Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Crocidolite asbestos elicits oxidative stress and cell proliferation, but the signaling cascades linked to these outcomes are unclear. To determine the role of mitogen-activated protein kinases (MAPK) in asbestos-induced cell signaling, we evaluated the effects of crocidolite asbestos, EGF and H2O2, on MAPK activation in murine lung epithelial cells (C10 line). In contrast to rapid and transient activation of extracellular signal-regulated kinase 5 (ERK5) by EGF or H2O2, asbestos caused protracted oxidant-dependent ERK5 activation that was inhibited by an Src kinase inhibitor (PP2), but not by an inhibitor of epidermal growth factor receptor (EGFR) phosphorylation (AG1478). ERK1/2 activation by asbestos was inhibited by either PP2 or AG1478. To confirm the involvement of Src in ERK1/2 and ERK5 activation, a dominant-negative Src construct was used. These experiments showed that Src was essential for ERK1/2 and also ERK5 phosphorylation by asbestos. Time frame studies indicated immediate activation of Src by asbestos fibers, whereas EGFR phosphorylation occurred subsequently. Data suggest that asbestos causes activation of ERK5 through an EGFR-independent pathway, whereas ERK1/2 activation is dependent on Src through a mechanism involving phosphorylation of the EGFR. Furthermore, Src, ERK1/2 and ERK5 activation are essential for cell proliferation by asbestos. The use of a dominant-negative ERK5 construct caused selective downregulation of c-jun expression, whereas inhibition of Src by PP2 or MEK1 by PD98059 caused decreases in c-fos, fra-1 and c-jun expression in asbestos-exposed C10 cells. These observations may have broad relevance to cell proliferation by carcinogenic mineral fibers and oxidants.
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PMID:Src-dependent ERK5 and Src/EGFR-dependent ERK1/2 activation is required for cell proliferation by asbestos. 1473 15

Aplidin is an antitumor drug that induces apoptosis and activates EGFR, Src, JNK and p38MAPK. Here, we show that Aplidin induces c-JUN, JUN B, JUN D, c-FOS, FRA-1 and FOS B genes of the activator-protein (AP)-1 family, and also p65/RELA, a major component of nuclear factor-kappa B (NF-kappaB). Concordantly, Aplidin increases AP-1 and NF-kappaB activity. c-FOS induction depends on EGFR, Src and JNK/p38MAPK. In contrast, induction of c-JUN does not require EGFR activity and p65/RELA induction is only partially dependent on these kinases. We used several genetically deficient cells to identify the critical target of Aplidin. Mouse embryo fibroblasts (MEFs) deficient for src, yes and fyn, and those lacking all p38MAPK isoforms displayed normal Aplidin sensitivity (IC50=12 nM). In contrast, MEFs lacking jnk1 and jnk2, which do not express any JNK isoform, were much less sensitive (IC50>500 nM). Furthermore, cells lacking c-jun or expressing a c-Jun protein in which JNK targets Ser(63/73) were mutated (c-JunAA) showed intermediate sensitivity (IC50=60 nM). Additionally, Aplidin has higher cytotoxic activity against proliferating than quiescent cells, which is reflected in higher JNK activation. We conclude that phosphorylation by JNK of c-Jun and additional substrate(s) is crucial for Aplidin activity.
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PMID:JNK activation is critical for Aplidin-induced apoptosis. 1512 39

Nuclear factor kappaB (NF-kappaB) and activator protein 1 (AP-1) transcription factors regulate many important biological and pathological processes. Activation of NF-kappaB is regulated by the inducible phosphorylation of NF-kappaB inhibitor IkappaB by IkappaB kinase. In contrast, Fos, a key component of AP-1, is primarily transcriptionally regulated by serum responsive factors (SRFs) and ternary complex factors (TCFs). Despite these different regulatory mechanisms, there is an intriguing possibility that NF-kappaB and AP-1 may modulate each other, thus expanding the scope of these two rapidly inducible transcription factors. To determine whether NF-kappaB activity is involved in the regulation of fos expression in response to various stimuli, we analyzed activity of AP-1 and expression of fos, fosB, fra-1, fra-2, jun, junB, and junD, as well as AP-1 downstream target gene VEGF, using MDAPanc-28 and MDAPanc-28/IkappaBalphaM pancreatic tumor cells and wild-type, IKK1-/-, and IKK2-/- murine embryonic fibroblast cells. Our results show that elk-1, a member of TCFs, is one of the NF-kappaB downstream target genes. Inhibition of NF-kappaB activity greatly decreased expression of elk-1. Consequently, the reduced level of activated Elk-1 protein by extracellular signal-regulated kinase impeded constitutive, serum-, and superoxide-inducible c-fos expression. Thus, our study revealed a distinct and essential role of NF-kappaB in participating in the regulation of elk-1, c-fos, and VEGF expression.
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PMID:NF-kappaB and AP-1 connection: mechanism of NF-kappaB-dependent regulation of AP-1 activity. 1531 85

Exposure to cigarette smoke (CS) can lead to the development of lung cancer, but the molecular mechanisms underlying this process remain unclear. Given that activator protein 1 (AP-1) regulates genes involved in both physiologic and pathophysiologic processes, we have investigated the effects of CS on Jun and Fos family member expression and regulation using a nonmalignant human bronchial epithelial cell line, 1HAEo. Exposure to CS caused a marked upregulation of c-Jun, c-Fos, and Fra-1, but not of Fra-2, Jun-B, and Jun-D expression. Because Fra-1 is overexpressed in various tumors and upregulates genes associated with tumor progression, we further elucidated the mechanisms that control CS-stimulated fra-1 induction. CS stimulated fra-1 induction primarily at the transcriptional level. However, epidermal growth factor receptor (EGFR)-specific inhibitor, AG1478, completely suppressed CS-stimulated fra-1 expression. Similarly, the specific inhibitors of extracellular signal-regulated kinase (ERK), c-Jun NH2 terminal kinase (JNK), and p38 kinase signaling markedly suppressed fra-1 induction. Consistent with this finding, AG1478 blocked CS-stimulated ERK, JNK, and p38 phosphorylation. These results suggest that EGFR-activated multiple kinase signaling is essential for fra-1 induction. Furthermore, treatment of cells with GM6001, which inhibits matrix metalloproteinase activity, significantly suppressed CS-stimulated EGF shedding, EGFR and ERK kinase phosphorylation, and subsequent fra-1 induction. Collectively, our findings indicate an obligatory role for metalloproteinase-EGFR-mediated mitogen-activated protein kinase signaling in controlling CS-induced fra-1 expression.
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PMID:Matrix metalloproteinase/epidermal growth factor receptor/mitogen-activated protein kinase signaling regulate fra-1 induction by cigarette smoke in lung epithelial cells. 1552 91

We describe cyclic hydrostatic pressure of 200/100 mmHg with a frequency of 85/min as a hemodynamically relevant pathological condition enforcing apoptosis in endothelial cells (EC) after 24 h of treatment. This went along with an increase of CD95 and CD95L surface expression, shedding of CD95L into the supernatant, cleavage of caspase-3 and caspase-8, and elevated JNK-2, c-Jun, and CD95L mRNA expression. Furthermore, increased DNA-binding activity of the AP-1 transcription factor family members FRA-1 and c-Jun was observed. This activation was reduced by inhibition of JNK, which subsequently prevented elevated CD95L mRNA expression. Caspase inhibitors and a CD95L-neutralizing antibody also reduced EC apoptosis. Most of the pressure-induced events were most prominent at 24 and 48 h. However, after 48 h, the CD95/CD95L expression pattern switched back to CD95-/CD95L+ and the specific death rate decreased. Cyclic pathological hydrostatic pressure is a novel type of stress to EC that renders them susceptible to CD95/CD95L-mediated autoapoptosis and/or paracrine apoptosis accompanied by upregulation of intracellular molecules known to trigger both apoptosis and survival.
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PMID:Pathologically elevated cyclic hydrostatic pressure induces CD95-mediated apoptotic cell death in vascular endothelial cells. 1577 24

The majority of ovarian cancer patients are treated with platinum-based chemotherapy, but the emergence of resistance to such chemotherapy severely limits its overall effectiveness. We have shown that development of resistance to this treatment can modify cell signaling responses in a model system wherein cisplatin treatment has altered cell responsiveness to ligands of the erbB receptor family. A cisplatin-resistant ovarian carcinoma cell line PE01CDDP was derived from the parent PE01 line by exposure to increasing concentrations of cisplatin, eventually obtaining a 20-fold level of resistance. Whereas PE01 cells were growth stimulated by the erbB receptor-activating ligands, such as transforming growth factor-alpha (TGFalpha), NRG1alpha, and NRG1beta, the PE01CDDP line was growth inhibited by TGFalpha and NRG1beta but unaffected by NRG1alpha. TGFalpha increased apoptosis in PE01CDDP cells but decreased apoptosis in PE01 cells. Differences in extracellular signal-regulated kinase and phosphatidylinositol 3-kinase signaling were also found, which may be implicated in the altered cell response to ligands. Microarray analysis revealed 51 genes whose mRNA increased by at least 2-fold in PE01CDDP cells relative to PE01 (including FRA1, ETV4, MCM2, AXL, MT3, TRAP1, and FANCG), whereas 36 genes (including IGFBP3, TRAM1, and KRT4 and KRT19) decreased by a similar amount. Differential display reverse transcriptase-PCR identified altered mRNA expression for TCP1, SLP1, proliferating cell nuclear antigen, and ZXDA. Small interfering RNA inhibition of FRA1, TCP1, and MCM2 expression was associated with reduced growth and FRA1 inhibition with enhanced cisplatin sensitivity. Altered expression of these genes by cytotoxic exposure may provide survival advantages to cells including deregulation of signaling pathways, which may be critical in the development of drug resistance.
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PMID:Altered ErbB receptor signaling and gene expression in cisplatin-resistant ovarian cancer. 1606 61

The eIF2alpha (eukaryotic initiation factor-2alpha) kinase PERK (doublestranded RNA-activated protein kinase-like ER kinase) is essential for the normal function of highly secretory cells in the pancreas and skeletal system, as well as the UPR (unfolded protein response) in mammalian cells. To delineate the regulatory machinery underlying PERK-dependent stress-responses, gene profiling was employed to assess global changes in gene expression in PERK-deficient MEFs (mouse embryonic fibroblasts). Several IE (immediate-early) genes, including c-myc, c-jun, egr-1 (early growth response factor-1), and fra-1 (fos-related antigen-1), displayed PERK-dependent expression in MEFs upon disruption of calcium homoeostasis by inhibiting the ER (endoplasmic reticulum) transmembrane SERCA (sarcoplasmic/ER Ca2+-ATPase) calcium pump. Induction of c-myc and egr-1 by other reagents that elicit the UPR, however, showed variable dependence upon PERK. Induction of c-myc expression by thapsigargin was shown to be linked to key signalling enzymes including PLC (phospholipase C), PI3K (phosphatidylinositol 3-kinase) and p38 MAPK (mitogen-activated protein kinase). Analysis of the phosphorylated status of major components in MAPK signalling pathways indicated that thapsigargin and DTT (dithiothreitol) but not tunicamycin could trigger the PERK-dependent activation of JNK (c-Jun N-terminal kinase) and p38 MAPK. However, activation of JNK and p38 MAPK by non-ER stress stimuli including UV irradiation, anisomycin, and TNF-alpha (tumour necrosis factor-alpha) was found to be independent of PERK. PERK plays a particularly important role in mediating the global cellular response to ER stress that is elicited by the depletion of calcium from the ER. We suggest that this specificity of PERK function in the UPR is an extension of the normal physiological function of PERK to act as a calcium sensor in the ER.
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PMID:PERK (eIF2alpha kinase) is required to activate the stress-activated MAPKs and induce the expression of immediate-early genes upon disruption of ER calcium homoeostasis. 1612 69

Human diploid fibroblasts (HDF) immortalized by hTERT and simian virus 40 (SV40) early region (ER) exhibit a limited degree of transformation upon the expression of activated H-RAS (H-RAS V12) compared with rat embryonic fibroblasts (REF) immortalized by SV40 ER. Here, we identified FRA1 as a determinant for this difference in RAS-induced transformation. FRA1 was not induced by H-RAS V12 in the immortalized HDF, in contrast to its marked accumulation in the immortalized REF. Ectopic expression of FRA1 significantly enhanced anchorage-independent growth of various HDF expressing hTERT, SV40 ER, and H-RAS V12. More importantly, FRA1 could induce anchorage-independent growth as well as nude mice tumor formation of the immortalized HDF in the absence of H-RAS V12. The results of an in vitro kinase assay clearly showed that the RAS-induced extracellular signal-regulated kinase (ERK) activation, which is responsible for FRA1 induction, was markedly attenuated in the HDF compared with that in the REF, despite no obvious differences in the phosphorylation status of ERK between the species. Our results strongly suggest that HDF negatively regulate the mitogen-activated protein kinase kinase (MEK)/ERK pathway more efficiently than REF, and consequently express less malignant phenotypes in response to H-RAS V12.
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PMID:FRA1 is a determinant for the difference in RAS-induced transformation between human and rat fibroblasts. 1656 92

The activating protein-1 (AP-1) transcription factor complex is a heterogeneous entity, composed in mammalian cells of dimers chosen from a group of at least eight proteins belonging to three families: jun, fos, and activating transcription factor (ATF). The AP-1 complexes participate in diverse biological processes that include cell proliferation, survival, and differentiation. These seemingly contrasting functions have been attributed to the intensity and duration of the signals provided by AP-1, but the biological consequences of changing composition of the AP-1 complex have not been fully explored. Here, we show that functional AP-1 is required for 1,25-dihydroxyvitamin D3 (1,25D)-induced monocytic differentiation, and that the composition of the AP-1 protein complex that binds TRE, its cognate DNA element, changes as cells differentiate. In HL60 cells in an early stage of differentiation, the principal AP-1 components detected by gel shift analysis include c-jun, ATF-2, fos-B, fra-1, and fra-2. In cells with a more established monocytic phenotype, the demonstrable AP-1 components are c-jun, ATF-2, jun-B, and fos-B. Following the addition of 1 nmol/L of 1,25D, the cellular content of each of these four proteins markedly increased in a sustained manner, whereas the increases in c-fos, fra-1, fra-2, and jun-D were minimal, if any. Small increases in mRNA levels encoding all AP-1 component proteins, except c-fos, were also noted. These findings provide a basis for the previously found participation of the c-Jun N-terminal kinase pathway in 1,25D-induced differentiation of myeloid leukemia cells, and direct attention to jun-B and fos-B as new cellular therapeutic targets, that may promote replicative quiescence associated with differentiation of malignant cells.
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PMID:The requirement for and changing composition of the activating protein-1 transcription factor during differentiation of human leukemia HL60 cells induced by 1,25-dihydroxyvitamin D3. 1661 66

Among the several effectors that mediate TNF-alpha action is AP-1, which consists of transcription factors belonging to the JUN and FOS families. Although the effects of TNF-alpha in immune cells, such as the induction of NF-kappaBeta, are well known, the mechanisms by which it induces transcriptional activation of AP-1 in pulmonary epithelial cells are not well defined. In this study, we report that TNF-alpha stimulates the expression of the FRA-1 protooncogene in human pulmonary epithelial cells using c-Jun, acting via a 12-O-tetradecanoylphorbol-13 acetate response element located at -318. Although TNF-alpha stimulates phosphorylation of c-Jun, the inhibition of JNK activity had no significant effect on FRA-1 induction. Consistent with this result, ectopic expression of a c-Jun mutant lacking JNK phosphorylation sites had no effect on the TNF-alpha-induced expression of the promoter. In contrast, inhibition of the ERK pathway or ectopic expression of an ERK1 mutant strikingly reduced FRA-1 transcription. ERK inhibition not only blocked phosphorylation of Elk1, CREB, and ATF1, which constitutively bind to the FRA-1 promoter, but also suppressed the recruitment of c-Jun to the promoter. We found that short interfering RNA-mediated silencing of FRA-1 enhances TNF-alpha-induced IL-8 expression, whereas overexpression causes an opposite effect. Our findings collectively indicate that ERK signaling plays key roles in both Elk1, CREB, and ATF-1 activation and the subsequent recruitment of c-Jun to the FRA-1 promoter in response to TNF-alpha in pulmonary epithelial cells.
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PMID:A JNK-independent signaling pathway regulates TNF alpha-stimulated, c-Jun-driven FRA-1 protooncogene transcription in pulmonary epithelial cells. 1708 37


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