERK1/2 and JNK pathways are involved in this bipartite response, which can lead to neurodegeneration or neuroprotection depending on the cellular and environmental conditions or cooperation with other signalling pathways such as Akt cascade.
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PMID:JNK and ERK1/2 pathways have a dual opposite effect on the expression of BACE1. 1825 90


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