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)

Basal cells lining prostatic acini have unique morphologic and immunophenotypic characteristics. The role of these uncommitted cells in the genesis of cancer in the prostate is intriguing. Here, we discuss immunophenotypic and molecular features of basal cells of prostatic acini, and compare them with those of cytologically transformed cells of prostatic intraepithelial neoplasia (PIN) in both human tissues and animal models. Following a summary of the current concepts of molecular events in prostatic cancer, we will discuss the role of the ras-dependent pathway in early prostate carcinogenesis with a special emphasis on mitogen-activated protein kinase phosphatase (MKP-1). We will also outline the importance of techniques such as differential display-polymerase chain reaction (ddPCR) followed by in situ hybridization in the characterization of genes which may have a critical role in early prostate carcinogenesis. Finally, we will underscore the role of animal models in understanding the early events leading to neoplastic transformation of prostate cells.
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PMID:Molecular events in the early phases of prostate carcinogenesis. 887 97

The neuropeptide substance P (SP) regulates many biological processes through binding to and activating the SP receptor (NK-1 subtype). Activation of the SP receptor induces mitogenesis in several cell types. In this study, we characterized the mitogenic response induced by SP peptide in the U-373MG astrocytoma cell line and showed that activation of the SP receptor induces [3H]thymidine incorporation into DNA. We also found that SP potently induces c-myc mRNA and protein in the U-373MG cells. Tyrphostin A25, which blocks activity of tyrosine kinases, significantly inhibited SP-induced mitogenesis, suggesting that the mitogenic response induced by SP peptide involves phosphorylation by tyrosine kinases. Furthermore, stimulation of the SP receptor activates tyrosine phosphorylation and enzymatic activity of extracellular signal-regulated kinases (Erk1 and Erk2), also called the mitogen-activated protein kinases (MAPKs). This result suggests that MAPKs participate in the SP peptide-induced signaling pathway. The addition of CP 96,345 ([(2S,3S)-cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl)-methyl]-1 -azabicyclo[2.2.2]octan-3-amine]; an NK-1 receptor antagonist) or PD 098059 (MEK1 inhibitor) inhibited both DNA synthesis and activation of the MAPK pathway, substantiating that SP stimulates mitogenesis by activating the MAPK pathway through receptors of the NK-1 subtype. Our results demonstrate that SP peptide is a strong mitogen in the U-373MG astrocytoma cell line and establish a clear correlation between SP-induced mitogenesis and activation of MAPK signaling pathway.
Cancer Res 1996 Nov 01
PMID:Substance P-induced mitogenesis in human astrocytoma cells correlates with activation of the mitogen-activated protein kinase signaling pathway. 889 54

The activation state of the members of the mitogen-activated protein kinase family following photodynamic therapy (PDT) with benzoporphyrin derivative monoacid ring A was investigated using a naturally transformed murine keratinocyte cell line, Pam 212. PDT involves the use of photosensitizer molecules and a specific wavelength of visible light. The process of PDT generates singlet oxygen and other reactive oxygen intermediates (ROIs), and the cytotoxic effect of these ROIs is the basis for the use of PDT to treat cancer and psoriasis. PDT caused a strong dose- and time-dependent activation of both stress-activated protein kinase (SAPK) and p38 HOG1. The maximum activation of SAPK and p38 HOG1 occurred between 20 and 30 min following PDT treatment with 200 ng/ml benzoporphyrin derivative monoacid ring A and 2 J/cm2 of red light at 690 nm. In our system, PDT did not cause significant activation of extracellularly regulated kinase (ERK) 1 and ERK2. Under the same experimental conditions, ultraviolet light irradiation caused strong activation of SAPK and p38 HOG1 and minimum activation of ERK1 and ERK2 in Pam212 cells. A number of ROI scavengers were tested for their effect on PDT-induced SAPK and p38 HOG1 activation. Both L-histidine and N-acetyl-L-cysteine showed a significant inhibitory effect on PDT-induced SAPK and p38 HOG1 activation. This indicated that PDT-induced SAPK and p38 HOG1 activation may be partially mediated by ROI.
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PMID:Stimulation of stress-activated protein kinase and p38 HOG1 kinase in murine keratinocytes following photodynamic therapy with benzoporphyrin derivative. 890 Feb 2

The SAPKs represent novel conduits through which the effects of cellular insults or injury are transmitted to the nucleus to influence gene expression. The SAPK pathway consists of at least four levels of protein kinases that are activated by a wide range of agents that adversely affect cell growth. Unlike the structurally related MAPK pathway, the stress induced kinases are not required for mitogenesis and instead induce growth arrest. Given the modulation of the pathway by inflammatory cytokines, reperfusion injury and chemotherapeutics, determination of the physiological functions of the pathway may uncover new possibilities for diagnosis and therapeutic intervention.
Cancer Surv 1996
PMID:The stress activated protein kinase pathway. 890 98

Tumor necrosis factor (TNF) promotes diverse responses in endothelial cells that are important to the host response to infections and malignancies; however, less is known of the postreceptor events important to TNF action in endothelial cells than in many other cell types. Since phosphorylation cascades are implicated in cytokine signaling, the effects of the protein kinase inhibitor dimethylaminopurine (DMAP) on TNF action in bovine aortic endothelial cells (BAEC) were investigated. In BAEC, TNF promotes phosphorylation of eukaryotic initiation factor 4E (eIF-4E), c-Jun N-terminal kinase (JNK) and ceramide-activated protein kinase activities, Jun-b expression, prostacyclin production, and, when protein synthesis is inhibited, cytotoxicity. DMAP abrogated or significantly attenuated each of these responses to TNF, without affecting the specific binding of TNF to its receptors. Histamine, another agent active in the endothelium, promotes phosphorylation of elongation factor-2 (EF-2) and prostacyclin production, but not phosphorylation of eIF-4E in BAEC. Histamine-stimulated EF-2 phosphorylation was not inhibited and prostacyclin production was unaffected by DMAP. These observations demonstrate that a distinct signal transduction cascade, which can be selectively inhibited by DMAP, promotes the response of BAEC to TNF. Thus, we have identified a reagent, DMAP, that may be useful for characterizing the TNF signal transduction pathway.
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PMID:Inhibition of tumor necrosis factor signal transduction in endothelial cells by dimethylaminopurine. 891 Apr 94

We studied the activation of c-jun N-terminal kinase 1 (JNK 1) and extracellular signal-regulated kinases 1 and 2 (ERK 1/2) of mitogen-activated protein kinase (MAPK) family by adriamycin (ADR) in the human T cell leukemia line, H9. ADR caused an elevation of JNK1 activity at sublethal or lethal concentrations; however, at lower doses, ADR did not activate JNK1. The induction of JNK1 peaked at 4 h of treatment (about ten-fold over the control), and was sustained up to 5 h post-treatment. This induction preceded the onset of apoptosis, as determined by morphological features and internucleosomal degradation of DNA. Upon treatment of cells with JNK1-inducing doses, ADR caused an elevation of steady-state levels of c-jun and ATF3 mRNAs, as measured by RT-PCR. In contrast, the activity of ERK 1/2 remained unchanged throughout the treatments, indicating that members of MAPK family are differentially regulated in ADR-treated cells. A possible role of JNK1 activation in ADR-induced apoptosis is discussed.
Cancer Lett 1996 Oct 01
PMID:Adriamycin activates c-jun N-terminal kinase in human leukemia cells: a relevance to apoptosis. 891 69

c-Jun NH2-terminal protein kinase (JNK), a member of the mitogen-activated protein kinase family, is activated in response to many stressful stimuli including heat shock, UV irradiation, protein synthesis inhibitors, and inflammatory cytokines. In this study, we investigated whether JNK plays a role in the cellular response to different drugs commonly used in cancer chemotherapy. Treatment of human KB-3 carcinoma cells with Adriamycin resulted in a time- and dose-dependent activation of JNK of up to 40-fold. Treatment with vinblastine or etoposide (VP-16) also activated JNK, with maximum increases of 6.5- and 4.3-fold, respectively. Consistent with these findings, increased c-Jun phosphorylation was observed after drug treatment of cells. In contrast, none of the drugs significantly activated the extracellular response kinase/mitogen-activated protein kinase pathway. Since these drugs are transport substrates for the MDR1 gene product, P-glycoprotein, JNK was assayed in two multidrug-resistant (MDR) KB cell lines, KB-A1 and KB-V1, selected for resistance to Adriamycin and vinblastine, respectively. Relative to KB-3 cells, basal JNK activity was increased 7-fold in KB-A1 cells and 4-fold in KB-V1 cells, with no change in JNK protein expression, indicating that JNK is present in a more highly activated form in the MDR cell lines. Under conditions optimal for JNK activation, Adriamycin, vinblastine, and VP-16 all induced MDR1 mRNA expression in KB-3 cells. Our findings suggest that JNK activation is an important component of the cellular response to several structurally and functionally distinct anticancer drugs and may also play a role in the MDR phenotype.
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PMID:Role of the stress-activated/c-Jun NH2-terminal protein kinase pathway in the cellular response to adriamycin and other chemotherapeutic drugs. 894 82

Potassium ferricyanide is known to elicit cell growth and mitogenesis in various cells by stimulating a transplasma membrane electron-transport system. When serum-starved PC12 cells were treated with potassium ferricyanide, stimulation of mitogenesis was evidenced by enhanced DNA synthesis, as well as by increased cell numbers. Intracellular pH (pH(i)) of PC12 cells was measured at 37 degrees C by microfluorimetric analysis of 2',7'-bis-(2-carboxyethyl)-5(and -6)-carboxyfluorescein (BCECF). The resting pH(i) of unstimulated cells was 7.52 (external pH 7.40). Addition of potassium ferricyanide (100 microM) decreased pH(i) by about 0.25 pH units. Lowering pH(i) to a similar extent, either by decreasing external pH (pH(o)) or by adding a weak acid, also elicited a mitogenic response, indicating that intracellular acidification by itself has growth factor-mimicking, mitogenic effects. Nerve growth factor (NGF) or basic fibroblast growth factor (bFGF) triggered proliferation without changes in pH(i). The mitogenic treatments eliciting intracellular acidification did not activate protein kinase C (PKC) but stimulated the p42/p44 mitogen-activated protein (MAP) kinase. Our results indicate that 2 distinct mitogenic pathways are active in PC12 cells: the first is independent of pH(i) and involves activation of the PKC pathway and the second requires a permissive pH(i) value around 7.25 and involves activation of the p42/p44 MAP kinase pathway.
Int J Cancer 1996 Nov 15
PMID:Intracellular acidification mediates the proliferative response of PC12 cells induced by potassium ferricyanide and involves MAP kinase activation. 894 28

A novel alteration in exon 1 of KRAS was detected by single strand conformational polymorphism analysis of DNA amplified from the bone marrow of a 4-year-old child with myeloid leukemia. Sequencing of this mutant allele revealed an insertion of three nucleotides between codons 10 and 11 resulting in an in-frame insertion of glycine. Expression of the mutant protein in NIH 3T3 cells caused cellular transformation, and expression in COS cells activated the Ras-mitogen-activated protein kinase signaling pathway. Surprisingly, Ras.GTP levels measured in COS cells established that this novel mutant accumulates to 90% in the GTP state, considerably higher than a residue 12 mutant. Biochemical analysis confirmed that the higher Ras.GTP levels correspond to a dramatic decrease in intrinsic GTP hydrolysis as well as resistance to GTPase-activating proteins. This mutation is the first dominant Ras mutation found in human cancer that does not involve residues 12, 13, or 61, and its biochemical properties should help elucidate the mechanism of oncogenic activation.
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PMID:Biochemical characterization of a novel KRAS insertion mutation from a human leukemia. 895 68

Asbestos fibers are human carcinogens with undefined mechanisms of action. In studies here, we examined signal transduction events induced by asbestos in target cells of mesothelioma and potential cell surface origins for these cascades. Asbestos fibers, but not their nonfibrous analogues, induced protracted phosphorylation of the mitogen-activated protein (MAP) kinases and extracellular signal-regulated kinases (ERK) 1 and 2, and increased kinase activity of ERK2. ERK1 and ERK2 phosphorylation and activity were initiated by addition of exogenous epidermal growth factor (EGF) and transforming growth factor-alpha, but not by isoforms of platelet-derived growth factor or insulin-like growth factor-1 in mesothelial cells. MAP kinase activation by asbestos was attenuated by suramin, which inhibits growth factor receptor interactions, or tyrphostin AG 1478, a specific inhibitor of EGF receptor tyrosine kinase activity (IC50 = 3 nM). Moreover, asbestos caused autophosphorylation of the EGF receptor, an event triggering the ERK cascade. These studies are the first to establish that a MAP kinase signal transduction pathway is initiated after phosphorylation of a peptide growth factor receptor following exposure to asbestos fibers.
Cancer Res 1996 Dec 01
PMID:Asbestos causes stimulation of the extracellular signal-regulated kinase 1 mitogen-activated protein kinase cascade after phosphorylation of the epidermal growth factor receptor. 896 79


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