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)

To study the mechanism by which v-mos induces cell transformation, we generated a transformed rat cell line (DTM) containing two functional copies of mos, one encoding the p37v-mos of the m1 wild-type strain of Moloney murine sarcoma virus (Mo-MuSV) and the other the p85gag-mos fusion protein of the ts110 mutant of Moloney murine sarcoma virus. Subsequently, we isolated a revertant cell line (F-1) following transfection of DTM with a mutant retroviral construct (pIC4Neo) carrying a selectable marker. Like DTM, the F-1 revertant contained two integrated copies of v-mos, expressed mos containing viral RNA, and contained rescuable transforming viruses. The revertant did not grow in soft agar, showed a greatly reduced ability to form tumors in nude mice, and exhibited organized tubulin and actin structures similar to those found in normal cells. Revertant cells were resistant to retransformation by v-mos and v-raf but could be retransformed by v-ras. MAP kinase (ERK-2) and MAP kinase kinase (MKK-1) activity, which are constitutively elevated in v-mos- and v-raf-transformed cells, exhibits levels in the F-1 revertant similar to those seen in nontransformed cells. F-1 and normal REF-1 cells express elevated levels of protein phosphatases in comparison to DTM cells. In vivo treatment with okadaic acid, a potent protein phosphatase inhibitor, leads to an increase in MKK-1 and MAP kinase activity in F-1 cells but not in REF-1. The results support the hypothesis that mos acts through the MAP kinase cascade (MKK-1 and ERK-2) to induce cell transformation and that blocking v-mos activation of that cascade (possibly because of increased levels of phosphatase) prevents transformation.
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PMID:Transformation-resistant mos revertant is unable to activate MAP kinase kinase in response to v-mos or v-raf. 771 84

By applying Western blot analysis using anti-phosphotyrosine antibodies, primary human dermal fibroblasts were examined after having been cultured on type I collagen-coated surfaces or in free-floating type I collagen gels. In both systems cells showed enhanced tyrosine phosphorylation of a M(r) 120,000 protein (pp120) and of a M(r) 42,000 protein (pp42). Phosphorylation was apparent 6 h at the latest after initiation of the culture and was only slightly induced on polylysine or on plastic. In contrast to pp42, pp120 was rapidly dephosphorylated in cells suspended by trypsinization or released from collagen gels by collagenase treatment, but regained phosphorylation in cells cultured in/on type I collagen. Two human sarcoma cell lines (HT-1080 and RD) exhibited identical tyrosine phosphorylation of pp120 but not of pp42. pp120 is identical with pp125FAK, a novel tyrosine kinase localized in focal adhesions, as proved by immunological cross-reactivity with anti-pp125FAK antibodies. Our results suggest that tyrosine phosphorylation is involved in signal transduction triggered by two- and three-dimensional type I collagen-fibroblast contact.
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PMID:Three-dimensional contact with type I collagen mediates tyrosine phosphorylation in primary human fibroblasts. 812 56

We have characterized activation of the MAP kinase cascade in an inducible system in response to the temperature-sensitive (ts) expression of the v-mos oncogene. Transformation of immortalized rat embryo fibroblasts by a ts isolate of Moloney murine sarcoma virus (Mo-MuSVts110) constitutively activates MAP kinases (ERK-1 and ERK-2) and MAP kinase kinases (MKK-1 and MKK-2) only at the permissive temperature when v-mos kinase is present and active. Following a shift of the ts-transformed, serum-starved cells from the nonpermissive to permissive temperature, MAP kinases and both MKK-1 and MKK-2 are activated within 1-2 h, concurrent with the reappearance of active mos kinase. Raf-1 kinase activity increases more slowly in response to the reappearance of v-mos, and the mobility shift indicative of hyperphosphorylation was only detected 18 h after the temperature transition. Our data show that MAP kinase cascade activation is an early event following the reappearance of v-mos expression and v-mos kinase activity upon temperature shift, while the first manifestation of morphological transformation appears 24 h after the shift to permissive temperature. These results support the hypothesis that mos acts through the MKK to induce cell transformation.
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PMID:Activation of the mitogen-activated protein kinase cascade in response to the temperature inducible expression of v-mos kinase. 851 89

Interstitial collagenases participate in the remodeling of skeletal matrix and are regulated by fibroblast growth factor (FGF). A 0.2-kb fragment of the proximal human interstitial collagenase [matrix metalloproteinase (MMP1)] promoter conveys 4- to 8-fold induction of a luciferase reporter in response to FGF2 in MC3T3-E1 osteoblasts. By 5'-deletion, this response maps to nucleotides -100 to -50 relative to the transcription initiation site. The 63- bp MMP1 promoter fragment -123 to -61 confers this FGF2 response on the rous sarcoma virus minimal promoter. Intact Ets and AP1 cognates in this element are both required for responsiveness. The AP1 site supports basal and FGF-inducible promoter activity. The intact Ets cognate represses basal transcriptional activity in both heterologous and native promoter contexts and is also required for FGF activation. FGF2 up-regulates a DNA-binding activity that recognizes the MMP1 AP1 cognate and contains immunoreactive Fra1 and c-Jun. Both constitutive and FGF-inducible DNA-binding activities are present in MC3T3-E1 cells that recognize the MMP1 Ets cognate; prototypic Ets transcriptional activators are not present in these complexes. Inhibitors of protein kinase C, phosphatidyl inositol 3-OH kinase, and calmodulin-dependent protein kinase do not attenuate MMP1 promoter activation. FGF2 activates ERK1/ERK2 signaling in osteoblasts; however, 25 microM MAPK-ERK kinase (MEK) inhibitor PD98059 (inhibits by > 85% the phosphorylation of ERK1/ERK2) has no effect on MMP1 promoter activation by FGF2. Ligand-activated and constitutively active FGF receptors initiate MMP1 induction. Dominant negative Ras abrogates MMP1 induction by constitutively active FGFR2-ROS, but dominant negative Rho and Rac do not inhibit induction. The mitogen-activated protein kinase (MAPK) phosphatase MKP2 [inactivates extracellular regulated kinase (ERK) = Jun N-terminal kinase (JNK) > p38 MAPK] completely abrogates MMP1 activation, whereas PAC1 (inactivates ERK = p38 > JNK) attenuates but does not completely prevent induction. Thus, a Ras- and MKP2-regulated MAPK pathway, independent of ERK1/ERK2 MAPK activity, mediates FGF2 transcriptional activation of MMP1 in MC3T3-E1 osteoblasts, converging upon the bipartite Ets-AP1 element. The DNA-protein interactions and signal cascades mediating FGF induction of the MMP1 promoter are distinct from two other recently described FGF response elements: the MMP1 promoter (-123 to -61) represents a third FGF-activated transcriptional unit.
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PMID:Fibroblast growth factor receptor signaling activates the human interstitial collagenase promoter via the bipartite Ets-AP1 element. 921 60

Theileria parasitises bovine leukocytes and transforms them into proliferating, metastatic tumours, where the infection resembles a leukaemia-like disease. We have studied the signal transduction pathways leading to activation of the transcription factor AP-1 in different transformed leukocytes. Parasite infection leads to an up-regulation of all members of the Jun/Fos family of proteins and surprisingly, this occurs in the absence of any detectable ERK, or p38 MAP kinase activity. In the parasitised B-sarcoma TBL3, AP-1 induction occurs in the absence of any JNK activity. In contrast, in infected macrophage and B-cell lines, AP-1 transcriptional activity is strictly associated with the parasite-induced constitutive activation of JNK and subsequent c-Jun N-terminal phosphorylation. Thus, constant AP-1 transcriptional activity involves both an upregulation in the levels of Jun and Fos proteins and constitutive JNK activation.
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PMID:Upregulation of Jun and Fos family members and permanent JNK activity lead to constitutive AP-1 activation in Theileria-transformed leukocytes. 974 72

Growth factor-responsive protein kinases regulate expression of genes involved in cell cycle control, cell proliferation and differentiation. To better understand the role of these kinases in the abnormal proliferation of malignant cells, we examined basal and epidermal growth factor (EGF)-inducible mitogen-activated protein kinase (MAPK), p70S6k and p90rsk activities in spontaneous hepatocellular neoplasms (adenomas and carcinomas) from CBA-T6 mice and in L1 sarcoma tumours implanted in livers of BALB/c mice. In spontaneous and implanted hepatic tumours, basal cytoplasmic and nuclear MAPK, p70S6k and p90rsk activities were significantly higher compared to the activities found in the part of the liver uninvolved by the tumour. Interestingly, the activities of these enzymes in the uninvolved tissue of the livers harbouring the tumour were higher compared to the livers from control mice. Basal kinase activities correlated with tumour morphology; they were lower in adenomas than in carcinomas and sarcomas. In contrast to basal activities, EGF-triggered kinase responses in normal livers and hepatic tumours were indistinguishable. Activating protein-1 (AP-1) DNA-binding activity was detected in tumours but not in the adjacent tissues. Constitutively activated kinases and AP-1 transcription factor found in hepatic malignancies are reminiscent of cells activated by EGF, suggesting that EGF and its intracellular effectors play a role in these malignancies.
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PMID:Increased activity of MAP, p70S6 and p90rs kinases is associated with AP-1 activation in spontaneous liver tumours, but not in adjacent tissue in mice. 1073 87

Vascular endothelial growth factor (VEGF) induces both angiogenesis and an increase in vascular permeability, 2 processes that are considered to be important for both tumor growth and the delivery of drugs to the site of tumors. This study demonstrates that transmembrane expression of tumor necrosis factor (tmTNF) is up-regulated in the endothelium of a murine methylcholanthrene (meth A)-induced sarcoma in comparison to the adjacent normal dermal vasculature and is also present on cultivated human endothelial cells. It is further shown that tmTNF is required for VEGF-mediated endothelial hyperpermeability in vitro and in vivo. This permissive activity of TNF appears to be selective, because anti-TNF antibodies ablated the VEGF-induced permeability but not proliferation of cultivated human endothelial cells. Furthermore, tnf gene-deficient mice show no obvious defects in vascularization and develop normally but failed to respond to administration of VEGF with an increase in vascular permeability. Subsequent studies indicated that the tmTNF and VEGF signaling pathways converge at the level of a secondary messenger, the "stress-activated protein kinase-2" (SAPK-2)/p38: (1) up-regulated endothelial expression of tmTNF resulted in the continuous activation of SAPK-2/p38 in vitro, and (2) an inhibitor of SAPK-2/p38 activation abolished the vascular permeability activity of VEGF in vivo. In conclusion, the study's finding that continuous autocrine signaling by tmTNF sensitizes endothelial cells to respond to VEGF by increasing their vascular permeability provides new therapeutic concepts for manipulating vascular hyperpermeability.
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PMID:A permissive role for tumor necrosis factor in vascular endothelial growth factor-induced vascular permeability. 1122 76

We previously reported that R7Delta447, a 2954-base-pair (bp) laboratory-generated Moloney murine sarcoma virus, induced subcutaneous tumors in about 14% of infected mice but did not induce brain lesions. We now report that R7Delta447K, a spontaneous mutant of R7Delta447, induced brain lesions as well as subcutaneous tumors in all injected mice. The genomes of the two viruses differ in a single base pair: the deduced Glu(62) of the Mos residue of the R7Delta447 Gag-tMos protein is changed to Lys(62). More R7Delta447 than R7Delta447K focus-forming units were detected in both NIH3T3 and mouse cerebral vascular endothelial (MCVE) cells. However, R7Delta447K transformed NIH3T3 and MCVE cells more acutely than did R7Delta447. A distinctive feature that distinguished the morphologic transformation of R7Delta447- and R7Delta447K-infected MCVE cells is the markedly prolonged spindle-shaped phase exhibited by R7Delta447-infected MCVE cells. In addition, R7Delta447K was more efficient in inducing the phosphorylation of ERK1/2 than R7Delta447 in both MCVE and NIH3T3 cells. Moreover morphologic transformation was inhibited, and levels of phosphorylated ERK1/2 were reduced when R7Delta447- or R7Delta447K-infected NIH3T3 or MCVE cells were grown in the presence of the MEK1/2-specific inhibitor PD98095. Thus, we have identified a key residue in the Gag-tMos protein that profoundly affects activation of the Mos/MEK/ERK pathway, virus and cell replication, morphologic transformation in vitro and pathogenicity in vivo.
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PMID:A single Glu(62)-to-Lys(62) mutation in the Mos residues of the R7Delta447Gag-tMos protein causes the mutant virus to induce brain lesions. 1131 3

K-ras codon 12 mutation is more oncogenic in in vitro and in vivo experimental systems than K-ras codon 13 mutation. Moreover, human colorectal tumors bearing a codon 12 mutation are more aggressive, invasive, and metastatic than the same tumor types carrying a codon 13 mutation. However, despite the association between specific sarcoma types and codon 12 or codon 13 mutations, the relationship between the position of the mutated codon at ras genes and tumor aggressiveness has not been studied in this tumor type. Here, we used a nude mice model to evaluate the tumorogenic capacity of stable transfectants of NIH3T3 fibroblasts, expressing K-ras mutated at codon 12 (K12) or 13 (K13), and morphologically, functionally, and molecularly compared these tumors. We found histopathological differences between them, K12-derived tumors showing fibrosarcoma-like features, whereas K13-derived tumors resembled malignant fibrous histiocytomas. Moreover, K12 tumors showed shorter latency of appearance, lower apoptotic and mitotic rates, and higher expression of markers for sarcoma aggressiveness (Ki67, p53 and c-myc) than K13 tumors. They also showed differences in the expression or activation of Ras, Ras downstream pathways [c-Jun N-terminal kinase (JNK), MAPK and AKT], and apoptotic [AKT, Bcl-2, Focal adhesion kinase (FAK)] and mitotic (cyclin B1) regulators, which could explain their functional differences. Most remarkably, the significantly diminished apoptotic rate observed in K12-derived tumors was associated with enhanced antiapoptotic signaling through the AKT pathway. These morphological, functional, and molecular differences demonstrate that codon 12 and codon 13 mutations in the K-ras oncogene can induce two different soft tissue sarcoma types in our in vivo model.
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PMID:Codon 12 and codon 13 mutations at the K-ras gene induce different soft tissue sarcoma types in nude mice. 1220 5

Salvianolic acid A (1) is one of the active components from Salvia miltiorrhiza, which was found to suppress the growth of mouse tumors. S-3-1 (a 2-allyl-3,4-dihydroxybenzaldehyde, 2) is a synthetic intermediate of a salvianolic acid A derivative with strong inhibitory effects on the growth of cancer cells in vitro. The inhibitory effects of 2 on tumor growth and its molecular targets were studied. 2 significantly suppressed the growth of mouse Lewis lung carcinoma, S180 sarcoma and H22 hepatic carcinoma in a dose-dependent manner. With a simple scrape-loading dye transfer method, 20 microg/ml of 2 was found to significantly enhance gap junction intercellular communication (GJIC) in human pancreatic adenocarcinoma PaCa Cells, human lung epithelial carcinoma W1-38 cells and human lung adenocarcinoma A549 cells, but 2 had no marked effect on GJIC in human colon cancer CACO2 cells. With Northern blot analysis, 2 was found to inhibit the expression of c-myc gene in A549 cells and have no marked effect on H-ras oncogene expression, and increase the cellular P53 mRNA contents, though it did not affect the expression of RB tumor suppressor gene. 2 also suppressed the P46 (JNK/SAPK) expression in A549 cells. Western blot analysis was applied to visualize the P21ras protein. Results shows that 2 at concentrations ranging from 10 to 20 microg/ml decreases the contents of the membranous P21ras and total P21ras and increases the contents of cytosolic P21ras protein in a time-dependent manner. However, 2 had no significant effects on farnesyl protein transferase activities at the concentrations that could efficiently decrease the membranous P21ras content. This suggested that 2 might suppress tumor growth partly through enhancement of GJIC and reversion of the transformed phenotypes. The other mechanisms may be that 2 can suppress the overexpression of c-myc oncogene, inhibit the function of Ras oncoprotein, increase the expression of P53 tumor suppressor gene and interrupt P46-associated mitogen-activated pathway other than farnesylation of Ras protein.
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PMID:Inhibition of tumor growth by S-3-1, a synthetic intermediate of salvianolic acid A. 1245 Feb 55


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