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)

Cells within human skin are permanently exposed to mechanical stretching. Here we present evidence that alterations in cell shape trigger biochemical signaling via MAP kinases in human keratinocytes. In an in vitro attempt we demonstrate a fast but transient activation of extracellular signal-regulated kinases 1/2 in response to cell stretch. This activation is reversed by preincubation with functional blocking antibodies directed towards beta1-integrins. As a second member of MAP kinases, stress-activated protein kinase/c-JUN NH2-terminal kinase was activated in a slower fashion, peaking at 1 h after the initial stimulus. The delay in signal transmission suggests that extracellular signal-regulated kinases 1/2 and stress-activated protein kinase/c-JUN NH2-terminal kinase do not share the same signaling pathway. p38 was not activated by cell stretching. The contribution of cytoskeletal elements in signal perception and transduction was evaluated by selective disruption of either actin filaments, microtubules, or keratin filaments but showed no clear effect on stretch-induced activation of extracellular signal-regulated kinases 1/2 and stress-activated protein kinase/c-JUN NH2-terminal kinase. In conclusion we found evidence of a cell-shape-dependent activation of MAP kinases in human keratinocytes disclosing beta1-integrins as putative mechano-transducers. It is likely that alterations of skin mechanics in vivo underlying pathogenic processes like wound formation and healing trigger physiologic responses via the MAP kinase pathway.
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PMID:Signaling of mechanical stretch in human keratinocytes via MAP kinases. 1144 68

In yeast and animal cells, distinct subfamilies of mitogen-activated protein kinases (MAPKs) have evolved for transmitting different types of signals, such as the extracellular signal-regulated kinase (ERK) for mitogenic stimuli and differentiation, p38 and JUN kinase (JNK) for stress factors. Based on sequence analysis, the presently known plant MAPKs are most similar to ERKs, even though compelling evidence implies a role in various forms of biotic and abiotic stress responses. However, knowledge of their involvement in controlling proliferation is just emerging. A subgroup of the plant MAPKs, containing the alfalfa MMK3 and tobacco NTF6, are only active in mitotic cells and their localisation to the cell plate suggests a role in cytokinesis. An upstream regulator of MAPKs, the tobacco NPK1, appears to be also activated during mitosis. NPK1 might be associated and regulated by a microtubule motor protein. The localisation of NPK1 to the cell plate and its mitosis-specific activation suggest that together with NTF6 it could constitute a mitotic MAPK signalling module in tobacco. NPK1 appears to have a second role in repression of auxin-induced gene expression. MAPKs might also be involved in signalling within the meristems as suggested by the recruitement of a small G-protein to the CLAVATA 1 receptor-like protein kinase upon activation. In animal and yeast cells some of the small G-proteins relay signals from receptors to MAPK pathways.
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PMID:Stressing the role of MAP kinases in mitogenic stimulation. 1108 71

Within the first 24 h after castration of an adult male rat, the vascular system of the ventral prostate gland undergoes a degenerative process that drastically reduces blood flow to the tissue. Since the vascular degeneration precedes the loss of the prostatic epithelium (by apoptosis), we have proposed that the onset of epithelial cell apoptosis in this tissue is caused by an ischemic/hypoxic environment resulting from the loss of blood flow. In order to further evaluate the extent to which ischemia/hypoxia might be a factor in apoptosis of the prostate epithelium after castration, we analyzed for biomarkers of cellular hypoxia in rat ventral prostates during the first 3 days following castration. Ventral prostate tissues removed from hypoxyprobe-1-treated adult male rats (uncastrated controls; surgically castrated for 24, 48 or 72 h, or sham-castrated for equivalent times) were directly analyzed for evidence of hypoxia by in situ immunohistochemical evaluation of hypoxyprobe-1 adduct formation in the prostate cells. Protein extracts from these tissues were also tested for expression of the 120 kDa hypoxia-inducible factor-1-alpha (HIF-1-alpha) protein as well as for expression of mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) proteins using a Western blot assay. The tyrosine phosphorylation status of the latter signaling molecules was also evaluated by Western blotting using anti-tyrosine phosphate antibodies. Our results showed that epithelial cells of the rat ventral prostate stained positively for hypoxyprobe-1 adducts at all times after castration, whereas cells in control tissues were unstained by this procedure. In addition, the prostatic expression of HIF-1-alpha protein was increased approximately 20-fold at 48 h after castration compared to control tissues. Finally, although prostatic MAPK and JNK protein expression was unaltered during the early period after castration, phosphorylation of the JUN kinase protein was significantly elevated, indicating that this stress-activated cellular signaling pathway becomes more active subsequent to castration. These results support our proposal that early castration-induced degeneration and constriction of the vascular system of the rat ventral prostate gland leads to reduced oxygenation of prostatic epithelial cells and the activation of hypoxic cellular signaling in these cells through upregulation of HIF-1-alpha expression and stimulation of the JUN kinase signaling pathway.
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PMID:Biomarker analysis demonstrates a hypoxic environment in the castrated rat ventral prostate gland. 1125 26

Cotreatment with a minimally toxic concentration of the protein kinase C (PKC) activator (and down-regulator) bryostatin 1 (BRY) induced a marked increase in mitochondrial dysfunction and apoptosis in U937 monocytic leukemia cells exposed to the proteasome inhibitor lactacystin (LC). This effect was blocked by cycloheximide, but not by alpha-amanitin or actinomycin D. Qualitatively similar interactions were observed with other PKC activators (eg, phorbol 12-myristate 13-acetate and mezerein), but not phospholipase C, which does not down-regulate the enzyme. These events were examined in relationship to functional alterations in stress (eg, SAPK, JNK) and survival (eg, MAPK, ERK) signaling pathways. The observations that LC/BRY treatment failed to trigger JNK activation and that cell death was unaffected by a dominant-interfering form of c-JUN (TAM67) or by pretreatment with either curcumin or the p38/RK inhibitor, SB203580, suggested that the SAPK pathway was not involved in potentiation of apoptosis. In marked contrast, perturbations in the PKC/Raf/MAPK pathway played an integral role in LC/BRY-mediated cell death based on evidence that pretreatment of cells with bisindolylmaleimide I, a selective PKC inhibitor, or geldanamycin, a benzoquinone ansamycin, which destabilizes and depletes Raf-1, markedly suppressed apoptosis. Furthermore, ERK phosphorylation was substantially prolonged in LC/BRY-treated cells compared to those exposed to BRY alone, and pretreatment with the highly specific MEK inhibitors, PD98059, U0126, and SL327, opposed ERK activation while protecting cells from LC/BRY-induced lethality. Together, these findings suggest a role for activation and/or dysregulation of the PKC/MAPK cascade in modulation of leukemic cell apoptosis following exposure to the proteasome inhibitor LC. (Blood. 2001;97:2105-2114)
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PMID:Synergistic induction of apoptosis in human leukemia cells (U937) exposed to bryostatin 1 and the proteasome inhibitor lactacystin involves dysregulation of the PKC/MAPK cascade. 1126 78

The current studies were designed to examine the mechanisms of acute effects of ethanol on cerebellar granule neurons (CGNs) during neurodevelopment, with specific reference to activator protein-1 (AP-1). CGNs, isolated from 3-day-old Sprague-Dawley rats and cultured for 3 days, were exposed to 0, 22.5, and 100 mM ethanol for 1 h. Gel shift assays performed on the nuclear protein extracts showed increased AP-1 and heat shock factor-1 (HSF-1) transcriptional activation in response to ethanol. Western blots and RT-PCR showed increased c-JUN and phosphorylated c-JUN (serine 73) protein, as well as c-jun mRNA. Ethanol paradoxically decreased the activity of stress-activated protein kinase-1 (SAPK-1) while increasing p44 and p42 mitogen-activated protein kinase (MAPK) activity. The protein synthesis-inhibiting and SAPK-1 activity-inducing antibiotic, anisomycin (30 and 500 microM) decreased AP-1 transcriptional activation to 47 and 23% of control values, respectively. The anisomycin effect was enhanced in the presence of 100 mM ethanol. Similarly, cycloheximide decreased ethanol-induced AP-1 transcriptional activation. Pretreatment with the MAPK kinase (MEK) pathway inhibitor PD98059 resulted in decreases in both ethanol-induced and control AP-1 DNA binding. Thus this acute ethanol-induced increased AP-1 transcriptional activation requires protein synthesis and involves MEK-independent increased MAPK phosphorylation, on the one hand, and decreased SAPK-1 activity on the other. The ethanol effect is thus ascribed to the activities of alternate kinase pathways and/or the inhibition of (a) protein phosphatase(s). Exposure of CGNs to ethanol for 24 h resulted in decreased AP-1 DNA binding, an observation that could have consequences for overall neuronal function under chronic exposure conditions.
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PMID:Acute exposure of cerebellar granule neurons to ethanol suppresses stress-activated protein kinase-1 and concomitantly induces AP-1. 1150 22

Androgen deficiency in males leads to an increase in osteoclastic bone resorption and a progressive decrease in bone mineral density. In the current studies, we examined the ability of 5 alpha-dihydrotestosterone to suppress osteoclast formation induced by receptor activator of NF-kB ligand (RANKL) and macrophage-colony stimulating factor in vitro. 5 alpha-Dihydrotestosterone suppressed the differentiation of bone marrow monocytes into osteoclasts from both sham-operated and orchidectomized mice. Androgen deficiency also led to an increase in the number of hematopoietic precursors capable of forming osteoclasts and increased the relative responsiveness of these cells to androgens in vitro. Interestingly, E2 was as effective as 5 alpha-dihydrotestosterone in suppressing osteoclast formation in bone marrow monocytes from both sham and orchidectomized mice. As with bone marrow monocytes, 5 alpha-dihydrotestosterone also suppressed RANKL-induced osteoclast formation in the monocyte-macrophagic cell line RAW264.7. In RAW264.7 cells, androgens appear to block RANKL-induced osteoclast formation through selective regulation of c-JUN: Accordingly, 5 alpha-dihydrotestosterone suppressed RANKL-induced c-Jun N-terminal kinase activation and reduced c-Jun expression levels. These effects resulted in a reduction in RANKL-induced activator protein-1 DNA binding activity and a corresponding suppression in activator protein-1-mediated transcriptional activation. These studies indicate that both E and androgens can suppress osteoclast formation via a direct, stromal cell-independent action on osteoclast precursors to block key transcription factors such as c-Jun essential for osteoclast differentiation.
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PMID:Androgens suppress osteoclast formation induced by RANKL and macrophage-colony stimulating factor. 1151 56

MKK7 is a recently discovered mitogen-activated protein kinase (MAPK) kinase that is unique in that it specifically activates only the c-JUN NH(2)-terminal protein kinase (JNK) family of enzymes. Very little is known about the biological role of MKK7. We generated inducible cell lines from the human embryonal kidney carcinoma cell line, HEK293, by stable transfection with a constitutively active mutant of MKK7, MKK7(3E), fused to green fluorescent protein (GFP), under the control of an ecdysone-inducible promoter. Treatment of cells with the synthetic ecdysone analog ponasterone A induced expression of GFP-MKK7(3E) and resulted in sustained activation of endogenous JNK, but neither of the other endogenous MAPKs, ERK or p38. Red and green fluorescing cDNA copies of mRNA extracted from cells obtained before and after induction of GFP-MKK7(3E) were hybridized to microarrays containing more than 6,000 cDNAs in eight independent experiments. By selection criteria, 23 genes were differentially regulated after 24 h of induction of GFP-MKK7(3E) and 16 after 48 h. The expression of 9 genes was consistently changed after both 24 and 48 h of induction. These changes included down-regulation of three genes, c-myc, angiopoietin-2, and glucose-regulated protein 58, and up-regulation of 6 genes, tissue factor pathway inhibitor-2, GRP78, autotaxin, PPP1R7, the DKFZ cDNA p434D0818, and 1 unknown gene. Consistent with previously described roles of several of the altered genes, MKK7(3E) inhibited cell proliferation. These data implicate active MKK7 in the negative regulation of cell proliferation and provide evidence for a new role for this kinase in the regulation of a distinct, hitherto unrecognized set of genes.
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PMID:Inducible expression of a constitutively active mutant of mitogen-activated protein kinase kinase 7 specifically activates c-JUN NH2-terminal protein kinase, alters expression of at least nine genes, and inhibits cell proliferation. 1171 98

In hypertension, increased transmural pressure directly influences vascular smooth muscle cells and causes cell proliferation. However, the mechanisms of transmural pressure-induced proliferation of vascular smooth muscle cells are unknown. We investigated the role of various protein kinases in pressure-induced proliferation of vascular smooth muscle cells. Pressure was applied to quiescent rat vascular smooth muscle cells in culture by compressed helium gas in a loading apparatus. Pressure application increased [3H]thymidine incorporation in a time- and pressure-dependent manner and significantly increased the cell number. The pressor response was significantly suppressed by various protein kinase inhibitors for protein kinase C (bisindolylmaleimide I), tyrosine kinase (genistein), extracellular signal-regulated kinase kinase (PD98059; 2'-amino-3'-methoxyflavone) and p38 mitogen-activated protein kinases (MAPK) (SB203580; 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole). Pressure rapidly increased the phosphorylation and activity of extracellular signal-regulated kinases (ERK). Pressure also caused increment of phosphorylation level of p38 MAPK but not that of c-JUN N-terminal protein kinase (JNK). In ERK-deficient cells prepared by transfection of an antisense oligonucleotide for ERK, pressure-induced DNA synthesis was almost abolished. Our results suggest that activation of ERK is essential for pressure-induced DNA synthesis in rat vascular smooth muscle cells, in addition to activation of protein kinase C, tyrosine kinase and p38 MAPK. These processes could be involved in the pathogenesis of hypertension-related atherosclerosis.
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PMID:Activation of extracellular signal-regulated kinases is essential for pressure-induced proliferation of vascular smooth muscle cells. 1209 81

The aromatic hydrocarbon (Ah) receptor (AHR) is the only known cellular receptor of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and of many other widespread environmental contaminants that cause diverse toxic effects in animals and humans. Most, if not all, the biological effects of TCDD are mediated by the activation of AHR, which is a ligand-activated transcription factor required for ligand-induced expression of several detoxification genes, including those encoding for cytochrome P450 enzymes CYP1A1, CYP1A2, and CYP1B1. Environmental agents also activate several mitogen-activated protein kinase (MAPK) pathways, believed to modulate transcription factor function and to regulate gene expression. However, the contribution to TCDD toxicity resulting from cross-talk between AHR and MAPK pathways has yet to be determined. In this study, we show that TCDD and other AHR ligands induced the immediate activation of the extracellular signal-regulated kinases and the Jun N-terminal kinases, but not the p38 MAPKs. MAPK activation by TCDD did not require the AHR, since it occurred equally well in AHR-negative CV-1 cells and in Ahr (-/-) mouse embryonic fibroblasts as in AHR-positive cells. Distinct from serum factors and the tumor promoter TPA-induced MAPKs, which resulted in transcriptional activation of ELK or c-JUN, TCDD-stimulated MAPKs were critical for the induction of AHR-dependent gene transcription and CYP1A1 expression. These data indicate that AHR ligands elicit AHR-independent non-genomic events that are essential for AHR activation and function.
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PMID:Activation of mitogen-activated protein kinases (MAPKs) by aromatic hydrocarbons: role in the regulation of aryl hydrocarbon receptor (AHR) function. 1221 69

Restoration of expression of the retinoblastoma gene to DU-145 prostate-cancer cells sensitizes them to apoptosis induced by gamma-irradiation. In contrast, RB expression-protected cells from UV-induced cell death. RB, a caspase substrate, remained intact during apoptosis in gamma-irradiated DU-145 cells because serine proteases, but not caspases, were activated. In DU-145 cells, RB-mediated apoptosis involved biphasic activation of ABL kinase. ABL kinase was activated within minutes of irradiation, but in the presence of RB expression ABL kinase activation was enhanced 48 h after irradiation, coincident with the onset of cell death. Apoptosis was inhibited by RB mutants with constitutive ABL binding, but ABL overexpression overcame the effect of the RB mutant constructs. Expression of kinase-dead ABL had a dominant-negative effect on RB-mediated cell death. Activation of JUN N-terminal kinase depended on the presence of RB and occurred within 8 h of irradiation. Mutant JUN proteins that lacked the N-terminal transactivation domain and serine substrates for JUN N-terminal kinase inhibited cell death in a dominant-negative manner. Irradiation of DU-145 cells caused activation of p38 MAPK independent of the expression of RB. Inhibitors of p38 MAPK blocked apoptosis after irradiation of RB-expressing cells. The data show that after gamma-irradiation, intact RB mediates transcriptional activation that leads to activation of JNK and late activation of ABL kinase. In addition, p38 MAPK activation occurred independent of RB. ABL kinase, JUN N-terminal kinase, and p38 MAPK activity were all required for RB-mediated DU-145 cell death after gamma-irradiation.
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PMID:Retinoblastoma protein-mediated apoptosis after gamma-irradiation. 1229 96


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