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)

The ATF-2 transcription factor can mediate adenovirus E1A-inducible transcriptional activation. Deletion analysis has indicated that the N-terminal region of ATF-2 is essential for this response. Furthermore, the N-terminus can activate transcription in the absence of E1A when fused to a heterologous DNA binding domain. However, in the intact protein this activation domain is masked. In this report we show that residues in the N-terminus required for activation are also required for mediating E1A stimulation. In particular two threonine residues at positions 69 and 71 are essential. These residues are phosphorylated in vivo and can be efficiently phosphorylated in vitro by the JNK/SAPK subgroup of the MAPK family. ATF-2 can bind to a UV-inducible kinase through a region in the N-terminus that is distinct from the sites of phosphorylation; this binding region is both necessary for phosphorylation by JNK/SAPK in vitro and for transcriptional activation in vivo. The activity of the N-terminus is stimulated by UV irradiation which stimulates the signalling pathway leading to JNK/SAPK. Finally, although ATF-2 binds to the E1A protein, the N-terminal activation domain is not required for this interaction. The results show that ATF-2, like other members of the ATF/CREB family of DNA binding proteins is regulated by specific signalling pathways.
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PMID:ATF-2 contains a phosphorylation-dependent transcriptional activation domain. 773 29

Glycogen synthase kinase-3 (GSK3) is implicated in the regulation of several physiological processes, including the control of glycogen and protein synthesis by insulin, modulation of the transcription factors AP-1 and CREB, the specification of cell fate in Drosophila and dorsoventral patterning in Xenopus embryos. GSK3 is inhibited by serine phosphorylation in response to insulin or growth factors and in vitro by either MAP kinase-activated protein (MAPKAP) kinase-1 (also known as p90rsk) or p70 ribosomal S6 kinase (p70S6k). Here we show, however, that agents which prevent the activation of both MAPKAP kinase-1 and p70S6k by insulin in vivo do not block the phosphorylation and inhibition of GSK3. Another insulin-stimulated protein kinase inactivates GSK3 under these conditions, and we demonstrate that it is the product of the proto-oncogene protein kinase B (PKB, also known as Akt/RAC). Like the inhibition of GSK3 (refs 10, 14), the activation of PKB is prevented by inhibitors of phosphatidylinositol (PI) 3-kinase.
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PMID:Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. 852 13

The transcription factors controlling the complex genetic response to ischemia and their modes of regulation are poorly understood. We found that ATF-2 and c-Jun DNA binding activity is markedly enhanced in post-ischemic kidney or in LLC-PK1 renal tubular epithelial cells exposed to reversible ATP depletion. After 40 min of renal ischemia followed by reperfusion for as little as 5 min, binding of ATF-2 and c-Jun, but not ATF-3 or CREB (cAMP response element binding protein), to oligonucleotides containing either an ATF/cAMP response element (ATF/CRE) or the jun2TRE from the c-jun promoter, was significantly increased. Binding to jun2TRE and ATF/CRE oligonucleotides occurred with an identical time course. In contrast, nuclear protein binding to an oligonucleotide containing a canonical AP-1 element was not detected until 40 min of reperfusion, and although c-Jun was present in the complex, ATF-2 was not. Incubating nuclear extracts from reperfused kidney with protein phosphatase 2A markedly reduced binding to both the ATF/CRE and jun2TRE oligonucleotides, compatible with regulation by an ATF-2 kinase. An ATF-2 kinase, which phosphorylated both the transactivation and DNA binding domains of ATF-2, was activated by reversible ATP depletion. This kinase coeluted on Mono Q column chromatography with a c-Jun amino-terminal kinase and with the peak of stress-activated protein kinase, but not p38, immunoreactivity. In conclusion, DNA binding activity of ATF-2 directed at both ATF/CRE and jun2TRE motifs is modulated in response to the extreme cellular stress of ischemia and reperfusion or reversible ATP depletion. Phosphorylation-dependent activation of the DNA binding activity of ATF-2, which appears to be regulated by the stress-activated protein kinases, may play an important role in the earliest stages of the genetic response to ischemia/reperfusion by targeting ATF-2 and c-Jun to specific promoters, including the c-jun promoter and those containing ATF/CREs.
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PMID:Ischemia and reperfusion enhance ATF-2 and c-Jun binding to cAMP response elements and to an AP-1 binding site from the c-jun promoter. 853 Apr 13

ATF3 gene, which encodes a member of the activating transcription factor/cAMP responsive element binding protein (ATF/CREB) family of transcription factors, is induced by many physiological stresses. As a step toward understanding the induction mechanisms, we isolated the human ATF3 gene and analyzed its genome organization and 5'-flanking region. We found that the human ATF3 mRNA is derived from four exons distributed over 15 kilobases. Sequence analysis of the 5'-flanking region revealed a consensus TATA box and a number of transcription factor binding sites including the AP-1, ATF/CRE, NF-kappa B, E2F, and Myc/Max binding sites. As another approach to understanding the mechanisms by which the ATF3 gene is induced by stress signals, we studied the regulation of the ATF3 gene in tissue culture cells by anisomycin, an approach that has been used to study the stress responses in tissue culture cells. We showed that anisomycin at a low concentration activates the ATF3 promoter and stabilizes the ATF3 mRNA. Significantly, co-transfection of DNAs expressing ATF2 and c-Jun activates the ATF3 promoter. A possible mechanism implicating the C-Jun NH2-terminal kinase/stress-activated protein kinase (JNK/SAPK) stress-inducible signaling pathway in the induction of the ATF3 gene is discussed.
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PMID:ATF3 gene. Genomic organization, promoter, and regulation. 857 71

We have evaluated the signaling pathways activated by parathyroid hormone (PTH) in SaOS2 human osteoblastlike cells correlating with induction of the c-fos proto-oncogene. Human PTH(1-34) (hPTH[1-34]) and hPTH(1-34) Nle8,18 Tyr34 induced the expression of c-fos mRNA in quiescent SaOS2 cells in a concentration-dependent manner. N-terminal truncations of hPTH(1-34) that fail to activate protein kinase A (PKA) also abolished c-fos mRNA induction. In gel retardation assays hPTH(1-34) led to a change in the mobility of specific, cyclic adenosine monophosphate (cAMP) response element binding protein (CREB)-containing protein-DNA complexes identical to that caused by other activators of PKA. The appearance of this altered mobility complex correlated temporally with the induction of c-fos mRNA. Using a c-fos serum response element probe, a slowed protein DNA complex appeared upon serum, epidermal growth factor, and basic fibroblast growth factor treatment. This slowed complex reflects phosphorylation of the transcription factor ternary complex factor (TCF) mediated via activation of the mitogen-activated protein (MAP) kinase pathway. The MAP kinase cascade is also activated by protein kinase C (PKC), and treatment with phorbol ester led to the induced TCF shift. In contrast, PTH did not produce this shift, ruling out PTH activation of c-fos via PKC and the MAP kinase signaling cascade. Further evidence for this was the lack of effect of the highly selective PKC inhibitor CGP 41251 on c-fos induction by hPTH(1-34). The janus kinase (JAK)/signal transducers and activators of transcription (STAT) signaling cascade targets the v-sis-inducible element in the c-fos promoter via the induced binding of STATs. Interferon gamma rapidly induced STAT binding in SaOS2 cells, unlike PTH. Thus, PTH induction of c-fos transcription appears to occur principally through activation of PKA that then targets CREB and the c-fos calcium/cAMP response element.
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PMID:Analysis of signaling pathways used by parathyroid hormone to activate the c-fos gene in human SaOS2 osteoblast-like cells. 885 42

Fibroblast growth factor (FGF) activates a protein kinase cascade in SK-N-MC cells that regulates gene expression at a cyclic-AMP response element (CRE) by stimulating the transcriptional activity of CREB. The activation of CREB is prevented by a dominant negative mutant of Ras and triggered via the same site (Ser133) that becomes phosphorylated in response to cyclic AMP and Ca2+. However, the effect of FGF is not mediated by cyclic AMP-dependent protein kinase, TPA-sensitive isoforms of protein kinase-C, p70S6K or p90rsk (all of which phosphorylate CREB at Ser133 in vitro). Instead, we identify the FGF-stimulated CREB kinase as MAP kinase-activated protein (MAPKAP) kinase-2, an enzyme that lies immediately downstream of p38 MAP kinase, in a pathway that is also stimulated by cellular stresses. We show that MAPKAP kinase-2 phosphorylates CREB at Ser133 in vitro, that the FGF- or stress-induced activation of MAPKAP kinase-2 and phosphorylation of CREB and ATF-1 are prevented by similar concentrations of the specific p38 MAP kinase inhibitor SB 203580, and that MAPKAP kinase-2 is the only detectable SB 203580-sensitive CREB kinase in SK-N-MC cell extracts. We also show that transfection of RK/p38 MAP kinase in SK-N-MC cells, but not transfection of p44 MAP kinase, activates Gal4-CREB-dependent transcription via Ser133. These findings identify a new growth factor and stress-activated signaling pathway that regulates gene expression at the CRE.
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PMID:FGF and stress regulate CREB and ATF-1 via a pathway involving p38 MAP kinase and MAPKAP kinase-2. 888 54

The deposition of amyloid beta protein (A beta) in the cerebral cortex is the pathological characteristic of Alzheimer's disease (AD), and patients with AD suffer from progressive memory loss. Transgenic experiments have revealed that long-term memory is dependent on cyclic AMP-response element binding protein, CREB. CREB phosphorylation at serine-133 is essential for its transcriptional activity. Here we demonstrated that A beta(1-40), at a concentration more than 1 microM, induced CREB phosphorylation at serine-133 in rat pheochromocytoma PC12 cells. A beta(1-40) induced phosphorylation of p44 and p42 MAP kinases (Erk1 and Erk2) at tyrosine-204, and PD98059, a MEK1 inhibitor, inhibited A beta(1-40)-induced CREB phosphorylation at serine-133. We conclude that elevated A beta(1-40) level induces CREB phosphorylation at serine-133 via p44/42 MAP kinase-dependent pathway.
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PMID:Elevated amyloid beta protein(1-40) level induces CREB phosphorylation at serine-133 via p44/42 MAP kinase (Erk1/2)-dependent pathway in rat pheochromocytoma PC12 cells. 912 27

ERK2 (extracellular-signal regulated kinase 2, also known as p42 mitogen-activated protein kinase) is an integral member of the mitogen-activated protein kinase cascade that is crucial for many cellular events such as proliferation and differentiation. Here, we determined the genomic organization of the Erk2 gene and characterized its promoter. The Erk2 gene spans over 60 kilobases, and the coding region is split into eight exons. In the coding region, exon-intron organization was exactly conserved between the two mouse genes for ERK2 and ERK1 except one junction shifted by one nucleotide. Primer extension and S1 nuclease analyses identified two major transcription start sites located at -219 and -223 relative to the translation start site. The 5'-flanking sequence lacked TATA box but contained a CCAAT box located approximately 60 base pairs upstream of transcription start sites. Sequencing of the 5'-flanking region also revealed potential cis-acting elements for multiple transcriptional regulatory factors including Sp1, zif268, Ets, CREB, and PuF sites. The promoter activity of the 5'-flanking region was examined using chloramphenicol acetyltransferase as a reporter gene. Transient transfection experiments using Chinese hamster ovary cells defined a maximal promoter activity in a 371-base pair region immediately upstream of the translation start site. Furthermore, we demonstrated, using mouse P19 embryonal carcinoma cells, that this 371-base pair sequence is likely to be sufficient to confer the transcriptional activation of the ERK2 promoter during the retinoic acid-induced differentiation of P19 cells.
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PMID:The mouse extracellular signal-regulated kinase 2 gene. Gene structure and characterization of the promoter. 926 Nov 78

Expression of the c-fos proto-oncogene is induced by numerous stimuli some of which are transmitted through the Ras/Raf/MAP kinase or the cAMP-dependent protein kinase (PKA) pathways. The effect of cell-specific interactions between these pathways on c-fos expression was investigated by exposing quiescent NIH3T3 cells to serum, forskolin, or a combination. Co-stimulation with serum and forskolin resulted in a more than additive increase in c-fos transcription. Synergistic increase in c-fos promoter activity was also observed in transient transfection studies after co-stimulation with serum plus forskolin or co-transfection with c-Raf and PKA expression plasmids. Analysis of the cAMP signaling pathway revealed that the synergy was neither due to an increase in PKA activity nor to Ser-133 phosphorylation/activation of CREB. The activation status of the MAP kinases ERK1 and ERK2 in co-treated cells was comparable to that in serum-treated cells. Co-stimulation with forskolin did not alter the phosphorylation state of Elk-1 compared to serum-induced phosphorylation of Elk-1. Deletion of c-fos promoter elements previously shown to be important for regulation of c-fos expression in response to mitogens indicates a role for SRE and FAP-1 elements.
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PMID:Synergistic increase in c-fos expression by simultaneous activation of the ras/raf/map kinase- and protein kinase A signaling pathways is mediated by the c-fos AP-1 and SRE sites. 951 70

The mechanisms by which growth factor-induced signals are propagated to the nucleus, leading to the activation of the transcription factor CREB, have been characterized. Nerve growth factor (NGF) was found to activate multiple signaling pathways that mediate the phosphorylation of CREB at the critical regulatory site, serine 133 (Ser-133). NGF activates the extracellular signal-regulated kinase (ERK) mitogen-activated protein kinases (MAPKs), which in turn activate the pp90 ribosomal S6 kinase (RSK) family of Ser/Thr kinases, all three members of which were found to catalyze CREB Ser-133 phosphorylation in vitro and in vivo. In addition to the ERK/RSK pathway, we found that NGF activated the p38 MAPK and its downstream effector, MAPK-activated protein kinase 2 (MAPKAP kinase 2), resulting in phosphorylation of CREB at Ser-133. Inhibition of either the ERK/RSK or the p38/MAPKAP kinase 2 pathway only partially blocked NGF-induced CREB Ser-133 phosphorylation, suggesting that either pathway alone is sufficient for coupling the NGF signal to CREB activation. However, inhibition of both the ERK/RSK and the p38/MAPKAP kinase 2 pathways completely abolished NGF-induced CREB Ser-133 phosphorylation. These findings indicate that NGF activates two distinct MAPK pathways, both of which contribute to the phosphorylation of the transcription factor CREB and the activation of immediate-early genes.
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PMID:Nerve growth factor activates extracellular signal-regulated kinase and p38 mitogen-activated protein kinase pathways to stimulate CREB serine 133 phosphorylation. 952 66


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