Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Irradiation of mammalian cells with short wavelength ultraviolet light (UVC) evokes a cascade of phosphorylation events leading to altered gene expression. Both the classic mitogen-activated protein (MAP) kinases and the distantly related c-Jun N-terminal kinases (JNK) contribute to the response via phosphorylation of transcription factors including AP-1. These kinases are themselves regulated via reversible phosphorylation, and several recently identified specific MAP kinase phosphatases (MKP) have been implicated in down-regulating MAP kinase-dependent gene expression in response to mitogens. Here, we provide evidence that MKP-1 plays a role in regulating transcriptional activation in response to UVC as well as another genotoxic agent, methyl methanesulfonate (MMS). We further demonstrate that JNK is a likely target for MKP-1. JNK is shown to be activated by UVC and MMS treatment, while MAP kinase activation occurs only with UVC. Like JNK activation, MKP-1 mRNA is induced by both treatments, and elevated MKP-1 expression coincides with a decline in JNK activity. Constitutive expression of MKP-1 in vivo inhibits JNK activity and reduces UVC- and MMS-induced activation of AP-1-dependent reporter genes.
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PMID:Role of mitogen-activated protein kinase phosphatase during the cellular response to genotoxic stress. Inhibition of c-Jun N-terminal kinase activity and AP-1-dependent gene activation. 772 28

The p38 mitogen-activated protein (MAP) kinase defines a subgroup of the mammalian MAP kinases that are induced in response to lipopolysaccharide, hyperosmolarity, and interleukin 1. p38 MAP kinase appears to play a role in regulating inflammatory responses, including cytokine secretion and apoptosis. Here we show that diverse classes of DNA-damaging agents such as cisplatinum, 1-beta-D-arabinofuranosylcytosine, UV light, ionizing radiation, and methyl methanesulfonate activate p38 MAP kinase. We also demonstrate that cells deficient in c-Abl fail to activate p38 MAP kinase after treatment with cisplatinum and 1-beta-D-arabinofuranosylcytosine but not after exposure to UV and methyl methanesulfonate. Reconstitution of c-Abl in the Abl-/- cells restores that response. Similar results were obtained for induction of the Jun-NH2-kinase/stress-activated protein kinase. These findings indicate that p38 MAP and Jun-NH2-kinase/stress-activated protein kinases are differentially regulated in response to different classes of DNA-damaging agents.
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PMID:Activation of p38 mitogen-activated protein kinase by c-Abl-dependent and -independent mechanisms. 879 4

The stress-activated protein kinases (SAPKs), c-Jun NH(2)-terminal kinases (JNKs) and p38 mitogen-activated protein kinases, were evaluated in the liver and brain of young and old rats in response to a direct-acting alkylating agent, methyl methanesulfonate (MMS). A slight but statistically significant increase in the baseline expression levels of JNK isoforms was detected in both the liver and brain of old as compared with young rats. In the liver of both young and old rats, no basal activities of JNKs were detected. In the brain, JNK activities were constitutively high and significantly increased in old rats compared with their young counterparts. Upon MMS treatment, JNKs were strongly activated in the liver, but not in the brain, of both young and old animals. The basal activity of p38 significantly increased in both the liver and brain of old rats as compared with young rats. An increase in the basal expression of p38 was detected in the brain but not in the liver of old rats. Upon treatment with MMS, p38 was activated in the liver of both young and old rats. In the brain, p38 was only activated in young but not in old rats. Taken together, these results demonstrate age-specific as well as organ-specific SAPKs signaling pathways in the rat in vivo. The possible implications of these findings in terms of resistance to endogenous and environmentally induced genotoxic stress during aging are discussed.
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PMID:Age-specific changes in expression, activity, and activation of the c-Jun NH(2)-terminal kinase and p38 mitogen-activated protein kinases by methyl methanesulfonate in rats. 1155 81

Alterations in apoptotic potential, due to perturbations in cell signaling cascades, could underlie age-related organ-specific cellular degeneration and death. While increased apoptosis could lead to cell loss, as in neuronal degeneration, loss of apoptosis competence might well result in the loss of phenotypic fidelity of somatic cells, which could explain to some extent, the age-related increase in cancer incidence. Results from our laboratory indicate that after subjecting young and old rats to genotoxic stress in the form of methyl methanesulfonate (MMS), an apoptotic response is quickly mounted in the liver of the young animals but virtually absent in the same organ of old animals (Nature Med. 8 (2002) 3). To address the possible molecular signaling defect(s) responsible for the age-related dysfunction of apoptosis in response to MMS, mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinases (ERKs), c-Jun NH(2)-terminal kinases (JNKs) and p38 MAPKs, were evaluated in the liver of young and old rats after MMS treatment. The results demonstrated distinct age-specific patterns of MMS-induced MAPKs activation, suggesting that the balance between cell survival and apoptosis after genotoxic stress may be impaired during aging. These results are discussed in terms of the relative importance in aging of biological redundancy, a concept put forward by the late Bernard Strehler, and cellular fidelity.
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PMID:Cell signaling in aging and apoptosis. 1204 36

In Ewing's sarcomas, chromosomal translocations cause the N-terminal domain of the EWS (Ewing's sarcoma protein) to fuse with the DNA-binding domains of the Ets (E26 transformation-specific) family of transcription factors. Here we show that EWS and EWS-Fli1 (Friend leukaemia virus integration 1), the fusion most frequently found in Ewing's sarcomas, become phosphorylated at Thr(79) in response to either mitogens or DNA-damaging agents. The much weaker mitogen-induced phosphorylation of EWS is catalysed by the MAPKs (mitogen-activated protein kinases) ERK1 (extracellular signal-regulated kinase 1) and ERK2, whereas the much stronger phosphorylation of EWS induced by the DNA alkylating agent MMS (methyl methanesulphonate) can be catalysed by JNK (c-Jun N-terminal kinase) and at least one other protein kinase distinct from ERK1/ERK2. In contrast, the phosphorylation of EWS-Fli1 induced by MMS was largely mediated by p38alpha/p38beta MAPKs. MMS induced a much stronger phosphorylation of EWS-Fli1 than EWS in heterodimers comprising both proteins.
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PMID:Phosphorylation of Ewing's sarcoma protein (EWS) and EWS-Fli1 in response to DNA damage. 1907 70