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)

We have recently shown that exposure of human keratinocytes to physiologic doses of ultraviolet B (UVB) activates epidermal growth factor receptor (EGFR)/extracellular-regulated kinases 1 and 2 (ERK1/2) and p38 signaling pathways via reactive oxygen species, an effect that can be modulated by antioxidants. Trolox, a water-soluble vitamin E analog, is among the antioxidants that are currently being investigated for their preventive and protective potential against harmful effects of UV radiation to the skin. We found that Trolox inhibits both basal and UVB-induced intracellular H(2)O(2) generation in primary keratinocytes in a concentration-dependent manner. Trolox did not significantly affect UVB-induced phosphorylation of EGFR. Stronger inhibition was observed for ERK1/2 activation at lower, and for p38 activation at higher, concentrations of Trolox added to cells before exposure to UVB. Similarly different effects were found with regard to length of pretreatment with Trolox before UVB exposure-increasing inhibition for ERK1/2 activation at shorter, and for p38 activation at longer, pretreatment intervals. UVB-induced c-jun-N-terminal kinase activation was potently suppressed by Trolox. Also, increasing the pretreatment time of Trolox decreased the rate of cell death following UVB. In conclusion, UVB-induced signaling pathway activation is differentially modulated by Trolox. Further investigation into the time-dependent biologic activation of Trolox and its metabolic products, and modulation of signal transduction with cell outcome should facilitate development of rational strategies for pharmacologic applications.
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PMID:Vitamin E analog modulates UVB-induced signaling pathway activation and enhances cell survival. 1118 98

Because of the potential of arsenic for causing cancer in humans, and of the fact of widespread environmental and occupational exposure, deriving acceptable human-limit values has been of major concern to industry as well as to regulatory agencies. Based upon epidemiological evidence and mechanistic studies, it has been argued that a non-linear dose-response model at low-level exposures is more appropriate for calculating risk than the more commonly employed linear-response models. In the present studies, dose-response relationships and recovery studies employing a cancer precursor marker, i.e., activating protein (AP)-1 DNA-binding activity, were examined in bladders of mice exposed to arsenic in drinking water and compared to histopathological changes and arsenic tissue levels in the same tissue. While AP-1 is a functionally pleomorphic transcription factor regulating diverse gene activities, numerous studies have indicated that activation of the MAP kinase pathway and subsequently increased AP-1 binding activities, is a precursor for arsenic-induced cancers of internal organs as well as the skin. We observed previously that within 8 weeks of exposure AP-1 activation occurs in urinary bladder tissue of mice exposed to arsenic in the drinking water. In the present studies, C57BL/6 mice were exposed to sodium arsenite at various concentrations in the drinking water for 8 consecutive weeks. Minimal but observable AP-1 activity occurred in bladder tissue at exposure levels below which histopathological changes or arsenic tissue accumulation was detected. Marked AP-1 DNA-binding activity only occurred at exposure levels of sodium arsenite above 20 microg/ml, where histopathological changes and accumulation of arsenic in the urinary bladder epithelium occurred. Although the experimental design did not allow statistical modeling of the entire dose-response curve, the general shape of the dose-response curve is not inconsistent with the previously proposed hypothesis that arsenic-induced cancer follows a non-linear dose-response model.
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PMID:Quantitative relationship between arsenic exposure and AP-1 activity in mouse urinary bladder epithelium. 1124 40

Hwansodan has been used as a prescription for senile and vascular dementia in Oriental medicine. We investigated the neuroprotective effects of Hwansodan water extract on the apoptotic death of PC12 cells by serum deprivation. Hwansodan significantly rescued PC12 cells from apoptotic death by serum deprivation in a dose-dependent manner. The nuclear staining of PC12 cells clearly showed that Hwansodan attenuated nuclear condensation and fragmentation, which represents typical neuronal apoptotic characteristics. Hwansodan also prevents DNA fragmentation and caspase-3-like protease activation in serum-deprived PC12 cells and induces the tyrosine phosphorylation of proteins around 44 kDa, which was identified as ERK1 with electrophoretic gel mobility shift by Western blot. In addition, MEK inhibitor PD98059 and Ras inactivator, alpha-hydroxyfarnesylphosphonic acid and mevastatin, attenuated the neuroprotective effects of Hwansodan in serum-deprived PC12 cells. These results indicate that Ras/MEK/ERK signaling pathway plays a role in neuroprotective effects of Hwansodan in serum-deprived PC12 cells.
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PMID:Hwansodan protects PC12 cells against serum-deprivation-induced apoptosis via a mechanism involving Ras and mitogen-activated protein (MAP) kinase pathway. 1128 16

Renal cells in culture have low viability when exposed to hypertonicity. We developed cell lines of inner medullary collecting duct cells adapted to live at 600 and 900 mosmol/kgH(2)O. We studied the three modules of the mitogen-activated protein (MAP) kinase family in the adapted cells. These cells had no increase in either extracellular signal-regulated kinase, c-Jun NH(2)-terminal kinase, or p38 MAP kinase protein or basal activity. When acutely challenged with further increments in tonicity, they had blunted activation of these kinases, which was not due to enhanced phosphatase activity. In contrast, the cells adapted to the hypertonicity displayed a marked increment in Na-K-ATPase expression (5-fold) and ouabain-sensitive Na-K-ATPase activity (10-fold). The changes were reversible on return to isotonic conditions. Replacement of 300 mosmol/kgH(2)O of NaCl by urea in cells adapted to 600 mosmol/kgH(2)O resulted in marked decrement in Na-K-ATPase and failure to maintain the cell line. Replacement of NaCl for urea in cells adapted to 900 mosmol/kgH(2)O did not alter either Na-K-ATPase expression, or the viability of the cells. The in vivo modulation of Na-K-ATPase was studied in the renal papilla of water-deprived mice (urinary osmolality 2,900 mosmol/kgH(2)O), compared with that of mice drinking dextrose in water (550 mosmol/kgH(2)O). Increased water intake was associated with a ~30% decrement in Na-K-ATPase expression (P < 0.02, n = 6), suggesting that this enzyme is osmoregulated in vivo. We conclude that whereas MAP kinases play a role in the response to acute changes in tonicity, they are not central to the chronic adaptive response. Rather, in this setting there is upregulation of other osmoprotective proteins, among which Na-K-ATPase appears to be an important component of the adaptive process.
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PMID:Long-term adaptation of renal cells to hypertonicity: role of MAP kinases and Na-K-ATPase. 1129 18

Cholinergic agents are known to affect the epithelial transport of H2O and electrolytes in the kidney. In proximal tubule cells, cholinergic agonists increase basolateral Na-HCO(3) cotransport activity via M(1) muscarinic receptor activation. The signaling intermediates that couple these G protein-coupled receptors to cotransporter activation, however, are not well defined. We therefore sought to identify distal effectors of muscarinic receptor activation that contribute to increased NBC activity in cultured proximal tubule cells. As demonstrated previously for acute CO2-regulated cotransport activity, we found that inhibitors of Src family kinases (SFKs) or the classic mitogen-activated protein kinase (MAPK) pathway prevented the stimulation of NBC activity by carbachol. The ability of carbachol to activate Src, as well as the proximal (Raf) and distal [extracellular signal-regulated kinases 1 and 2 (ERK1/2)] elements of the classic MAPK module, was compatible with these findings. Cholinergic stimulation of ERK1/2 activity was also completely prevented by overexpression of a dominant negative mutant of Ras (N17-Ras). Taken together, these findings suggest a requirement for the sequential activation of SFKs, Ras, and the classic MAPK pathway [Raf-->MAPK/ERK kinase (MEK)-->ERK]. These findings provide important insights into the molecular mechanisms underlying cholinergic regulation of NBC activity in renal epithelial cells. They also suggest a specific mechanism whereby cholinergic stimulation of the kidney can contribute to pH homeostasis.
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PMID:SFKs, Ras, and the classic MAPK pathway couple muscarinic receptor activation to increased Na-HCO(3) cotransport activity in renal epithelial cells. 1129 27

Plants are continuously exposed to all kinds of water stress such as drought and salinity. In order to survive and adapt, they have developed survival strategies that have been well studied, but little is known about the early mechanisms by which the osmotic stress is perceived and transduced into these responses. During the last few years, however, a variety of reports suggest that specific lipid and MAPK pathways are involved. This review briefly summarises them and presents a model showing that osmotic stress is transmitted by multiple signalling pathways.
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PMID:Osmotic stress activates distinct lipid and MAPK signalling pathways in plants. 1141 51

We examined the activation of memory-related processes in the hippocampus and the amygdala following spatial learning under stress, in the rat. Animals were trained in a water maze in a massed spatial task under two stress conditions (cold and warm water). In the dorsal CA1, training was accompanied by increased phosphorylation of ERK2 only in animals that have acquired the task (irrespective of whether they were trained in cold or warm water). In the amygdala, significant activation of ERK2 was found only in animals that learned the task well under high levels of stress. Hence, the results suggest that the amygdala and the hippocampus are differentially activated following spatial learning, depending on the level of stress involved.
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PMID:Differential activation of hippocampus and amygdala following spatial learning under stress. 1155 96

ERK2 belongs to the mitogen-activated protein kinase subfamily, which plays a pivotal role in cell signal transduction, in which it mediates effects on proliferation and differentiation by growth factors and hormones. While its cellular function has been under intense scrutiny since its initial discovery nearly 15 years ago, little progress has been made in understanding its kinetic mechanism. Such an understanding is important for the development of potent and specific inhibitors. A contributory factor has been the lack of a protein substrate suitable for rigorous mechanistic studies. Here we report the expression, purification, and characterization of the N-terminus (residues 1 through 138) of the transcription factor Ets-1, an excellent model substrate for ERK2 mechanistic studies. (His(6)-tagged)Ets-1(1-138) was expressed in Escherichia coli and rapidly purified in two steps by nickel-agarose-affinity chromatography, followed by high-resolution Mono-Q anion-exchange chromatography. A yield of 60 mg of the purified protein per liter of culture was obtained and could be stored conveniently at -80 degrees C in water. Rigorous characterization demonstrated that under the assay conditions, (His(6)-tagged)Ets-1(1-138) is exclusively phosphorylated on residue Thr-38 by ERK2 with the following Michaelis parameters: k(cat) = 17 s(-1), K(ATP)(m) = 140 microM, K(ATP)(i) = 68 microM, K(Ets-1)(m) = 19 microM, and K(Ets-1)(i) = 9.3 microM.
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PMID:Purification of a model substrate for transcription factor phosphorylation by ERK2. 1157 Aug 62

Some species of marine sponge have been shown to produce metabolites with endocrine-altering and cell growth regulatory properties. Since cell division and differentiation are controlled, in part, by the mitogen-activated protein kinase-extracellular signal-regulated kinase (MAPK/ERK) cascade, we tested extracts (1.0mg/ml) from six shallow water marine species obtained in the Florida Keys for effects on MAPK/ERK(l,2) (sub-variant of EC 2.7.1.37) activity in incubations with SW-13 human adrenal carcinoma cells in culture. In these short-term incubations, extracts from two species, the purple bleeding sponge (Iotrochota birotulata) and the West Indian bath sponge (Spongia barbara), significantly inhibited MAPK/ERK(1,2) activity (to 51 and 44% of control levels, respectively) without altering cell survival. Western blots for phosphorylated and total ERK showed that ERK(2) predominated over ERK(1) by a factor of about 4:1 and that the phosphorylated forms of these isozymes were strongly suppressed by active extracts from both sponges. Another species, the green sponge (Haliclona veridis), whose extract has been shown previously to activate guanylate cyclase and to inhibit adenylate cyclase in a variety of mammalian tissues, was found not to affect MAPK/ERK(1,2) in human adrenal carcinoma cultures but did lyse and kill most of these cultured cells. Extracts from the sheepswool sponge (Hippospongia lachne) and the bleeding sponge (Oligoceras hemorrhages) did not significantly affect either MAPK/ERK(1,2) activity or the survival of attached cells. An extract from the fire sponge (Tedania ignis) did not alter MAPK/ERK(1,2) activity but did modestly decrease cell viability. These studies document for the first time species-specifc effects of marine sponge extracts on the MAPK/ERK(1,2) cascade and on the growth and survival of human adrenal carcinoma cells in culture.
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PMID:Effects of marine sponge extracts on mitogen-activated protein kinase (MAPK/ERK(1,2)) activity in SW-13 human adrenal carcinoma cells. 1160 Jan 45

How lead manifests its neurotoxicity is not well understood. The hypothesis that lead may activate nuclear transcription factors NF-kappaB, activator protein-1 (AP-1), c-Jun N-terminal kinase (JNK), mitogen-activated protein kinase kinase (MAPKK) and caspases in the rat brain leading to the manifestation of its neurotoxic effects, was tested in 21-day-old male Long-Evans rats exposed to 50 ppm Pb in drinking water for 90 days. After the 90-day exposure, blood lead levels of the rats in control group were 4+/-0.2 microg/dl, while those of the Pb-exposed group were 18+/-0.3 microg/dl (n=50). Similarly, at the end of the exposure period, the Pb-exposed group showed significantly higher accumulation of Pb in brain regions such as, frontal cortex (FC), brain stem (BS), striatum (ST), and hippocampus (HIP) (338.6+/-7.7, 391.6+/-3.8, 288.3+/-6.7, and 382.3+/-3.3 ng/g wet tissue, respectively, in FC, BS, ST, and HIP) than the control group (126.6+/-2.7, 127.6+/-1.8, 201.3+/-9.4, and 180.3+/-4.4 ng/g wet tissue, respectively, in FC, BS, ST, and HIP). There was a 3-4-fold increase in NF-kappaB and AP-1 level in all the four regions of the brain of lead-treated animals. All four regions showed 4-10-fold activation of JNK and a 5-6-fold activation of MAPKK. As indicated by poly(ADP ribose) polymerase cleavage, lead exposure induced the activation of caspases in all four regions. Overall our results indicate that lead exposure induces the activation of NF-kappaB, AP-1, JNK, MAPKK, and caspases in the brain, which may contribute to its neurotoxic effects.
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PMID:Lead exposure activates nuclear factor kappa B, activator protein-1, c-Jun N-terminal kinase and caspases in the rat brain. 1164 Oct 47


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