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

The present studies have characterized the regulation of interleukin-6 (IL-6) gene expression during pokeweed mitogen (PWM)-driven human B-cell differentiation. PWM induced an early and transient increase in the expression of immediate-early response genes of the jun/fos leucine zipper family (c-jun, jun B, c-fos, and fos-B). The induction of c-jun mRNA by PWM was concentration dependent. Nuclear run-on assays showed that PWM treatment is associated with an increased rate of c-jun gene transcription. The induction of c-jun mRNA precedes the induction of IL-6 gene expression and IL-6 secretion by the B cells. c-Jun antisense, but not sense, oligodeoxynucleotide (ODN) significantly decreases PWM-related B-cell (1) proliferation; (2) IL-6 mRNA induction; (3) IL-6 secretion; and (4) nuclear extract binding to AP-1 in electrophoretic mobility shift assay. In contrast, c-Fos anti-sense ODN did not effect either IL-6 mRNA induction or IL-6 secretion triggered in B cells by PWM. The results further show activation of c-Raf-1 kinase in PWM-treated B cells. Raf-1 acts upstream to mitogen-activated protein (MAP) kinase; therefore, studies were performed to assay for MAP kinase activation in these cells. The results show an increase in phosphorylation of myelin basic protein (MBP) and c-Jun "Y" peptide in PWM-treated B cells. Taken together, these findings suggest that PWM is able to initiate an intracytoplasmic signaling cascade in normal human splenic B cells, which, at least in part, involves serine/threonine protein kinases. These results show transient induction of immediate-early response genes in B cells and support a potential role for the c-jun gene product in regulation of IL-6 transcription and secretion.
 ...
PMID:Identification of upstream signals regulating interleukin-6 gene expression during in vitro treatment of human B cells with pokeweed mitogen. 791 42

NF-IL6, a member of the basic leucine zipper (bZIP) family transcription factors, is involved in expression of inducible genes involved in immune and inflammatory responses. We observed that coexpression of oncogenic p21ras stimulated the transactivating activity of NF-IL6 and induced phosphorylation of Thr-235 located just N-terminal to the DNA binding domain of NF-IL6. Recently, mitogen-activated protein (MAP) kinases have been shown to be implicated in the cellular response to activated ras. Purified MAP kinases specifically phosphorylated Thr-235 of NF-IL6 in vitro. Mutation of Thr-235 abolished the ras-dependent activation of NF-IL6. From these results, we conclude that NF-IL6 is regulated through phosphorylation by MAP kinases in response to activated ras.
 ...
PMID:Phosphorylation at threonine-235 by a ras-dependent mitogen-activated protein kinase cascade is essential for transcription factor NF-IL6. 838 17

Most carcinogens require activation to electrophilic metabolites or species that generate reactive oxygen in order to initiate the tumorigenic process. These reactive intermediates can, in turn, be detoxified by endogenous enzyme systems that and in the protection of cells from either toxic or mutagenic product formation. The levels of many of these enzymes are elevated by numerous compounds found in the diet, or by antioxidants. Recent evidence describes the mechanism for this induction of carcinogen detoxication enzymes to be regulated at the transcriptional level. Nuclear transcription factors bound to sites common among these carcinogen detoxication genes are activated by as yet unknown signal transduction pathways. The activity of these nuclear transcription factors are modulated by pro- and antioxidant reagents, suggesting that a redox-sensitive component governs the induction of enzymes involved in carcinogen metabolism. In this review, evidence for the redox regulation of the genes encoding carcinogen detoxication enzymes is presented. Evidence is also presented suggesting the participation of nuclear factor kappa B (NF-kappa B), mitogen-activated protein (MAP) kinase, and basic leucine zipper (bZIP) proteins and their activation pathways in this induction.
 ...
PMID:Redox regulation of genes that protect against carcinogens. 946 61

Several protein-nucleic acid complexes are observed when nuclear extracts from hepatoma cells are assayed for binding to the cAMP response element found in the phosphoenolpyruvate carboxykinase-cytosolic (PEPCK-C) promoter. Although cAMP response element-binding protein and CCAAT/enhancer binding proteins alpha and beta have been identified as liver factors that bind this motif, an uncharacterized, slower migrating complex was also observed. We identify activating transcription factor-2 (ATF-2) as the factor in this complex and show that ATF-2 stimulates expression from the PEPCK-C promoter. ATF-2 is a basic-leucine zipper transcription factor and a target for stress-activated protein kinases. We demonstrate that p38beta mitogen-activated protein (MAP) kinase augments ATF-2 transactivation activity on the PEPCK-C promoter, which is consistent with the interpretation that PEPCK-C promoter activity is maintained under stress through a p38 MAP kinase dependent pathway. In this regard, we show that treatment with sodium arsenite, a known activator of p38 MAP kinases, also stimulates expression from the PEPCK promoter. These results show that ATF-2 can stimulate transcription of the PEPCK-C promoter and support a role for stress inducible kinases in the maintenance of PEPCK-C expression.
 ...
PMID:Activating transcription factor-2 regulates phosphoenolpyruvate carboxykinase transcription through a stress-inducible mitogen-activated protein kinase pathway. 971 2

The mouse heme oxygenase-1 (HO-1) gene, ho-1, contains two inducible enhancers, E1 and E2. Of several cell lines tested, induction of an E1/luciferase fusion construct, pE1-luc, by CdCl(2) is most pronounced in MCF-7 cells. In these cells, E1, but not E2, is necessary and sufficient for ho-1 gene activation. Exposure of MCF-7 cells to 10 micrometer CdCl(2) stimulates phosphorylation of ERK, JNK, and p38 mitogen-activated protein kinases, implicating one or more of these signaling pathways in ho-1 gene induction. SB203580, an inhibitor of p38, diminishes cadmium-stimulated pE1-luc expression and HO-1 mRNA levels by up to 70-80%. PD098059, an ERK pathway inhibitor, does not affect HO-1 mRNA induction at the highest concentration (40 micrometer) tested. Similarly, co-expression of a dominant-negative mutant of p38alpha, but not of ERK1, ERK2, JNK1, or JNK2, reduces basal and cadmium-induced pE1-luc activity. E1 contains binding sites for the activator protein-1 (Fos/Jun), Cap'n'Collar/basic leucine zipper (CNC-bZIP), and CCAAT/enhancer-binding protein (C/EBP) families of transcription factors. A dominant-negative mutant of Nrf2 (a CNC-bZIP member), but not of c-Jun or C/EBPbeta, inhibits pE1-luc activation by cadmium. Induction of the endogenous ho-1 gene is also inhibited by the Nrf2 mutant. Mutations of E1 that inhibit cadmium inducibility also suppress the trans-activation and DNA binding activities of Nrf2, and SB203580, but not PD098059, attenuates Nrf2-mediated trans-activation of pE1-luc. Taken together, these results indicate that cadmium induces ho-1 gene expression via sequential activation of the p38 kinase pathway and Nrf2.
 ...
PMID:Mechanism of heme oxygenase-1 gene activation by cadmium in MCF-7 mammary epithelial cells. Role of p38 kinase and Nrf2 transcription factor. 1087 44

We previously described the identification of quail MafA, a novel transcription factor of the Maf bZIP (basic region leucine zipper) family, expressed in the differentiating neuroretina (NR). In the present study, we provide the first evidence that MafA is phosphorylated and that its biological properties strongly rely upon phosphorylation of serines 14 and 65, two residues located in the transcriptional activating domain within a consensus for phosphorylation by mitogen-activated protein kinases and which are conserved among Maf proteins. These residues are phosphorylated by ERK2 but not by p38, JNK, and ERK5 in vitro. However, the contribution of the MEK/ERK pathway to MafA phosphorylation in vivo appears to be moderate, implicating another kinase. The integrity of serine 14 and serine 65 residues is required for transcriptional activity, since their mutation into alanine severely impairs MafA capacity to activate transcription. Furthermore, we show that the MafA S14A/S65A mutant displays reduced capacity to induce expression of QR1, an NR-specific target of Maf proteins. Likewise, the integrity of serines 14 and 65 is essential for the MafA ability to stimulate expression of crystallin genes in NR cells and to induce NR-to-lens transdifferentiation. Thus, the MafA capacity to induce differentiation programs is dependent on its phosphorylation.
 ...
PMID:Phosphorylation of MafA is essential for its transcriptional and biological properties. 1141 24

Many chemopreventive agents have been shown to modulate gene expression including induction of phase II detoxifying enzymes, such as glutathione S-transferases (GST) and quinone reductases (QR). Induction of phase II enzymes in general leads to protection of cells/tissues against exogenous and/or endogenous carcinogenic intermediates. The antioxidant or electrophile response element (ARE/EpRE) found at the 5'-flanking region of these phase II genes may play important role in mediating their induction by xenobiotics including chemopreventive agents. Members of the basic leucine zipper (bZIP) transcription factor, Nrf2 which heterodimerizes with Maf G/K, are found to bind to the ARE, and transcriptionally-activated ARE. Recently, we showed that the mitogen-activated protein kinases (MAPK) were activated by phase II gene inducers such as phenolic antioxidant butylated hydroxyanisol (BHA) and isothiocyanate sulforaphane (SUL), and involved in the transcription activation of ARE-mediated reporter gene. Transfection studies with wild-type and dominant negative mutants of Nrf2 and MAPK showed synergistic response during co-transfection as well as to phase II gene inducers. However, increasing the concentrations of these compounds such as BHA, the activities of cell death signaling molecules, caspases, were stimulated and resulted in apoptotic cell death. At these concentrations, BHA stimulated loss of mitochondrial membrane potential, cytochrome c release, and activation of caspase 3, 8 and 9 preceding apoptosis. Further increase in concentrations led to rapid cell necrosis. A model is proposed for BHA and SUL, in that at low concentrations, these potential chemopreventive agents may modulate MAPK pathway leading to transcription activation of Nrf2 and ARE with subsequent induction of cellular defensive enzymes including phase II detoxifying enzymes as well as other defensive genes, which may protect the cells against cellular injury, which is a homeostatic response. At higher concentrations, these agents may activate the caspase pathways, leading to apoptosis, a potential beneficial effect if occurs at preneoplastic/neoplastic tissues, but a potential cytotoxic response if occurs in normal tissues. On the other hand, some phenolic compounds such as resveratrol inhibits TPA- or UV-induced AP-1-mediated activity through the inhibition of c-Src non-receptor tyrosine kinase and MAPK pathways. It is possible that in proliferating or stimulated cells, these chemopreventive compounds may block proliferation by inhibiting these signaling kinases, whereas in non-proliferating or quiescent cells, some of these compounds may activate these signaling kinases leading to gene expression of cellular defensive enzymes such as phase II detoxifying enzymes. The studies of these and other signaling pathways may yield insights into the development of potential chemopreventive compounds.
 ...
PMID:Signal transduction events elicited by cancer prevention compounds. 1150 17

The c-Jun N-terminal kinase (JNK) signaling pathway is a major mediator of stress responses in cells. Similar to other mitogen-activated protein kinases (MAPKs), JNK activity is controlled by a cascade of protein kinases and by protein phosphatases, including dual-specificity MAPK phosphatases. Components of the JNK pathway associate with scaffold proteins that modulate their activities and cellular localization. The JNK-interacting protein-1 (JIP-1) scaffold protein specifically binds JNK, MAPK kinase 7 (MKK7), and members of the mixed lineage kinase (MLK) family, and regulates JNK activation in neurons. In this study we demonstrate that distinct regions within the N termini of MKK7 and the MLK family member dual leucine zipper kinase (DLK) mediate their binding to JIP-1. We have also identified amino acids in JNK required for: (a) binding to JIP-1 and for JIP-1-mediated JNK activation, (b) docking to MAPK kinase 4 (MKK4) and efficient phosphorylation by MKK4, and (c) docking to its substrate c-Jun and efficient c-Jun phosphorylation. None of the amino acids identified were essential for JNK docking to MKK7 or the dual-specificity phosphatase MAPK phosphatase 7 (MKP7). These findings uncover molecular determinants of JIP-1 scaffold complex assembly and demonstrate that there are overlapping, but also distinct, binding determinants within JNK that mediate interactions with scaffold proteins, activators, phosphatases, and substrates.
 ...
PMID:Docking interactions in the c-Jun N-terminal kinase pathway. 1469 11

In response to environmental stresses, a family of protein kinases phosphorylate eIF2 (eukaryotic initiation factor 2) to alleviate cellular injury or alternatively induce apoptosis. Phosphorylation of eIF2 reduces global translation, allowing cells to conserve resources and to initiate a reconfiguration of gene expression to effectively manage stress conditions. Accompanying this general protein synthesis control, eIF2 phosphorylation induces translation of specific mRNAs, such as that encoding the bZIP (basic leucine zipper) transcriptional regulator ATF4 (activating transcription factor 4). ATF4 also enhances the expression of additional transcription factors, ATF3 and CHOP (CCAAT/enhancer-binding protein homologous protein)/GADD153 (growth arrest and DNA-damage-inducible protein), that assist in the regulation of genes involved in metabolism, the redox status of the cells and apoptosis. Reduced translation by eIF2 phosphorylation can also lead to activation of stress-related transcription factors, such as NF-kappaB (nuclear factor kappaB), by lowering the steady-state levels of short-lived regulatory proteins such as IkappaB (inhibitor of NF-kappaB). While many of the genes induced by eIF2 phosphorylation are shared between different environmental stresses, eIF2 kinases function in conjunction with other stress-response pathways, such as those regulated by mitogen-activated protein kinases, to elicit gene expression programmes that are tailored for the specific stress condition. Loss of eIF2 kinase pathways can have important health consequences. Mice devoid of the eIF2 kinase GCN2 [general control non-derepressible-2 or EIF2AK4 (eIF2alpha kinase 4)] show sensitivity to nutritional deficiencies and aberrant eating behaviours, and deletion of PEK [pancreatic eIF2alpha kinase or PERK (RNA-dependent protein kinase-like endoplasmic reticulum kinase) or EIF2AK3] leads to neonatal insulin-dependent diabetes, epiphyseal dysplasia and hepatic and renal complications.
 ...
PMID:Coping with stress: eIF2 kinases and translational control. 1624 68

BASH/BLNK/SLP-65 is an adaptor protein necessary for the B cell receptor (BCR) signal transduction. Here we report the identification through the yeast two-hybrid system of a novel 26-kDa protein, BASH N-terminus-associated protein 1 (BNAS1), which interacts with the conserved and functionally important N-terminal domain of BASH/BLNK/SLP-65. BNAS1 presumably contains four transmembrane domains and the leucine zipper (LZ) motif, and is expressed ubiquitously. The association of BNAS1 with BASH/BLNK/SLP-65 through its LZ motif in vertebrate cells was demonstrated by immunoprecipitation assay. Confocal microscopy revealed that exogenously expressed BNAS1 is localized to the endoplasmic reticulum (ER) and the nuclear envelope. BASH/BLNK/SLP-65 alone was present diffusely in the cytoplasm, but localized to the same position as BNAS1 when co-expressed with BNAS1. Their co-localization was dependent on the domains containing the LZ motif of both molecules. BCR-signaled transcriptional activation of Elk-1 was suppressed by over-expression of BNAS1 in DT40 chicken B cells, and conversely augmented in the BNAS1-deficient DT40 cells, which was restored by BNAS1 reconstitution. This augmentation of Elk-1 activation in the BNAS1-deficient cells was abolished selectively by Jun N-terminal kinase (JNK) inhibitor, suggesting that BNAS1 regulates Elk-1 activation through JNK. Taken together, these results suggest that BNAS1 interacts with BASH/BLNK/SLP-65 at the ER and/or the outer nuclear membrane and is involved in the regulation of the signal transmission via mitogen-activated protein kinases leading to Elk-1 activation.
 ...
PMID:The BASH/BLNK/SLP-65-associated protein BNAS1 regulates antigen-receptor signal transmission in B cells. 1648 41


1 2 Next >>