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: UMLS:C0027651 (tumor)
685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The prototype strain of minute virus of mice [MVM(p)] is an autonomous parvovirus with a tropism for cells expressing a neoplastically transformed phenotype. To generate gene transfer vectors for tumor-specific gene expression, human interleukin-2 (IL-2) and murine interleukin-4 (IL-4) genes were cloned under the control of the p38 late promoter of MVM(p). Upon transfection into permissive cells, the recombinant MVMIL2 or MVMIL4 DNA was excised, amplified, and, in the presence of a helper plasmid, packaged into recombinant viral particles. The recombinant viruses were able to transfer fully functional IL-2 and IL-4 genes to permissive target cells and retained the oncotropic host range properties of the parental virus. Following infection with MVMIL2, nontransformed fibroblasts of rodent (FR3T3) or human (MRC-5) origin produced minimal IL-2 compared with the high levels of IL-2 production observed in their transformed derivatives (FREJ4 and MRC-5V1).
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PMID:Transformation-dependent expression of interleukin genes delivered by a recombinant parvovirus. 156 May 27

Bovine leukemia virus (BLV) gene expression is exquisitely regulated at multiple levels, including a transcriptional control effected by virus-encoded trans-acting factors and cis-acting target sequences. Like the human T-cell leukemia viruses type I and type II, but unlike other RNA tumor viruses, BLV contains several open reading frames at the 3' end of its genome. A subgenomic mRNA which encodes two overlapping reading frames from this region could produce proteins of 38 and 18 kilodaltons (kDa). A series of cis-trans experiments using transfected virus gene constructs in different combinations revealed that expression of the 38-kDa protein was both necessary and sufficient to activate, in trans, the BLV promoter. This activation was specific for the BLV long terminal repeat, as a variety of related retroviral promoters were not responsive to the expression of the 38-kDa protein p38(XBL). Deletion analysis and construction of chimeric promoters identified a 75-base-pair long terminal repeat region which functions like a p38(XBL)-dependent enhancer element.
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PMID:Bovine leukemia virus transcription is controlled by a virus-encoded trans-acting factor and by cis-acting response elements. 303 9

Trivalent arsenic (As3+) is highly carcinogenic, but devoid of known mutagenic activity. Therefore, it is likely to act as a tumor promoter. To understand the molecular basis for the tumor-promoting activity of As3+, we examined its effect on transcription factor AP-1, whose activity is stimulated by several other tumor promoters. We found that As3+, but not As5+, which is toxic but not carcinogenic, is a potent stimulator of AP-1 transcriptional activity and an efficient inducer of c-fos and c-jun gene expression. Induction of c-jun and c-fos transcription by As3+ correlates with activation of Jun kinases (JNKs) and p38/Mpk2, which phosphorylate transcription factors that activate these immediate early genes. No effect on ERK activity was observed. As5+, on the other hand, had a negligible effect on JNK or p38/Mpk2 activity. Biochemical analysis and co-transfection experiments strongly suggest that the primary mechanism by which As3+ stimulates JNK activity involves the inhibition of a constitutive dual-specificity JNK phosphatase. This phosphatase activity appears to be responsible for maintaining low basal JNK activity in non-stimulated cells and its inhibition may lead to tumor promotion through induction of proto-oncogenes such as c-jun and c-fos, and stimulation of AP-1 activity. The same phosphatase may also regulate p38/Mpk2 activity.
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PMID:The tumor promoter arsenite stimulates AP-1 activity by inhibiting a JNK phosphatase. 894 50

Mitogen-activated protein kinase phosphatases (MKPs) play a central role in a variety of signaling pathways. We recently described a novel murine MKP, M3/6, which is uniquely specific for c-Jun N-terminal kinase/stress-activated protein kinase and p38 kinase. Here we report the localization of the human orthologue of this gene, HB5, to within 150 kb of H19 on human chromosome 11p15.5. The gene consists of six exons. Two of the introns in HB5 are not found in other genes of this family, suggesting an evolutionary split between MKPs displaying specificity toward different MAP kinases. An intronless pseudogene is present on chromosome 10q11.2. Although 11p15.5 is an imprinted region, HB5 is almost entirely unmethylated on both alleles in lymphocytes. Chromosome 11p15 has been implicated in the development of a number of tumor types, including lung, a tissue known to express this gene. Loss of heterozygosity was found in one of eight informative lung tumors studied.
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PMID:Genomic organization and chromosomal localization of a member of the MAP kinase phosphatase gene family to human chromosome 11p15.5 and a pseudogene to 10q11.2. 919 49

Phorbol ester tumor promoters, such as phorbol 12-myristate 13-acetate (PMA), are potent activators of extracellular signal-regulated kinase 2 (ERK2), stress-activated protein kinase (SAPK), and p38 mitogen-activated protein kinase (MAPK) in U937 human leukemic cells. These kinases are regulated by the reversible dual phosphorylation of conserved threonine and tyrosine residues. The dual specificity protein phosphatase MAPK phosphatase-1 (MKP-1) has been shown to dephosphorylate and inactivate ERK2, SAPK, and p38 MAPK in transient transfection studies. Here we demonstrate that PMA treatment induces MKP-1 protein expression in U937 cells, which is detectable within 30 min with maximal levels attained after 4 h. This time course coincides with the rapid inactivation of PMA-induced SAPK activity, but not ERK2 phosphorylation, which remains elevated for up to 6 h. To examine directly the role of MKP-1 in the regulation of these protein kinases in vivo, we established a U937 cell line that conditionally expresses MKP-1 from the human metallothionein IIa promoter. Conditional expression of MKP-1 inhibited PMA-induced ERK2, SAPK, and p38 MAPK activity. By titrating the levels of MKP-1 expression from the human metallothionein IIa promoter, however, it was found that p38 MAPK and SAPK were much more sensitive to inhibition by MKP-1 than ERK2. This differential substrate specificity of MKP-1 can be functionally extended to nuclear transcriptional events in that PMA-induced c-Jun transcriptional activity was more sensitive to inhibition by MKP-1 than either Elk-1 or c-Myc. Conditional expression of MKP-1 also abolished the induction of endogenous MKP-1 protein expression in response to PMA treatment. This negative feedback regulatory mechanism is likely due to MKP-1-mediated inhibition of ERK2, as studies utilizing the MEK1/2 inhibitor PD98059 suggest that ERK2 activation is required for PMA-induced MKP-1 expression. These findings suggest that ERK2-mediated induction of MKP-1 may play an important role in preferentially attenuating signaling through the p38 MAPK and SAPK signal transduction pathways.
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PMID:Conditional expression of the mitogen-activated protein kinase (MAPK) phosphatase MKP-1 preferentially inhibits p38 MAPK and stress-activated protein kinase in U937 cells. 920 1

Tumor-necrosis factor(TNF)-alpha inhibited in a dose-dependent fashion the proliferation of epidermal-growth-factor(EGF)-stimulated MCF-7 breast cancer cells with an IC50 of 0.25 nM. A comparable TNF-alpha-mediated inhibition of p42/44 mitogen-activated protein (MAP) kinase activity was observed in 10 nM EGF-stimulated cells. The MAP kinase activity dropped 50% within 3 min of TNF-alpha (1 nM) addition to EGF-stimulated MCF-7 cells. EGF and TNF-alpha, when added independently, led to a transient stimulation of MAP kinase activity with maximal activations within 6-8 min and 1-2 min, respectively. These observations suggest that MAP kinase activity in EGF-stimulated MCF-7 cells is modulated by the growth-inhibitory receptor pathways of TNF-alpha. Phosphorylation measurements on western blots determined the involvement of several individual MAP kinases, namely p42/44 MAP kinases, p38 MAP kinase and c-Jun N2-terminal kinase 1 (JNK1), in EGF and TNF-alpha-induced signalling. Phosphorylation of p42 and p38 MAP kinases only was observed after treatment with either TNF-alpha or EGF. A combination of both ligands inhibited p42 and p38 MAP kinase phosphorylation in MCF-7 cells. In contrast, no JNK1 phosphorylation was detected in these cells. Simultaneous addition of okadaic acid, a potent inhibitor of phosphatases 1 and 2A, blocked the decay of EGF-stimulated MAP kinase activity over 40 min. TNF-alpha added to EGF-stimulated and okadaic-acid-treated cells increased the MAP kinase activity twofold within 1 min. Similarly, okadaic acid treatment partly reverted the TNF-alpha-inhibited growth of MCF-7 cells. These experiments suggest that phosphatases are involved in the rapid shut-down by TNF-alpha of p42 MAP kinase activity.
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PMID:Tumor-necrosis factor-alpha modulates mitogen-activated protein kinase activity of epidermal-growth-factor-stimulated MCF-7 breast cancer cells. 937 Mar 49

Prostate carcinoma (PCA) is the most commonly diagnosed malignancy in American men. Our knowledge of PCA growth regulation lags behind that of other cancers, such as breast and colon carcinomas. Among receptor tyrosine kinases, the ErbB family is most frequently implicated in neoplasia. We report here the expression of ErbB family kinases and their ligands in PCA cell lines and a xenograft. While ErbB1/EGFR, ErbB2/NEU, and ErbB3 were always observed in a distinct pattern, ErbB4 was not observed. Interestingly, while TGF-alpha was expressed in the majority of PCA lines, the ligand Neu Differentiation Factor/Heregulin (NDF) was expressed only in an immortalized, non-transformed prostate epithelial line. Concomitantly, there was a significant difference in biological response to these ligands. NDF inhibited LNCaP growth and induced an epithelial-like morphological change, in contrast to TGF-alpha, which accelerated cell growth. We also performed the first comprehensive analysis of NDF signaling in a prostate line. LNCaP stimulated with NDF demonstrated crosstalk between ErbB3 and ErbB2 which did not involve ErbB1. NDF also turned on several cascades, including those of PI3-K, ERK/MAPK, mHOG/p38 and JNK/SAPK, but not those of PLCgamma or the STAT family. This signaling pattern is distinct from that of TGF-alpha. The activation of mHOG by ErbB2 or ErbB3 has not been reported, and may contribute to the unusual phenotype. PI3-K activation is characterized by the formation of a striking 'activation complex' with multiple tyrosine-phosphorylated species, including ErbB3. Our studies provide a framework in which to dissect the growth and differentiation signals of prostate cancer cells.
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PMID:ErbB kinases and NDF signaling in human prostate cancer cells. 940 Sep 97

The tumor promoter palytoxin has been found to activate the stress-activated protein kinase/c-Jun NH2-terminal kinase 1 (SAPK/JNK1), and it also potentiates, as demonstrated here, the p38/HOG1 mitogen-activated protein kinase and the upstream activator of SAPK/JNK1, SEK1/MKK4. In search of possible mechanisms for both the cytotoxicity and the activation of stress kinases by palytoxin, we found that palytoxin is a potent inhibitor of cellular protein synthesis. The inhibition of translation by palytoxin does not result from its direct binding to the translational apparatus. We have previously demonstrated that ribotoxic stressors (Iordanov, M. S., Pribnow, D., Magun, J. L., Dinh, T.-H., Pearson, J. A., Chen, S. L.-Y., and Magun, B. E. (1997) Mol. Cell. Biol. 17, 3373-3381) signal the activation of SAPK/JNK1 by binding to or covalently modifying 28 S rRNA in ribosomes that are active at the time of exposure to the stressor. Palytoxin acted as a ribotoxic stressor, inasmuch as it required actively translating ribosomes at the time of exposure to activate SAPK/JNK1. Palytoxin has been shown to augment ion fluxes by binding to the Na+/K+-ATPase in the plasma membrane of cells. To determine whether altered fluxes of either Na+ or K+ could be responsible for the effects of palytoxin on translation and on activation of SAPK/JNK1, cells were exposed to palytoxin in modified culture medium in which a major portion of the Na+ was replaced by either K+ or by choline+. The substitution of Na+ by K+ strongly inhibited the ability of palytoxin both to inhibit protein translation and to activate SAPK/JNK1, whereas the substitution of Na+ by choline+ did not. These results suggest that palytoxin-induced efflux of cellular K+ mimics ribotoxic stress by provoking both translational inhibition and activation of protein kinases associated with cellular defense against stress.
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PMID:Loss of cellular K+ mimics ribotoxic stress. Inhibition of protein synthesis and activation of the stress kinases SEK1/MKK4, stress-activated protein kinase/c-Jun NH2-terminal kinase 1, and p38/HOG1 by palytoxin. 945 78

Heme oxygenase-1 is an inducible enzyme that catalyzes heme degradation and has been proposed to play a role in protecting cells against oxidative stress-related injury. We investigated the induction of heme oxygenase-1 by the tumor promoter arsenite in a chicken hepatoma cell line, LMH. We identified a heme oxygenase-1 promoter-driven luciferase reporter construct that was highly and reproducibly expressed in response to sodium arsenite treatment. This construct was used to investigate the role of mitogen-activated protein (MAP) kinases in arsenite-mediated heme oxygenase-1 gene expression. In LMH cells, sodium arsenite, cadmium, and heat shock, but not heme, induced activity of the MAP kinases extracellular-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38. To examine whether these MAP kinases were involved in mediating heme oxygenase-1 gene expression, we utilized constitutively activated and dominant negative components of the ERK, JNK, and p38 MAP kinase signaling pathways. Involvement of an AP-1 site in arsenite induction of heme oxygenase-1 gene expression was studied. We conclude that the MAP kinases ERK and p38 are involved in the induction of heme oxygenase-1, and that at least one AP-1 element (located -1576 base pairs upstream of the transcription start site) is involved in this response.
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PMID:Mechanism of sodium arsenite-mediated induction of heme oxygenase-1 in hepatoma cells. Role of mitogen-activated protein kinases. 953 75

Mitogen-activated protein kinase (MAPK) kinase 4 (MKK4) is a component of a stress and cytokine-induced signal transduction pathway involving MAPK proteins. The MKK4 protein has been implicated in activation of JNK1 and p38 MAPK on phosphorylation by conserved kinase pathways. A recent report on the deletion and mutation of the MKK4 gene in human pancreatic, lung, breast, testicle, and colorectal cancer cell lines suggests an additional role for MKK4 in tumor suppression. Both the gene function and the infrequency of mutations might be considered atypical for many human tumor suppressor genes, and constitutional DNA was not previously available to determine whether the reported sequence variants had preceded tumor development. Here, we report that homozygous deletions are detected in 2 of 92 pancreatic adenocarcinomas (2%), 1 of 16 biliary adenocarcinomas (6%), and 1 of 22 breast carcinomas (when combined with reported sequence alterations, 3 of 22 or 14%). In addition, in a panel of 45 pancreatic carcinomas prescreened for loss of heterozygosity, one somatic missense mutation of MKK4 is observed and confirmed in the primary tumor (2%). Mapping of the homozygous deletions further indicated MKK4 to lie at the target of deletion. The finding of a somatic missense mutation in the absence of any other nucleotide polymorphisms or silent nucleotide changes continues to favor MKK4 as a mutationally targeted tumor suppressor gene. Coexistent mutations of other tumor suppressor genes in MKK4-deficient tumors suggest that MKK4 may participate in a tumor suppressive signaling pathway distinct from DPC4, p16, p53, and BRCA2.
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PMID:Alterations in pancreatic, biliary, and breast carcinomas support MKK4 as a genetically targeted tumor suppressor gene. 962 70


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