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)

The Schizosaccharomyces pombe stress-activated Sty1p/Spc1p mitogen-activated protein (MAP) kinase regulates gene expression through the Atf1p and Pap1p transcription factors, homologs of human ATF2 and c-Jun, respectively. Mcs4p, a response regulator protein, acts upstream of Sty1p by binding the Wak1p/Wis4p MAP kinase kinase kinase. We show that phosphorylation of Mcs4p on a conserved aspartic acid residue is required for activation of Sty1p only in response to peroxide stress. Mcs4p acts in a conserved phospho-relay system initiated by two PAS/PAC domain-containing histidine kinases, Mak2p and Mak3p. In the absence of Mak2p or Mak3p, Sty1p fails to phosphorylate the Atf1p transcription factor or induce Atf1p-dependent gene expression. As a consequence, cells lacking Mak2p and Mak3p are sensitive to peroxide attack in the absence of Prr1p, a distinct response regulator protein that functions in association with Pap1p. The Mak1p histidine kinase, which also contains PAS/PAC repeats, does not regulate Sty1p or Atf1p but is partially required for Pap1p- and Prr1p-dependent transcription. We conclude that the transcriptional response to free radical attack is initiated by at least two distinct phospho-relay pathways in fission yeast.
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PMID:Peroxide sensors for the fission yeast stress-activated mitogen-activated protein kinase pathway. 1117 24

Smad7 transcription is known to be regulated by TGF-beta to form a negative-feedback loop of TGF-beta-mediated biological responses. In this study, we sought to determine whether other signaling cascades, especially mitogen-activated protein (MAP) kinases, might be involved in the transcriptional regulation of Smad7. Hyperosmolarity (500 mOsm/kg H(2)O) or anisomycin (10 microg/ml) potentiated TGF-beta-induced increases of Smad7 mRNA abundance in normal rat kidney fibroblasts. SB203580 (10 microM) treatment had no effect on basal and TGF-beta-induced Smad7 mRNA abundance, and the overexpression of kinase-negative ATF2 had no effect on Smad7 promoter activity. On the other hand, overexpression of dominant-negative JNK and dominant-negative c-Jun significantly attenuated the TGF-beta-induced increases of Smad7 mRNA abundance and promoter activity, respectively. Mutations of the AP-1 element near the Smad-binding element in the rat Smad7 promoter also completely abolished TGF-beta-induced Smad7 promoter activity. These results suggested that the JNK cascade, not p38 kinase, cooperated with the Smad signaling to induce Smad7 transcription through the AP-1 element. Serum treatment (10%) attenuated the TGF-beta-induced Smad7 mRNA increase, and PD98059 (30 microM) treatment increased the basal and TGF-beta-induced Smad7 promoter activity. Gel shift analysis revealed that serum treatment decreased the amount of nuclear Smad complex that PD98059 treatment was shown to restore. These results indicated that ERK activation negatively regulated Smad7 transcription possibly by inhibiting translocation of Smad complex to nuclei. In conclusion, JNK cascade and ERK cascade are important positive and negative regulators of Smad7 transcription, respectively.
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PMID:Involvement of MAP kinase cascades in Smad7 transcriptional regulation. 1171 83

The c-Jun N-terminal kinases (JNKs) are a subfamily of the mitogen-activated protein kinases (MAPKs). Although progress in evaluating the functions of other MAPKs has been facilitated by the characterization of specific inhibitors, no JNK-directed inhibitor is commercially available. We have identified a 21-amino acid peptide inhibitor of activated JNKs, based on amino acids 143-163 of the JNK-binding domain (JBD) of the JNK scaffolding protein, JNK-interacting protein-1 (JIP-1). This peptide, I-JIP (Inhibitor of JNK-based on JIP-1), inhibited JNK activity in vitro toward recombinant c-Jun, Elk, and ATF2 up to 90%. A truncated I-JIP (TI-JIP), the C-terminal 11 amino acids of I-JIP, directly interacted with recombinant JNKs but not its substrates as shown by surface plasmon resonance analysis. Scanning alanine replacement within truncated I-JIP identified 4 residues (Arg-156, Pro-157, Leu-160, or Leu-162) as independently critical for inhibition. JBD peptide sequences from JIP-2 and JIP-3 shared these critical residues and accordingly were effective JNK inhibitors. In contrast, peptides based on the JBDs of ATF2 and c-Jun inhibited JNK activity by <40%, which agreed with their lack of homology to the critical Arg-156 and Pro-157. These studies thus define a small peptide inhibitor sequence of JNKs based on the JIP proteins.
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PMID:Identification of the critical features of a small peptide inhibitor of JNK activity. 1179 Jul 67

Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase activated by collagen. DDR1 is constitutively expressed in a variety of normal and transformed epithelial cells and plays a role in cell migration and differentiation through as yet unidentified signaling pathways. We previously reported inducible expression of DDR1 in human leukocytes and suggested a role for the DDR1a isoform in leukocyte migration through extracellular matrix. Here, we evaluated the contribution of DDR1 in the differentiation of the human monocytic THP-1 cells overexpressing these isoforms and of primary macrophages. Interestingly, collagen activation of DDR1b, but not DDR1a, further promoted phorbol ester-induced differentiation of THP-1 cells as determined by reduced cell proliferation and up-regulated expression of HLA-DR, CD11c, CD14, and CD40. Collagen activation of DDR1b also induced the recruitment and phosphorylation of Shc and subsequent phosphorylation of p38 mitogen-activated protein (MAP) kinase and its substrate ATF2. A p38 MAP kinase inhibitor, SB203580, completely inhibited DDR1b-mediated HLA-DR expression. Activation of DDR1 endogenously expressed on macrophages also up-regulated their HLA-DR expression in a p38 MAP kinase-dependent manner. Thus, DDR1b in response to collagen transduces signals that promote maturation/differentiation of HLA-DR-positive antigen-presenting cells and contributes to the development of adaptive immunity in a tissue microenvironment.
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PMID:Interaction of discoidin domain receptor 1 isoform b (DDR1b) with collagen activates p38 mitogen-activated protein kinase and promotes differentiation of macrophages. 1972 Jun 26

ATF2 and c-Jun are key components of activating protein-1 and function as homodimers or heterodimers. c-Jun-ATF2 heterodimers activate the expression of many target genes, including c-jun, in response to a variety of cellular and environmental signals. Although it has been believed that c-Jun and ATF2 are constitutively localized in the nucleus, where they are phosphorylated and activated by mitogen-activated protein kinases, the molecular mechanisms underlying the regulation of their transcriptional activities remain to be defined. Here we show that ATF2 possesses a nuclear export signal in its leucine zipper region and two nuclear localization signals in its basic region, resulting in continuous shuttling between the cytoplasm and the nucleus. Dimerization with c-Jun in the nucleus prevents the export of ATF2 and is essential for the transcriptional activation of the c-jun promoter. Importantly, c-Jun-dependent nuclear localization of ATF2 occurs during retinoic acid-induced differentiation and UV-induced cell death in F9 cells. Together, these findings demonstrate that ATF2 and c-Jun mutually regulate each other by altering the dynamics of subcellular localization and by positively impacting transcriptional activity.
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PMID:Mutual regulation of c-Jun and ATF2 by transcriptional activation and subcellular localization. 1651 68

One of the most important challenges that cardiomyocytes experience is an increase in the levels of reactive oxygen species (ROS), i.e., during ischemia, reperfusion as well as in the failing myocardium. HOX-1 has been found to protect cells and tissues against oxidative damage; therefore, we decided to study the signalling cascades involved in its transcriptional regulation. HOX-1 mRNA levels were found to be maximally induced after 6h of treatment with 200 microM H2O2 and remained elevated for at least 24h. Inhibition of JNKs, p38-MAPK and MSK1 pathways, by pharmacological inhibitors, reduced HOX-1 mRNA levels in H2O2-treated H9c2 cells. In parallel, we observed that all three subfamilies of the mitogen-activated protein kinases (MAPKs) attained their maximal phosphorylation levels at 5-15 min of H2O2 treatment, with mitogen- and stress-activated-protein kinase 1 (MSK1) also being maximally phosphorylated at 15 min. H2O2-induced MSK1 phosphorylation was completely abrogated in the presence of the selective p38-MAPK inhibitor SB203580. In an effort to define possible substrates of MSK1, we found that ATF2 as well as cJun phosphorylation were equally induced after 30 min and 60 min, respectively, a response inhibited by SP600125 (JNKs inhibitor) and H89 (MSK1 inhibitor), indicating the involvement of these kinases in the observed response. This finding was further substantiated with the detection of a potential signalling complex composed of either p-MSK1 and p-cJun or p-MSK1 and p-ATF2 (co-immunoprecipitation). ATF2 and cJun are known AP1 components. Given the presence of an AP-1 site in HOX-1 promoter region, the activity of AP1 transcription factor was examined. Electrophoretic mobility shift assays performed showed a maximal upregulation of AP1 binding activity after 60 min of H2O2 treatment, which was significantly inhibited by SP600125 and H89. Our results show for the first time the potential role of JNKs, p38-MAPK and MSK1 in the mechanism of transducing the oxidative stress-signal to HOX-1, possibly promoting cell survival and preserving homeostasis.
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PMID:Involvement of JNKs and p38-MAPK/MSK1 pathways in H2O2-induced upregulation of heme oxygenase-1 mRNA in H9c2 cells. 1653 Oct 7

A sequence of intermittent interruptions of oxygen supply (i.e., postconditioning, Postcon) at reoxygenation reduces oxidant-induced cardiomyocyte loss. This study tested the hypothesis that prevention of cardiomyocyte apoptosis by Postcon is mediated by mitogen-activated protein kinases pathways. Primary cultured neonatal rat cardiomyocytes were exposed to 3 h hypoxia followed by 6 h of reoxygenation. Cardiomyocytes were postconditioned by three cycles each of 5 min reoxygenation and 5 min hypoxia after prolonged hypoxia. Relative to hypoxia alone, reoxygenation stimulated expression of JNKs and p38 kinases, corresponding to increased activity of JNKs (phospho-c-Jun) and p38 (phospho-ATF2). The level of TNFalpha in cell lysates, activity of cytosolic caspases-8, -3, expression of Bax and the number of apoptotic cardiomyocytes were increased while expression of Bcl-2 was decreased with reoxygenation. Consistent with an attenuation in generation of superoxide anions detected by lucigenin-enhanced chemiluminescence at early period of reoxygenation, treatment of cardiomyocytes with Postcon further reduced expression and activity of JNKs and p38 kinases, level of TNFalpha, the frequency of apoptotic cells and expression of Bax. However, the inhibitory effects of Postcon on these changes were lost when its application was delayed by 5 min after the start of reoxygenation. Addition of a JNK/p38 stimulator, anisomycin into cardiomyocytes at the beginning of reoxygenation eliminated protection by Postcon. These data suggest that 1) hypoxia/reoxygenation elicits cardiomyocyte apoptosis in conjunction with expression and activation of JNK and p38 kinases, release of TNFalpha, activation of caspases, and an increase in imbalance of pro-/anti-apoptotic proteins; 2) Postcon attenuates cardiomyocyte apoptosis, potentially mediated by inhibiting JNKs/p-38 signaling pathways and reducing TNFalpha release and caspase expression.
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PMID:Postconditioning attenuates cardiomyocyte apoptosis via inhibition of JNK and p38 mitogen-activated protein kinase signaling pathways. 1682 Sep 62

HTLV-1 Tax oncoprotein induces persistent activation of the transcription factor NF-kappaB and CREB (cAMP-response element-binding protein)/ATF. Transforming growth factor-beta-activated kinase 1 (TAK1) has been shown to play a critical role in these transcription factors. Here, we found that TAK1 was constitutively activated in Tax-positive HTLV-1-transformed T cells. Tax induced persistent overexpression of TAK1-binding protein 2 (TAB2), but not TAB3, which is essential for TAK1 activation. Surprisingly, TAK1 was not involved in the activation of NF-kappaB. On the other hand, JNK and p38 mitogen-activated protein kinases were activated by TAK1. In addition, ATF2, but not CREB, was a target for the TAK1-JNK pathway, and p38 negatively regulated TAK1 activity through TAB1 phosphorylation. These results indicate that Tax-mediated TAK1 activation is important for the activation of ATF2 rather than NF-kappaB.
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PMID:Constitutive activation of TAK1 by HTLV-1 tax-dependent overexpression of TAB2 induces activation of JNK-ATF2 but not IKK-NF-kappaB. 1762 13

The ATF2 transcription factor is phosphorylated by the stress-activated mitogen-activated protein kinases (MAPKs) JNK and p38. We show that this phosphorylation is essential for ATF2 function in vivo, since a mouse carrying mutations in the critical phosphorylation sites has a strong phenotype identical to that seen upon deletion of the DNA-binding domain. In addition, combining this mutant with a knockout of the ATF2 homolog, ATF7, results in embryonic lethality with severe abnormalities in the developing liver and heart. The mutant fetal liver is characterized by high levels of apoptosis in developing hepatocytes and haematopoietic cells. Furthermore, we observe a significant increase in active p38 due to loss of a negative feedback loop involving the ATF2-dependent transcriptional activation of MAPK phosphatases. In embryonic liver cells, this increase drives apoptosis, since it can be suppressed by chemical inhibition of p38. Our findings demonstrate the importance of finely regulating the activities of MAPKs during development.
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PMID:Feedback regulation of p38 activity via ATF2 is essential for survival of embryonic liver cells. 1769 53

Neonatal encephalopathy with seizures (NEWS) is a previously undescribed autosomal recessive disease of standard poodle puppies. Affected puppies are small and weak at birth. Many die in their first week of life. Those surviving past 1 week develop ataxia, a whole-body tremor, and, by 4 to 6 weeks of age, severe generalized clonic-tonic seizures. None have survived to 7 weeks of age. Cerebella from affected puppies were reduced in size and often contained dysplastic foci consisting of clusters of intermixed granule and Purkinje neurons. We used deoxyribonucleic acid samples from related standard poodles to map the NEWS locus to a 2.87-Mb segment of CFA36, which contains the canine ortholog of ATF2. This gene encodes activating transcription factor 2 (ATF-2), which participates in the cellular responses to a wide variety of stimuli. We amplified and sequenced all coding regions of canine ATF2 from a NEWS-affected puppy and identified a T > G transversion that predicts a methionine-to-arginine missense mutation at amino acid position 51. Methionine-51 lies within a hydrophobic docking site for mitogen-activated protein kinases that activate ATF-2 so the arginine substitution is likely to interfere with ATF-2 activation. All 20 NEWS-affected puppies in the standard poodle family were homozygous for the mutant G allele. The 58 clinically normal family members were either G/T heterozygotes or homozygous for the ancestral T allele. There are no previous reports of spontaneous ATF2 mutations in people or animals; however, atf2-knockout mice have cerebellar lesions that are similar to those in puppies with NEWS.
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PMID:A neonatal encephalopathy with seizures in standard poodle dogs with a missense mutation in the canine ortholog of ATF2. 1807 59


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