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)

Ten years have passed since the molecular cloning of interleukin 6 (IL-6) in 1986. IL-6 is a typical cytokine, exhibiting functional pleiotropy and redundancy. IL-6 is involved in the immune response, inflammation, and hematopoiesis. The IL-6 receptor consists of an IL-6 binding alpha chain and a signal transducer, gp130, which is shared among the receptors for the IL-6 related cytokine subfamily. The sharing of a receptor subunit is a general feature of cytokine receptors and provides the molecular basis for the functional redundancy of cytokines. JAK tyrosine kinase is a key molecule that can initiate multiple signal-transduction pathways by inducing the tyrosine-phosphorylation of the cytokine receptor, gp130 in the case of IL-6, on which several signaling molecules are recruited, including STAT, a signal transducer and activator of transcription, and SHP-2, which links to the Ras-MAP kinase pathway. JAK can also directly activate signaling molecules such as STAT and Tec. These multiple signal-transduction pathways intimately regulate the expression of several genes including c-myc, c-myb, junB, IRF1, egr-1, and bcl-2, leading to the induction of cell growth, differentiation, and survival. The deregulated expression of IL-6 and its receptor is involved in a variety of diseases.
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PMID:Interleukin 6 and its receptor: ten years later. 950 91

Although nicotine has been implicated as a potential factor in the pathogenesis of human lung cancer, its mechanism of action in the development of this cancer remains largely unknown. The present study provides evidence that nicotine (a) activates the mitogen-activated protein (MAP) kinase signalling pathway in lung cancer cells, specifically extracellular signal-regulated kinase (ERK2), resulting in increased expression of the bcl-2 protein and inhibition of apoptosis in these cells; and (b) blocks the inhibition of protein kinase C (PKC) and ERK2 activity in lung cancer cells by anti-cancer agents, such as therapeutic opioid drugs, and thus can adversely affect cancer therapy. Nicotine appears to have no effect on the activities of c-jun NH2-terminal protein kinase (JNK) and p38 MAP kinases, which have also been shown to be involved in apoptosis. While exposure to nicotine can result in the activation of the two major signalling pathways (MAP kinase and PKC) that are known to inhibit apoptosis, nicotine regulation of MAP (ERK2) kinase activity is not dependent on PKC. These effects of nicotine occur at concentrations of 1 microM or less, that are generally found in the blood of smokers, and could lead to disruption of the critical balance between cell death and proliferation, resulting in the unregulated growth of cells. The findings suggest caution in the use of smokeless tobacco products to treat smoking addiction, as they could have a potentially deleterious effect in patients with undetectable early tumour development.
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PMID:Signalling pathways involved in nicotine regulation of apoptosis of human lung cancer cells. 960 Mar 37

p38, a subfamily of the mitogen-activated protein kinase, regulates gene expression in response to various extracellular stimuli. The pyridinyl imidazoles like SB202190 are specific inhibitors of p38alpha and p38beta and have been widely used in investigation of the biological functions of p38. Here we show that SB202190 by itself was sufficient to induce cell death, with typical apoptotic features such as nucleus condensation and intranucleosomal DNA fragmentation. SB202190 stimulated the activity of CPP32-like caspases, and its apoptotic effect was completely blocked by the protease inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone and expression of bcl-2. In addition, SB202190 was able to potentiate apoptosis induced by Fas(APO-1) ligation or UV irradiation. Expression of p38beta attenuated the apoptotic effect of SB202190 and the cell death induced by Fas ligation and UV irradiation. In contrast, expression of p38alpha induced cell death mildly. These results indicate that SB202190 induces apoptosis through activation of CPP32-like caspases and suggest that distinct members of the p38 subfamily of mitogen-activated protein kinase have different functions in apoptosis.
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PMID:Induction of apoptosis by SB202190 through inhibition of p38beta mitogen-activated protein kinase. 963 6

The extracellular microenvironment of tumors differs from that of most normal tissues. Many tumors have relatively acidic extracellular pH, although the intracellular pH of tumor cells remains normal due to the efficient maintenance of a large proton gradient across the membrane. This difference between tumors and normal tissues might be exploited therapeutically by disruption of the mechanisms that regulate intracellular pH, so that tumor cells are killed by intracellular acid-induced injury. To investigate the mechanisms by which intracellular acidification leads to cell death, we have studied the roles of the antiapoptotic gene bcl-2 and its proapoptotic binding partner bax, the stress-activated protein kinases (SAPK/JNK), and the caspase proteases in mediating acid-induced cell death. Whereas the expression of bcl-2 in human bladder cancer MGH-U1 cells had no effect on acid-induced death, overexpression of bax enhanced cell death, consistent with its proapoptotic function. Inhibition of SAPK, through the expression of a dominant negative mutant of its activator, SEK1, protected cells from acid-induced cell death. Caspase activation, as measured by poly(ADP-ribose) polymerase cleavage, was absent after lethal intracellular acidification. Consistent with this observation, inhibition of interleukin 1beta-converting enzyme proteases by the peptide z-Val-Ala-Asp(OMe)-CH2F did not protect against acid-induced cell killing. We conclude that acid-induced cell death depends on bax and on SAPK signaling pathways, but not on the caspase proteases. Therapeutic manipulation of bax and SAPK may enhance acid-induced tumor cell killing.
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PMID:Death of tumor cells after intracellular acidification is dependent on stress-activated protein kinases (SAPK/JNK) pathway activation and cannot be inhibited by Bcl-2 expression or interleukin 1beta-converting enzyme inhibition. 966 94

We have explored the role of bcl-2 as a potential modulator of intracellular signal transduction. Stable expression of bcl-2 in fibroblasts inhibited the activation of the c-jun amino terminal kinase (JNK) by the nonapoptotic cytokine interleukin-1 beta (IL-1 beta). This effect appeared to be selective for JNK activation as bcl-2 did not appear to alter the other aspects of IL-1 beta signal transduction. Similarly, bcl-2 did not inhibit all all activators of JNK as it had no effect on JNK activation by the protein synthesis inhibitor anisomycin. Treatment with nonlethal concentrations of H2O2, which resulted in the simultaneous stimulation of mitogen-activated protein kinase (MAPK) and JNK, demonstrated that bcl-2 appeared to alter the balance of activation of these two kinase cascades. The pathway by which bcl-2 inhibits JNK activation is demonstrated to be independent of the rac1 GTPase. In contrast, the reduction in JNK activity in cells expressing bcl-2 can be restored by costimulation with a calcium ionophore. This suggests that bcl-2 can regulate certain nonapoptotic signaling pathways. Such results therefore expand the functions of bcl-2 and may have important implication in the understanding of the role of this protein in a variety of human diseases.
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PMID:Bcl-2 regulates nonapoptotic signal transduction: inhibition of c-Jun N-terminal kinase (JNK) activation by IL-1 beta and hydrogen peroxide. 968 14

The extracellular microenvironment of tumors differs from most normal tissues. Many tumors have relatively acidic extracellular pH (pHe), although the intracellular pH (pHi) of tumor cells remains normal due to efficient maintenance of a large proton gradient across the membrane. This difference between tumors and normal tissues might be exploited therapeutically by disruption of the mechanisms which regulate pHi, so that tumor cells are killed by intracellular acid-induced injury. To investigate the mechanisms by which intracellular acidification leads to cell death, we have studied the roles of the anti-apoptotic gene bcl-2 and its pro-apoptotic binding partner bax, the Stress Activated Protein Kinases (SAPK/JNK), and the caspase proteases in mediating acid-induced cell death. While expression of bcl-2 in human bladder cancer MGH-U1 cells had no effect on acid-induced death, overexpression of bax enhanced cell death, consistent with its pro-apoptotic function. Inhibition of SAPK, through expression of a dominant negative mutant of its activator, SEK1 protected cells from acid-induced cell death. Caspase activation, as measured by poly (ADP-ribose) polymerase cleavage, was absent after lethal intracellular acidification. Consistent with this observation, inhibition of ICE proteases by the peptide z-VAD.fmk did not protect against acid-induced cell killing. We conclude that acid-induced cell death depends on bax and on SAPK signaling pathways but not on the caspase proteases. Therapeutic manipulation of bax and SAPK may enhance acid-induced tumor cell killing.
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PMID:Inhibition of apoptotic signaling pathways in cancer cells as a mechanism of chemotherapy resistance. 977 Jan 20

DNA topoisomerase II (topo II) is an essential nuclear enzyme required for chromatin condensation and chromosome segregation during mitosis. Forced overexpression of topo IIalpha was found to cause morphological changes in recipient cells associated with apoptosis. This induction of apoptosis required nuclear localization of topo IIalpha, yet was independent of the DNA cleavage-religation activity of the enzyme. Apoptosis mediated by topo IIalpha deregulation was blocked by overexpression of crmA, a specific inhibitor of certain caspases, but not by bcl-2. topo IIalpha-induced apoptosis was also blocked by overexpression of a dominant-acting mutant of stress-activated protein kinase kinase (SEK1/MKK4) but not by the overexpression of its normal counterpart. Furthermore, apoptosis was blocked by coexpression of a dominant-negative form of the cyclin-dependent kinase cdk2 but not by dominant-negative cdc2. These results provide a rationale for the tight regulation of topo IIalpha levels through the cell cycle in that deregulation of topo IIalpha expression results in apoptotic cell death.
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PMID:Induction of apoptosis by deregulated expression of DNA topoisomerase IIalpha. 978 93

In previous reports we demonstrated that glucose deprivation induces metabolic oxidative stress in drug-resistant human breast carcinoma MCF-7/ADR cells (Lee, Y. J., Galoforo, S. S., Berns, c. M., Chen, J. C., Davis, B. H., Swim, J. E., Corry, P. M., and Spitz, D. R. (1998) J. Biol. Chem. 273, 5294-5299). In the study described here, we investigated intracellular responses to metabolic oxidative stress. Northern blots show an increase in the level of HSP70 and HSP28 mRNA in cells exposed to glucose-free medium for 1 h. One- and two-dimensional polyacrylamide gel analyses confirmed that glucose deprivation induced a family of HSPs, particularly an inducible HSP70. Overexpression of bcl-2 suppressed glucose deprivation-induced HSP70 gene expression, heat shock transcription factor-heat shock element binding activity, as well as c-Jun NH2-terminal kinase (JNK1) activation. Expression of a dominant-negative mutant of JNK1 also suppressed glucose deprivation-induced JNK1 activation as well as HSP70 gene expression. Taken together, the stress-activated protein kinase signal transduction pathway is involved in glucose deprivation-induced heat shock gene expression.
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PMID:Metabolic oxidative stress-induced HSP70 gene expression is mediated through SAPK pathway. Role of Bcl-2 and c-Jun NH2-terminal kinase. 979 2

The ATP/ubiquitin-dependent 26S proteasome is a central regulator of cell cycle progression and stress responses. While investigating the application of peptide aldehyde proteasome inhibitors to block signal-induced IkappaBalpha degradation in human LNCaP prostate carcinoma cells, we observed that persistent inhibition of proteasomal activity signals a potent cell death program. Biochemically, this program included substantial upregulation of PAR-4 (prostate apoptosis response-4), a putative pro-apoptotic effector protein and stabilization of c-jun protein, a potent pro-death effector in certain cells. We also observed modest downregulation of bcl-XL, a pro-survival effector protein. However, in contrast to some recent reports stable, high level, expression of functional bcl-2 protein in prostate carcinoma cells failed to signal protection against cell death induction by proteasome inhibitors. Also in disagreement to a recent report, no evidence was found for activation of the JNK stress kinase pathway. A role for p53, a protein regulated by the proteasome pathway, was ruled out, since comparable cell death induction by proteasome inhibitors occurred in PC-3 cells that do not express functional p53 protein. These data signify that the ubiquitin/proteasome pathway represents a potential therapeutic target for prostate cancers irrespective of bcl-2 expression or p53 mutations.
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PMID:Prostate carcinoma cell death resulting from inhibition of proteasome activity is independent of functional Bcl-2 and p53. 987 95

The effectiveness of chemotherapy for human cancers is limited by pharmacokinetic parameters such as variation in metabolism and is determined by the cellular response. In this work, we aimed to gain a more holistic understanding of the molecular basis of glioma response to the DNA-alkylating agent 1, 3-bis(2-chloroethyl)-1-nitrosourea (BCNU) by using a systematic approach: we investigated the expression of 588 genes with various cellular functions in a BCNU-resistant glioblastoma cell line and a BCNU-sensitive subline before and after treatment with BCNU. Our gene expression profiling revealed major differences in gene expression between these two cell lines, especially after treatment with BCNU. One striking example was that BCNU decreased the expression of six DNA-repair genes in sensitive but not in resistant cells. In sensitive cells, BCNU treatment resulted in the induction of two MAP kinase genes; this finding suggests that the specific response to BCNU in sensitive cells may involve the Jun kinase signal transduction pathway. After BCNU treatment, marked induction of tumor necrosis factor was detected only in sensitive cells, suggesting that tumor necrosis factor is a mediator of BCNU-induced cell death. Bcl-2 family members were not altered by BCNU in sensitive cells, suggesting that BCNU-induced cell death may be independent of the bcl-2 pathway. Results of the present study demonstrate that gene expression profiling may facilitate identification of cellular pathways associated with specific responses to chemotherapeutic agents and contribute to an understanding of the molecular basis of drug action.
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PMID:Characterization of cellular pathways involved in glioblastoma response to the chemotherapeutic agent 1, 3-bis(2-chloroethyl)-1-nitrosourea (BCNU) by gene expression profiling. 1002 10


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