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)

Selenium, an essential biological trace element, is an integral component of several enzymes, and its use as a nutritional supplement has been popularized recently due to its potential role in low concentrations as an antioxidant and in higher concentrations as an anticancer agent. Selenium has also been reported to act as an insulin-mimetic agent with regard to normalization of blood glucose levels and regulation of some insulin-mediated metabolic processes. Little work, however, has been done concerning the pathway(s) by which this insulin-mimetic action occurs. In this study, we investigated the mechanism by which selenate exhibits insulin-mimetic properties in two different insulin responsive cell types, primary rat hepatocytes and 3T3 L1 adipocytes. We found that two proteins associated with the insulin signal cascade, the beta-subunit of the insulin receptor and IRS-1, increased in tyrosyl phosphorylation in the presence of selenium. The third identified selenium activated signal protein, MAP kinase, has been implicated not only in the insulin signal transduction pathway but also in other growth factor-mediated responses. Using an in-gel activity assay for MAP kinase, we demonstrated that both the p42 and p44 MAP kinases are activated when either hepatocytes or adipocytes are incubated in the presence of selenate. In addition to the activation of these specific proteins, we found that selenium also eventually profoundly affected overall tyrosyl phosphorylation. Our results therefore show that selenium not only increased the phosphorylation of proteins identified in the insulin signal cascade but also affected the overall phosphorylation state of the cell.
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PMID:Selenium: potent stimulator of tyrosyl phosphorylation and activator of MAP kinase. 906 Sep 97

Peroxynitrite is a mediator of toxicity in pathological processes in vivo and causes damage by oxidation and nitration reactions. Here, we report a differential induction of mitogen-activated protein kinases (MAPKs) in WB-F344 rat liver epithelial cells by peroxynitrite. For the exposure of cultured cells with peroxynitrite, we employed a newly developed infusion method. At 6.5 microM steady-state concentration, the activation of p38 MAPK was immediate, while JNK1/2 and ERK1/2 were activated 60 min and 15 min subsequent to 3 min of exposure to peroxynitrite, respectively. Protein-bound 3-nitrotyrosine was detected. When cells were grown in a medium supplemented with sodium selenite (1 microM) for 48 h, complete protection was afforded against the activation of p38 and against nitration of tyrosine residues. These data suggest a new role for peroxynitrite in activating signal transduction pathways capable of modulating gene expression. Further, the abolition of the effects of peroxynitrite by selenite supplementation suggests a protective role of selenium-containing proteins.
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PMID:Activation pattern of mitogen-activated protein kinases elicited by peroxynitrite: attenuation by selenite supplementation. 1021 97

Selenium, an essential biological trace element, has been shown to modulate functions of many regulatory proteins involved in signal transduction and to affect a variety of cellular activities including cell growth, survival, and death. The molecular mechanism by which selenium exerts its action on the cellular events, however, remains unclear. In our present study, we observed that selenite suppresses both the c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) and the p38 mitogen-activated protein kinase pathway in 293T cells. In contrast, selenite had little effect on the extracellular signal-regulated kinase pathway. Furthermore, selenite directly inhibited JNK/SAPK activity in vitro but not the p38 activity. The in vitro inhibition of JNK/SAPK by selenite was reversed by the addition of reducing agents such as dithiothreitol and beta-mercaptoethanol. Replacement of cysteine 116 in JNK1 by serine abolished the inhibitory effect of selenite on JNK1 activity both in vitro and in vivo. Selenite also suppressed a c-Jun-dependent luciferase reporter activity stimulated through the JNK signaling pathway. Taken together, our findings strongly suggest that selenite differentially modulates the mammalian mitogen-activated protein kinase pathways and that it can repress the JNK/SAPK signaling pathway by inhibiting JNK/SAPK through a thiol redox mechanism.
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PMID:Selenite inhibits the c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) through a thiol redox mechanism. 1064 9

The physiological significance of the selenium-independent glutathione peroxidase (GPx) activity of glutathione S-transferases (GSTs), associated with the major Alpha class isoenzymes hGSTA1-1 and hGSTA2-2, is not known. In the present studies we demonstrate that these isoenzymes show high GPx activity toward phospholipid hydroperoxides (PL-OOH) and they can catalyze GSH-dependent reduction of PL-OOH in situ in biological membranes. A major portion of GPx activity of human liver and testis toward phosphatidylcholine hydroperoxide (PC-OOH) is contributed by the Alpha class GSTs. Overexpression of hGSTA2-2 in K562 cells attenuates lipid peroxidation under normal conditions as well as during the oxidative stress and confers about 1.5-fold resistance to these cells from H(2)O(2) cytotoxicity. Treatment with 30 microm H(2)O(2) for 48 h or 40 microm PC-OOH for 8 h causes apoptosis in control cells, whereas hGSTA2-2-overexpressing cells are protected from apoptosis under these conditions. In control cells, H(2)O(2) treatment causes an early (within 2 h), robust, and persistent (at least 24 h) activation of JNK, whereas in hGSTA2-2-overexpressing cells, only a slight activation of JNK activity is observed at 6 h which declines to basal levels within 24 h. Caspase 3-mediated poly(ADP-ribose) polymerase cleavage is also inhibited in cells overexpressing hGSTA2-2. hGSTA2 transfection does not affect the function of antioxidant enzymes including GPx activity toward H(2)O(2) suggesting that the Alpha class GSTs play an important role in regulation of the intracellular concentrations of the lipid peroxidation products that may be involved in the signaling mechanisms of apoptosis.
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PMID:Role of glutathione S-transferases in protection against lipid peroxidation. Overexpression of hGSTA2-2 in K562 cells protects against hydrogen peroxide-induced apoptosis and inhibits JNK and caspase 3 activation. 1127 91

Apoptosis induction may be a mechanism mediating the anticancer activity of selenium. Our earlier work indicated that distinct cell death pathways are likely involved in apoptosis induced by the CH3SeH and the hydrogen selenide pools of selenium metabolites. To explore the role of caspases in cancer cell apoptosis induced by selenium, we examined the involvement of these molecules in the death of the DU-145 human prostate carcinoma cells induced by methylseleninic acid (MSeA), a novel penultimate precursor of the putative critical anticancer metabolite CH3SeH. Sodium selenite, a representative of the genotoxic selenium pool, was used as a reference for comparison. The results show that MSeA-induced apoptosis was accompanied by the activation of multiple caspases (caspase-3, -7, -8, and -9), mitochondrial release of cytochrome c (CC), poly(ADP-ribose) polymerase (PARP) cleavage, and DNA fragmentation. In contrast, selenite-induced apoptotic DNA fragmentation was observed in the absence of these changes, but was associated with the phosphorylation of c-Jun-NH2-terminal kinase 1/2 and p38 mitogen-activated protein kinase/stress-activated protein kinase 2. A general caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp-(OMe) fluoromethyl ketone, blocked MSeA-induced cleavage of procaspases and PARP, CC release, and DNA nucleosomal fragmentation, but did not prevent cell detachment. Furthermore, PARP cleavage and caspase activation were confined exclusively to detached cells, indicating that MSeA induction of cell detachment was a prerequisite for caspase activation and apoptosis execution. This process therefore resembled "anoikis," a special mode of apoptosis induction in which adherent cells lose contact with the extracellular matrix. Additional experiments with irreversible caspase inhibitors show that MSeA-induced anoikis involved caspase-3- and -7-mediated PARP cleavage that was initiated by caspase-8 and probably amplified through CC-caspase-9 activation and a feedback activation loop from caspase-3. Taken together, the data support a methyl selenium-specific induction of DU-145 cell apoptosis that involves cell detachment as a prerequisite (anoikis) and is executed principally through caspase-8 activation and its cross-talk with multiple caspases.
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PMID:Caspases as key executors of methyl selenium-induced apoptosis (anoikis) of DU-145 prostate cancer cells. 1130 88

Accumulated evidence from prospective studies, intervention trials and studies on animal models of cancer have suggested a strong inverse correlation between selenium intake and cancer incidence. Several putative mechanisms have been suggested to mediate the chemopreventive activities of selenium: of these, the inhibition of cellular proliferation and the induction of apoptosis are particularly attractive. The mitogen activated protein kinase (MAPK) pathways are known to be important regulators of cell death and our recent work has focused on the involvement of these pathways in selenium-induced apoptosis in primary cultures of oral cancers and corresponding normal mucosa derived from biopsy material. Using this system, the oral carcinoma cells were found to have enhanced sensitivity to apoptosis when treated with certain selenium compounds compared to normal oral mucosa. Induction of Fas ligand was associated with selenium-induced apoptosis. Signal transduction studies suggests that selenium induces several changes in the MAPK signalling pathways but functional intervention/inhibitor studies indicate that activation of the JNK pathway seems to be most important.
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PMID:Selenium and signal transduction: roads to cell death and anti-tumour activity. 1156 49

Inhibiting the mitogenic response of vascular endothelial cells may in part mediate the antiangiogenic and anticancer activity of supranutritional selenium supplements. Our previous work had shown that methylseleninic acid (MSeA), a precursor of the critical anticancer methylselenol metabolite pool, was a potent inhibitor of the growth and survival of human umbilical vein endothelial cells (HUVECs). Here we investigated the effects of MSeA on selected protein kinase signaling transduction pathways to characterize their role in methylselenium induction of HUVEC cell cycle arrest and apoptosis. Exposure of asynchronous HUVECs for 30 h to 3-5 microM MSeA led to a profound G(1) arrest, and exposure to higher levels of MSeA not only led to G(1) arrest but also to DNA fragmentation and caspase-mediated cleavage of poly(ADP-ribose)polymerase, both biochemical hallmarks of apoptosis. Immunoblot analyses indicated that G(1) arrest induced by the sublethal doses of MSeA was associated with dose-dependent reductions of the levels of phospho-protein kinase B (also known as AKT or PKB), phospho-extracellular signal regulated kinase (ERK) 1/2, and phospho-Jun NH(2)-terminal kinases 1/2 in the absence of any change in p38 mitogen-activated protein kinase (MAPK) phosphorylation. Apoptosis induced by MSeA was associated with an increased phosphorylation of p38 MAPK in addition to the dephosphorylation of the above kinases. In HUVECs deprived of endothelial cell growth supplement (ECGS) for 48 h, resumption of ECGS stimulation resulted in an approximately 10-fold increase in mitogenic response, as indicated by [(3)H]thymidine incorporation into DNA. The ECGS-stimulated mitogenic response was inhibited in a dose-dependent manner by MSeA exposure with a IC(50) approximately 1 microM and a complete blockage at 3 microM. Wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI3K) upstream of AKT, potently inhibited the ECGS-stimulated DNA synthesis (IC(50), approximately 40 nM). Combining MSeA with Wortmannin showed an additive antimitogenic effect. An inhibitor of MAPK/ERK kinase 1, PD98059, also inhibited ECGS-stimulated DNA synthesis (IC(50), approximately 55 microM), but combining PD98059 with MSeA had an effect similar to that when PD98059 was used alone. A time-course experiment indicated that PI3K (AKT and ribosomal protein S6 kinase) activation occurred between 6 and 12 h of ECGS stimulation, and 3 microM MSeA exposure decreased AKT phosphorylation after 12 h of exposure, whereas no inhibitory effect was observed for ERK1/2 phosphorylation throughout the 30-h exposure duration. Additional experiments indicated that MSeA, Wortmannin, or a more specific PI3K inhibitor, LY294002, seemed to target, in the mid- to late-G(1) phase, a common mechanism(s) controlling G(1) progression to S while having no inhibitory effect on DNA synthesis once S-phase had initiated. Taken together, the results support a potent inhibitory activity at achievable serum levels of MSeA on ECGS-stimulated mitogenesis in the mid- to late-G(1) phase, and the target(s) of this inhibitory activity seems to be PI3K or components of this signal pathway. At pharmacological levels of exposure, modulation of ERK1/2 and other protein kinases may be relevant for the proapoptotic action of MSeA.
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PMID:Antimitogenic and proapoptotic activities of methylseleninic acid in vascular endothelial cells and associated effects on PI3K-AKT, ERK, JNK and p38 MAPK signaling. 1158 51

Reactive oxygen species (ROS) during normal metabolism signal cells to stimulate proliferation or to cause cellular damages, depending on a specific concentration. Energy restriction (ER) increases life span in animals, which can explain an effective modulator for reducing oxidative stress. Oxidative stress can result from a decrease in the protection against ROS. The deleterious effects of oxidative stress generally occur after exposure to a relatively high concentration of ROS. Alternatively, it has been suggested that a low concentration of ROS can exert important physiological roles in cellular signaling and proliferation. Signal pathways are crucial for cell survival or death. It is generally acceptable that aged cells have less response to stresses such as ROS than young cells. Oxidative stresses induce JNK and p38 kinase pathways regulated by redox regulatory proteins: thioredoxin and glutathione s-transferase, respectively. Antioxidants such as selenium block apoptosis induced by ROS through blocking apoptotic signal ASK1 and stimulating survival signal Akt activity. Old hepatocytes are more susceptible to ROS-induced apoptosis than young hepatocytes, which is associated with low expression of ERK and Akt kinases. Pharmacological inhibition of ERK and Akt activation in the young cells markedly increase their sensitivity to H(2)O(2), and ER, by preventing loss of ERK and Akt activities, enhances survival of old hepatocytes to a level similar to those of young cells. Expressions of signal pathways such as survival and apoptotic signals can regulate cells' fate and aging process. Further studies on the interaction of signal pathways may change the scientific direction of the study of aging.
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PMID:Dose effect of oxidative stress on signal transduction in aging. 1247 Aug 97

Selenium has been implicated as a promising chemopreventive agent for prostate cancer. Whereas the anticancer mechanisms have not been clearly defined, one hypothesis relates to selenium metabolites, especially the monomethyl selenium pool, generated under supranutritional selenium supplementation. To explore potential molecular targets for mediating the chemopreventive activity, we contrasted the effects of methylseleninic acid (MSeA), a novel precursor of methylselenol, versus sodium selenite, a representative of the hydrogen selenide metabolite pool, on apoptosis execution, cell cycle distribution, and selected protein kinases in DU145 human prostate cancer cells. Exposure of DU145 cells to 3 microM MSeA led to a profound G1 arrest at 24 h, and exposure to greater concentrations led to not only G1 arrest, but also to DNA fragmentation and caspase-mediated cleavage of poly(ADP-ribose) polymerase (PARP), two biochemical hallmarks of apoptosis. Immunobiot analyses indicated that G1 arrest induced by the subapoptogenic doses of MSeA was associated with increased expression of p27kip1 and p21cip1, but apoptosis was accompanied by dose-dependent decreases of phosphorylation of protein kinase AKT and extracellular signal-regulated kinase (ERK1/2) in the absence of any phosphorylation change in p38 mitogen-activated protein kinase (p38MAPK) and c-Jun NH2-terminal kinase (JNK1/2). In contrast, selenite exposure caused S-phase arrest and caspase-independent apoptotic DNA fragmentation, which were associated with decreased expression of p27kip1 and p21cip1 and increased phosphorylation of AKT, JNK1/2, and p38MAPK. Although apoptosis induction by MSeA exposure was not sensitive to superoxide dismutase added into the cell culture medium, cell detachment and DNA nucleosomal fragmentation induced by selenite exposure were greatly attenuated by this enzyme, supporting a chemical mediator role of superoxide for these processes. Despite a temporal relationship of AKT and ERK1/2 de-phosphorylation changes before the onset of PARP cleavage in MSeA-exposed cells, experiments with phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002 did not show an enhancing effect of specific blocking of AKT on MSeA-induction of PARP cleavage. Taken together, exposure of DU145 cells to MSeA versus selenite induced differential patterns of cell cycle arrest and apoptosis execution as well as distinct patterns of effects on AKT, ERK1/2, JNK1/2, and p38MAPK phosphorylation and p27kip1 and p21cip1 expression. Multiple molecular pathways are likely differentially targeted by selenium metabolite pools to mediate cancer chemoprevention.
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PMID:Distinct effects of methylseleninic acid versus selenite on apoptosis, cell cycle, and protein kinase pathways in DU145 human prostate cancer cells. 1248 29

Low levels of hepatic selenium (Se)-dependent glutathione peroxidase 1 (GPX1) activity have been shown to protect against oxidative liver injury in Se-deficient mice. The objective of the present study was to determine if the GPX1 protection was associated with phosphorylations of c-Jun N-terminal kinase (JNK) and p53 on Ser-15, two key signalling events in oxidative-stress-mediated cell death. Both Se-deficient GPX1 knockout (GPX1(-/-)) and wild-type (WT) mice ( n =64) were pretreated with an intraperitoneal injection of Se (as sodium selenite, 50 microg/kg body weight) 6 h before an intraperitoneal injection of paraquat (12.5 mg/kg). Liver aponecrosis, a mixed form of cell death sharing apoptosis and necrosis, was induced by paraquat in both groups of mice. However, its appearance was remarkably delayed and the severity was decreased by the repletion of hepatic GPX1 activity to <4% of the normal level by the Se injection in the WT mice, compared with that in the GPX1(-/-) mice. Consistently, the WT mice had lower levels of hepatic phospho-JNK, p53 and phospho-p53 (Ser-15) when compared with the GPX1(-/-) mice at 1-10 h after paraquat injection. Incubating liver homogenates with antibodies raised against JNK or phospho-JNK resulted in co-immunoprecipitation of phospho-p53 (Ser-15), and the amounts of the precipitated phospho-p53 were greater in the GPX1(-/-) mice when compared with that in the WT mice. The co-precipitated complex by the anti-phospho-JNK antibody was capable of phosphorylating intrinsic or extrinsic p53 on Ser-15. In conclusion, phospho-JNK may catalyse phosphorylation of p53 on Ser-15 in Se-deficient mouse liver under moderate oxidative stress, and attenuation of that cascade by low levels of GPX1 activity is associated with its protection against the pro-oxidant-induced liver aponecrosis.
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PMID:Low levels of glutathione peroxidase 1 activity in selenium-deficient mouse liver affect c-Jun N-terminal kinase activation and p53 phosphorylation on Ser-15 in pro-oxidant-induced aponecrosis. 1249


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