Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.25 (MEKK1)
 1,856 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pancreatic adenocarcinoma is a leading cause of adult cancer mortality in the United States. Recent studies have revealed that point mutation of the K-ras oncogene is a common event in pancreatic cancer, and oncogenesis mediated by Ras may also involve activation of Rel/nuclear factor (NF)-kappa B transcription factors. Furthermore, the c-rel member of Rel/NF-kappa B transcription factor family was first identified as a cellular homologue of the v-rel oncogene, suggesting that other members of the Rel/NF-kappa B family are potentially oncogenes. We therefore investigated the possibility that Rel/NF-kappa B transcription factors are activated in pancreatic cancer. Immunohistochemical analysis, Western blot and Northern blot analysis, electrophoretic mobility shift assays, and chloramphenicol acetyltransferase assays were performed to determine RelA activity in human pancreatic adenocarcinomas and normal tissues and nontumorigenic or tumorigenic cell lines. RelA, the p65 subunit of NF-kappa B, was constitutively activated in approximately 67% (16 of 24) of pancreatic adenocarcinomas but not in normal pancreatic tissues. Constitutive RelA activity was also detected in 9 of 11 human pancreatic tumor cell lines but not in nontumorigenic Syrian golden hamster cell lines. I kappa B alpha, a previously identified NF-kappa B-inducible gene, was overexpressed in human pancreatic tumor tissues and cell lines, and RelA activation could be inhibited by curcumin and dominant-negative mutants of I kappa B alpha, raf, and MEKK1. This is the first report demonstrating constitutive activation of RelA in nonlymphoid human cancer. These data are consistent with the possibility that RelA is constitutively activated by the upstream signaling pathway involving Ras and mitogen-activated protein kinases in pancreatic tumor cells. Constitutive RelA activity may play a key role in pancreatic tumorigenesis through activation of its downstream target genes.
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PMID:The nuclear factor-kappa B RelA transcription factor is constitutively activated in human pancreatic adenocarcinoma cells. 991 9

Human pancreatic cancers harbor mutations in the K-ras gene, and these mutations convert the gene oncogenic and constitutively active forms. However, in pancreatic cancer cells little is known about the activation of the downstream pathways of Ras, MEK-ERK and MEKK1-JNK, and their roles in cell survival and proliferation. An analysis of nine pancreatic cancer tissues revealed JNK activation in all tumor samples and ERK activation in three tumor samples. Colony formation assays by transfection of dominant negative mutants of Ras, ERK or MEKK1 into pancreatic cancer cell lines (BxPC-3, PANC-1, MIAPaCa-2 and AsPC-1) and an amnion-derived cell line (FL) revealed that DN-MEKK strongly inhibits the survival of colonies in pancreatic cancer cells, but not in FL cells. In vitro kinase assays and luciferase assays using the Gal4c-Jun system revealed that in pancreatic cancer cells DN-MEKK fails to inhibit JNK activation. In PANC-1 cells, c-Jun was found to be a major component of protein component binding to AP-1 site and CRE, but not in FL cells. The inhibitory effect of DN-MEKK in PANC-1 cells was thought to be the result of the inhibition of c-Jun DNA-binding. The difference of suppression in pancreatic cancer cells and non-pancreatic cancer cells suggested that the MEKK1 pathway mainly contributes to cell survival in pancreatic cancer cells and may provide an advantage for the gene therapy of pancreatic cancers using DN-MEKK expression vectors.
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PMID:Dominant negative MEKK1 inhibits survival of pancreatic cancer cells. 1218 92

Over 90% of human pancreatic cancers harbor an activating point mutation in the K-ras gene at codon 12. However, it is not clear whether all downstream K-ras are activated and which downstream contributes to the cell survival and proliferation of pancreatic cancer cells. MEK kinase 1 (MEKK1)-c-Jun N-terminal kinase (JNK)-c-Jun pathway has an important role in cell proliferation, survival and apoptosis in various cells. We previously demonstrated that the dominant negative form of MEKK1 (DN-MEKK) inhibits the survival of human pancreatic cancer cell lines. In this study we investigated whether JNK-c-Jun, the downstream pathway of DN-MEKK, affects the survival of human pancreatic cancer cell lines. Colony formation assays indicated that c-Jun failed to inhibit the survival of pancreatic cancer cells, whereas c-Jun remarkably inhibited the cell survival of non-pancreatic cancer cells. Reporter gene assays using Gal4-c-Jun and gel retardation assays indicated that c-Jun functions were activated in growing pancreatic cancer cells. These results revealed that c-Jun activation does not prevent the cell survival of pancreatic cancer cells in contrast to non-pancreatic cancer cells. It appears that MEKK1-JNK-c-Jun pathway fails to act as a negative regulator for the cell survival of pancreatic cancer cells. Greater understanding of these mechanisms may be helpful in the treatment of pancreatic cancer.
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PMID:Survival regulation in pancreatic cancer cells by c-Jun. 1296 95