Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
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 Runx family of transcription factors plays pivotal roles during normal development and in neoplasias. In mammals, Runx family genes are composed of Runx1 (Pebp2alphaB/Cbfa2/Aml1), Runx2 (Pebp2alphaA/Cbfa1/Aml3) and Runx3 (Pebp2alphaC/Cbfa3/Aml2). Runx1 and Runx3 are known to be involved in leukemogenesis and gastric carcinogenesis, respectively. Runx2, on the other hand, is a common target of transforming growth factor-beta1 (TGF-beta1) and bone morphogenetic protein-2 (BMP-2) and plays an essential role in osteoblast differentiation. Runx2 is induced by the receptor-activated Smad; Runx2 mediates the blockage of myogenic differentiation and induces osteoblast differentiation in C2C12 pluripotent mesenchymal precursor cells. However, Smad does not directly induce Runx2 expression; an additional step of de novo protein synthesis is required. Here we report that Smad-induced junB functions as an upstream activator of Runx2 expression. Furthermore, not only the Smad pathway but also the mitogen-activated protein kinase (MAPK) cascades are involved in the induction of Runx2 by TGF-beta1 and BMP-2. Our results demonstrate that following TGF-beta and BMP induction, both the Smad and p38 MAPK pathways converge at the Runx2 gene to control mesenchymal precursor cell differentiation.
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PMID:Both the Smad and p38 MAPK pathways play a crucial role in Runx2 expression following induction by transforming growth factor-beta and bone morphogenetic protein. 1237 Aug 5

The signal pathway mediating induction of p15(INK4b) and p16(INK4a) during HepG2 growth inhibition triggered by the phorbol ester tumor promoter TPA (12-O-tetradecanoylphorbol 13-acetate) and the Chinese herb Saikosaponin a was investigated. Western blot of three activated forms of mitogen-activated protein kinase (MAPK) (p-ERK, p-JNK and p-p38) demonstrated that phosphorylation of ERK is dramatically induced (11.6-fold ) by TPA during 15 min to 1 h and significantly induced (2.5-fold) by Saikosaponin alpha at 30 min, whereas phosphorylation of JNK was induced only by TPA during 30 min to 1 h. Phosphorylation of p38 was not induced by either drug. During this period, phosphorylation of one of the downstream transcriptional factors of MAPK cascade, ATF2, was 3.2- and 2.0-fold induced by TPA and Saikosaponin a, respectively, whereas that of another transcriptional factor, c-jun, was induced by TPA only. On the other hand, expressions of proto-oncogene c-jun, junB and c-fos were induced by TPA and Saikosaponin a during 30 min to 6 h of treatment. Pretreatment of 20 microg/ml PD98059, an inhibitor of MEK which is the upstream kinase of ERK, prevents the TPA- and Saikosaponin a-triggered HepG2 growth inhibition by 50 and 30%, respectively, accompanied by a 50 - 85% decrease of the p15(INK4b)/p16(INK4a) RNAs and proteins induced by both drugs. Inductions of c-fos RNA by both drugs and c-jun phosphorylation by TPA were also significantly reduced by PD98059 pretreatment. In addition, AP-1 DNA-binding assay using nonisotopic capillary electrophoresis and laser-induced fluorescence (CE/LIF) demonstrated that the AP-1-related DNA-binding activity was significantly induced by TPA and Saikosaponin a, which can be reduced by PD98059 pretreatment. These results suggested that activation of ERK together with its downstream transcriptional machinery mediated p15(INK4b) and p16(INK4a) expression that led to HepG2 growth inhibition.
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PMID:ERK signaling pathway is involved in p15INK4b/p16INK4a expression and HepG2 growth inhibition triggered by TPA and Saikosaponin a. 1259 82

The tyrosine kinase inhibitor (tyrphostin) AG 555 selectively interferes with viral transcription in bovine papillomavirus type 1 (BPV-1)-transformed fibroblasts and induces suppression of cyclin-dependent kinase activity and cell cycle arrest. Concomitant with inhibition of viral transcription, c-Jun was strongly up-regulated, which was consistent with the observation that AG 555 treatment also led to an activation of the mitogen-activated protein kinase pathway by enhancing phosphorylation of JNK and p38. Increased JNK and p38 activity resulted in higher phosphorylation of the AP-1 family members c-Jun and activating transcription factor 2. Scanning the BPV-1 genome for potential binding sequences, an intragenic AP-1 site (BAP-1) within the E7 open reading frame was detected. Enhanced dimerization of phosphorylated activating transcription factor 2 together with c-Jun and binding to BAP-1 seem to be responsible for viral dysregulation because both suppression of BPV-1 and induction of c-Jun mRNA could be almost entirely abrogated by simultaneous treatment with SB 203580, an inhibitor of p38 mitogen-activated protein kinase activity. Moreover, dissecting the complex transcriptional pattern of episomal BPV-1 with specific primer sets for reverse transcription-PCR analysis, the repressive effect could be attributed to a selective down-regulation of the mRNA encoding the E2 transactivator function in favor of the E2 repressor, whose mRNA level remained constant during AG 555 treatment. These data indicate that tyrphostin AG 555 disturbs the balance of negative and positive regulatory factors necessary to maintain the homeostasis of a virus-transformed phenotype.
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PMID:Tyrphostin AG 555 inhibits bovine papillomavirus transcription by changing the ratio between E2 transactivator/repressor function. 1286 21

Hepatitis B virus x gene product (HBx) is known to be a transactivator of transcriptional elements that regulate the expression of a variety of genes associated with the growth, differentiation, survival and the apoptosis of cells. However, the exact mechanism of the activation and inhibition of cellular events by HBx remains uncertain. The present study was designed to measure the effect of HBx, on the signal transduction pathways associated with intracellular Ca(2+) mobilization following HBx transfection in the stable Chang liver cells (CHL-X). Enhanced cell proliferation by HBx in CHL-X was confirmed by MTT assay and by the immunodetection of PCNA. The transactivation of AP-1 by HBx induced in CHL-X was inhibited by cyclosporin A (CsA), a mitochondrial Ca(2+) channel blocker and by BAPTA-AM, a cytosolic Ca(2+) blocker. Activation of the SAPK/JNK signaling pathway by HBx was evidenced by the increased phosphorylations of c-Jun (Ser63) and of JNK (Thr183/Tyr185). Increased phospho-Erk/Erk and phospho-Raf1/Raf in HBx-induced CHL-X indicated that HBx might stimulate the MAPK pathway. PI3K activity and cytosolic free Ca(2+) levels were elevated in HBx-induced CHL-X. These results imply that HBx transactivates both JNK and MAPK signal transduction pathways in association with the mobilization of cytosolic Ca(2+).
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PMID:Activation of calcium signaling by hepatitis B virus-X protein in liver cells. 1450 71

Pax proteins are DNA-binding transcription factors that regulate embryonic development through the activation and repression of downstream target genes. The Pax2 gene is absolutely required for kidney development and for patterning specific regions of the nervous system such as the eye, ear and hindbrain. The Pax2/5/8 family of proteins contains both transcription activation and repression domains. The activation domain of Pax2 is phosphorylated by the c-Jun N-terminal kinase (JNK) to enhance Pax2-dependent transcription. In this report, we demonstrate that the Groucho/TLE family protein, Grg4, interacts with Pax2 to suppress transactivation. Grg4 is able to specifically inhibit phosphorylation of the Pax2 activation domain, even in the presence of activated JNK. Furthermore, the Grg4 interaction and suppression of phosphorylation depends on Pax2 binding to its target DNA sequence and is independent of histone deacetylation. These data suggest a new model for Groucho mediated suppression of transcription through the specific inhibition of modifications in the activation domain of a transactivator.
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PMID:Groucho suppresses Pax2 transactivation by inhibition of JNK-mediated phosphorylation. 1453 24

Transforming growth factor-beta1 (TGF-beta1) plays a pivotal role in the angiogenesis during the development of placenta, but the intracellular signaling mechanism by which TGF-beta1 stimulates this process remains poorly understood. In this article, we demonstrated that exposure of normal human cytotrophoblast cells to TGF-beta1 stimulated the secretion of the VEGF gene encoding vascular endothelial growth factor, which is a key factor in angiogenesis. Meanwhile, treatment of normal human cytotrophoblast cells with TGF-beta1-induced expression of HIF-1a, the regulated subunit of hypoxia-inducible factor 1, a known transactivator of the VEGF gene. Our data indicated that TGF-beta1 induced extracellular signal- regulated kinase (ERK) 1/2 phosphorylation in normal human cytotrophoblast cells. Moreover, treating cells with PD98059, an inhibitor of ERK1/2 signaling, inhibited TGF-beta1 stimulation of VEGF secretion and HIF-1a protein expression. These data indicated that in normal human cytotrophoblast cells, TGF-beta1 induced HIF-1a-mediated VEGF secretion, and TGF-beta1-stimulated-ERK1/2 activation may be involved in this process.
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PMID:Involvement of ERK1/2 pathway in TGF-beta1-induced VEGF secretion in normal human cytotrophoblast cells. 1509 41

To clarify the mechanisms underlying enhancement of carcinogenesis in transgenic mice carrying a human prototype c-Ha- ras gene (rasH2 mouse), animals received a single intraperitoneal injection of 120 mg/kg N-ethyl-N-nitrosourea (ENU) and at 20 weeks thereafter expression profiles in three induced forestomach squamous cell carcinomas were assessed using high-density oligonucleotide microarrays. In addition, the reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to assess mRNA expression of human c-Ha- ras gene and some molecules involved in the Ras-regulated mitogen-activated protein kinase (MAPK) pathway. Compared with normal forestomach tissue from control mice, 416 and 368 genes, respectively, were found to be commonly up- and down-regulated by 2-fold or more in the three tumors. Many genes involved in tumor invasion and metastasis such as transforming growth factor beta1 and matrix metalloproteinases were up-regulated, reflecting tumor progression. RT-PCR analysis confirmed up-regulation of transgene, mouse endogenous Ha- ras, N- ras, raf, Mekk2, c- fos, junB, c- myc and cyclin D1. These results suggest that activation of the Ras-MAPK cascade following up-regulation of both human and mouse endogenous ras genes is involved in the enhanced tumorigenesis of ENU-induced forestomach squamous cell carcinomas in rasH2 mice.
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PMID:Analysis of gene expression profiles of forestomach tumors in rasH2 mice initiated with N-ethyl-N-nitrosourea. 1524 93

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

Ets proteins play a vital role in the regulation of mammalian immunity, and family members Ets-1 and Ets-2 regulate a variety of genes that participate in the propagation of an inflammatory response. Heme oxygenase (HO)-1, although acutely induced by inflammatory stimuli, has cytoprotective properties and prevents an exaggerated inflammatory response. Ets-1 and Ets-2 both induce HO-1 promoter activity; however, Ets-2 was a more potent transactivator of HO-1 in macrophages. A potent inflammatory mediator, bacterial lipopolysaccharide (LPS), induced Ets-2 at the mRNA and protein level, and this induction preceded the up-regulation of HO-1. To further delineate the role of Ets-2 in regulating HO-1 transcription, we performed HO-1 promoter analysis studies in macrophages. Deletion mutants down to -137/+74 maintained an activity analogous to that of the largest construct, -4045/+74. Further deletion constructs (starting with -117/+74) showed a significant reduction in promoter activity when co-transfected with Ets-2 or exposed to LPS. Promoter sequence analysis revealed two putative Ets binding sites (EBSs) in this region, and mutation of these sites showed that EBS -93, more than EBS -125, was critical for full HO-1 promoter activity. Additional studies showed that EBS -93 binds Ets-2 and that mutation of the DNA binding domain of Ets-2 entirely prevented transactivation of HO-1. Finally, overexpression of a dominant negative form of Ets-2 blunted HO-1 promoter induction by LPS, and kinase inhibitors (PI3K more than JNK) that reduced Ets-2 expression markedly decreased endogenous HO-1 expression. Our data provide evidence that Ets-2 contributes to the up-regulation of HO-1 by the potent inflammatory stimulus LPS in macrophages.
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PMID:Role of Ets-2 in the regulation of heme oxygenase-1 by endotoxin. 1559 Jun 57

C-reactive protein (CRP) is significantly associated with the risk of ischemic cardiovascular disease in epidemiological studies. To explore if CRP has a functional role, we investigated its effect on the gene expression profile of vascular endothelial cells. Human vascular endothelial cells (human umbilical vein endothelial cells and human aortic endothelial cells) were incubated with CRP at various concentrations (0-10 mug/ml). Microarray analysis showed that a total of 11 genes increased (IL-8, core promoter element binding protein, activin A, monocyte chemoattractant protein 1, Exostoses 1, Cbp/p300-interacting transactivator with Glu/Asp-rich COOH-terminal domain 2, plasminogen activator inhibitor 1, fibronectin-1, gravin, connexin43, and sortilin-related receptor-1) and 6 genes decreased (methionine adenosyltransferase 2A, tryptophan-rich basic protein, reticulocalbin 1, membrane-associated RING-CH protein VI, cytoplasmic dynein1, and annexin A(1)) by more than twofold for their mRNA levels. IL-8 was the most significantly upregulated gene (13.6-fold), which demonstrated a clear dose- and time-dependent pattern revealed by quantitative real-time PCR. Cell adhesion assay showed that CRP enhanced the monocyte adhesion to endothelial cell monolayer by 2-fold (P < 0.01), which was partially blocked by an anti-IL-8 antibody (34.2% inhibition, P < 0.01). Inhibition of ERK MAPK pathway using U0126 prevented CRP-induced IL-8 upregulation, and Western blot analysis revealed a rapid activation of ERK1/2 after CRP stimulation. These data showed that CRP can significantly influence gene expressions in vascular endothelium. The CRP-responsive genes suggested that CRP may have a broad functional role in cell growth and differentiation, vascular remodeling and solid tumor development.
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PMID:Effect of C-reactive protein on gene expression in vascular endothelial cells. 1559 Oct 95


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