UMLS:C0027651 - FACTA Search

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

Since tumor promoter benzoyl peroxide (BPO) mimics phorbol esters in some aspects, its effects on protein kinase C (PKC) were previously studied. However, in those studies due to the presence of thiol agents in the PKC preparations, the sensitive reaction of BPO with redox-active cysteine residues in PKC was not observed. In this study, by excluding thiol agents present in the purified PKC preparation, low concentrations of BPO modified PKC, resulting in the loss of both kinase activity and phorbol ester binding (IC50 = 0. 2 to 0.5 microM). This modification, which was not dependent on transition metals, was totally blocked by a variety of thiol agents including GSH, which directly reacted with BPO. Substoichiometric amounts of BPO (0.4 mol/mol of PKC) oxidized two sulfhydryls in PKC and inactivated the enzyme which was readily reversed by dithiothreitol. The regulatory domain having zinc thiolate structures supporting the membrane-inserting region provided the specificity for PKC reaction with BPO, which partitioned into the membrane. Unlike H2O2, BPO did not induce the generation of the Ca2+/lipid-independent activated form of PKC. Other redox-sensitive enzymes such as protein kinase A, phosphorylase kinase, and protein phosphatase 2A required nearly 25- to 100-fold higher concentrations of BPO for inactivation. BPO also inactivated PKC in a variety of cell types. In the JB6 (30 P-) nonpromotable cell line and other normal cell lines, where BPO was more cytotoxic, it readily inactivated PKC due to a slow reversibility of this inactivation by the cell. However, in the JB6 (41 P+) promotable cell line, C3H10T1/2 and B16 melanoma cells, where BPO was less cytotoxic, it did not readily inactivate PKC due to a rapid reversibility of this inactivation by an endogenous mechanism. Nevertheless, BPO inactivated PKC at an equal rate in the homogenates prepared from all these cell types. Inclusion of NADPH reversed this inactivation in the homogenates to a different extent, presumably due to a difference in distribution of a protein disulfide reductase, which reverses this oxidative modification. BPO-induced modification of PKC occurred independent of the cellular status of GSH. However, externally added GSH and cell-impermeable thiol agents prevented the BPO-induced modification of PKC. Since BPO readily partitions into membranes, its reaction with redox-cycling thiols of membrane proteins such as PKC may trigger epigenetic events to prevent cytotoxicity, but favor tumor promotion.
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PMID:Tumor promoter benzoyl peroxide induces sulfhydryl oxidation in protein kinase C: its reversibility is related to the cellular resistance to peroxide-induced cytotoxicity. 1006 46

11q23-24 chromosome is a region containing frequent allelic loss (loss of heterozygosity; LOH) in human cancers. To examine cancer-related allelic loss in the region between D11S940 and APOC3, we used 17 polymorphic markers and allotyped 28 lung cancer-derived cell lines and their corresponding matched lymphoblastoid cell lines. LOH was found in 71.4% (20/28) of the lung cancer cell lines and was localized to two distinct minimal regions of loss. One region is bracketed by markers D11S1647 and NCAM2 and contains the gene encoding the beta isoform of the A subunit of the human protein phosphatase 2A (PPP2R1B). Recently, mutations in this gene were described in lung and colon cancers, suggesting that PPP2R1B functions as a tumor-suppressor gene. A second minimal region of loss was defined between markers D11S1792 and D11S1885, a region estimated to be less than I Mb. Thus, chromosome 11 likely harbors two sites of suppressor oncogene activity in lung cancer, one defined by the PPP2R1B gene and the second located telomeric to PPP2R1B. This study facilitates the identification and cloning of a second critical tumor-suppressor gene involved in lung cancer, and possibly a variety of other cancers, on human chromosome band 11q23.
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PMID:Refined mapping of two regions of loss of heterozygosity on chromosome band 11q23 in lung cancer. 1033 99

The 1997-1998 period brought many new developments to the phycotoxin field. There were several reviews on phycotoxins in general, on their toxicological evaluation, and on their analysis. The ecophysiology, biosynthesis, and metabolism of polyether toxins and paralytic shellfish poisoning (PSP) toxins were also reviewed. The proceedings of the Eighth International Conference on Harmful Algae (Vigo, Spain, June 25-29, 1997) have been published and provide an excellent source of information on phycotoxins and toxic plankton bloom research. In addition, the much anticipated proceedings of the IX International IUPAC Symposium on Mycotoxins and Phycotoxins (Rome, Italy, May 27-31, 1996) have been published. Further evidence was provided to support the theory that Prorocentrum lima is the source organism for diarrhetic shellfish poisoning (DSP) toxins in Nova Scotian shellfish. In another study, different Prorocentrum species and isolates were analyzed for DSP toxins. In addition to detecting some new compounds, such as a DTX1 isomer, it was found that toxins were produced by both axenic and nonaxenic batch cultures, indicating that bacteria are probably not involved in the biosynthesis. The source organism for the spirolides, a family of fast-acting toxins reported from Nova Scotia, Canada, was determined to be Alexandrium ostenfeldii, a species that is found worldwide. The biogenetic origin of yessotoxin was reported to be Protoceratium reticulatum, another widely occurring organism. A great deal of attention and research funding has been directed at the serious problems associated with Pfiesteria piscicida. Analysts are eagerly awaiting publication of toxin structures, which will then allow the development of analytical methods. An incident of the mass mortality of California sea lions was reported in the Monterey area in May 1998. Analyses of tissue and urine samples revealed the presence of domoic acid. High levels of domoic acid were also found in anchovies and sardines, a common food source of sea lions. This is reminiscent of an incident of mass bird mortality in 1992 in the same region. Toxicological studies of domoic acid continue with one investigation on the effect of pH on toxicity in the mouse assay and others examining toxic effects in rats and cynomolgus monkeys. A study on the uptake and depuration of domoic acid in the Dungeness crab was reported. On October 20, 1997, EU (European Union) directive CE97/61 established a regulatory limit of 20 ppm for domoic acid in European shellfish, the same level as in North America. A detailed study on the oral toxicity of DSP toxins in mice was reported. Recent work by several researchers has revealed the genotoxic potential of okadaic acid and other DSP toxins. Previous work had clearly demonstrated the tumor-promoting potential of DSP toxins, but this recent evidence, which shows mutations in the progeny of okadaic acid-treated cells and the formation of DNA-adducts, increases concerns over the hazards associated with DSP-contaminated shellfish. The toxicology of yessotoxin was evaluated by Ogino et al. The toxin showed weak cytotoxicity, but was not orally lethal to mice at 10 mg/kg, and did not cause intestinal fluid accumulation, inhibition of protein phosphatase 2A (PP2A), or hemolytic effects. Similarly, Tubaro et al. saw no evidence for diarrheogenicity of homoyessotoxin isolated from mussels and from the proposed planktonic producer, Lingulodinium polyedrum. All this provides further evidence that yessotoxin should not be classed as a DSP toxin. A number of new toxins have been detected and identified. Two analogues of yessotoxin, homoyessotoxin, and 45-hydroxyhomoyessotoxin were isolated from mussels of the Adriatic Sea and identified by Satake et al. A recent DSP event in Ireland associated with cultured mussels led to the identification of azaspiracid, a unique marine toxin with spiro ring assemblies. (ABSTRACT TRUNCATED)
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PMID:Phycotoxins. 1036 95

Telomerase, a specialized RNA-directed DNA polymerase that extends telomeres of eukaryotic chromosomes, is repressed in normal human somatic cells but is activated during development and upon neoplasia. Whereas activation is involved in immortalization of neoplastic cells, repression of telomerase permits consecutive shortening of telomeres in a chromosome replication-dependent fashion. This cell cycle-dependent, unidirectional catabolism of telomeres constitutes a mechanism for cells to record the extent of DNA loss and cell division number; when telomeres become critically short, the cells terminate chromosome replication and enter cellular senescence. Although neither the telomere signaling mechanisms nor the mechanisms whereby telomerase is repressed in normal cells and activated in neoplastic cells have been established, inhibition of telomerase has been shown to compromise the growth of cancer cells in culture; conversely, forced expression of the enzyme in senescent human cells extends their life span to one typical of young cells. Thus, to switch telomerase on and off has potentially important implications in anti-aging and anti-cancer therapy. There is abundant evidence that the regulation of telomerase is multifactorial in mammalian cells, involving telomerase gene expression, post-translational protein-protein interactions, and protein phosphorylation. Several proto-oncogenes and tumor suppressor genes have been implicated in the regulation of telomerase activity, both directly and indirectly; these include c-Myc, Bcl-2, p21(WAF1), Rb, p53, PKC, Akt/PKB, and protein phosphatase 2A. These findings are evidence for the complexity of telomerase control mechanisms and constitute a point of departure for piecing together an integrated picture of telomerase structure, function, and regulation in aging and tumor development-Liu, J.-P. Studies of the molecular mechanisms in the regulation of telomerase activity.
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PMID:Studies of the molecular mechanisms in the regulation of telomerase activity. 1059 57

Rho is a member of the Ras-related family of small molecular weight GTP-binding proteins, and works as a molecular switch by shuttling between the GDP-bound inactive form and the GTP-bound active form. Cellular functions of Rho have been studied by two ways; one is to express or microinject constitutively active Rho mutants in cells to identify the active phenotype of Rho, and the other is to use botulinum C3 exoenzyme that specifically ADP-ribosylates and inactivates Rho in cells to find out phenotypes of Rho inactivation. These analyses have revealed that Rho is involved in cell to substratum adhesion and motility, cell contraction and cytokinesis through the reorganization of the actincytoskeleton and modulation of its activity. These actions of Rho are mediated by downstream Rho effectors. Several putative Rho effectors have been isolated on the basis of their selective binding to the GTP-bound form of Rho. Among them, the ROCK family of Rho-associated serine/threonine protein kinases inactivates cofilin and myosin phosphatase to induce stabilization of filamentous actin and increase in the actomyosin-based contractility. mDia binds profilin likely to promote actin polymerization. Thus, these effectors in combination are supposed to work in organization of various forms of the actin cytoskeleton. Furthermore, analyses using a ROCK specific inhibitor Y-27632 have suggested that the Rho-ROCK pathway works in contractions of vascular and bronchial smooth muscles under various pathological conditions and is involved in malignant cell transformation and tumor invasion and metastasis.
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PMID:[Cellular functions & pharmacological manipulations of the small GTPase Rho & Rho effectors]. 1062 46

The transcription factor Sp1 regulates the activity of a large number of eukaryotic gene promoters, including early SV40 and human immunodeficiency virus type 1 (HIV-1). Here, we report that expression of SV40 small tumor antigen (small t) in quiescent CV-1 cells transactivates two Sp1-responsive promoters, including a deletion mutant of HIV-1 LTR, through specific inhibition of endogenous AC and ABalphaC forms of protein phosphatase 2A (PP2A). Expression of a small t mutant, lacking the PP2A-binding domain, failed to transactivate Sp1. Overexpression of the B56alpha, B56beta, and B56gamma1 regulatory PP2A subunits strongly inhibited the ability of small t, but not the phosphatase inhibitor, okadaic acid, to enhance Sp1-driven gene expression. Using inhibitors and co-expression of kinase-deficient mutants, we also show that functional phosphatidylinositol 3-kinase (PI 3-kinase) and atypical protein kinase C zeta are required for small t-induced Sp1-dependent promoter transcriptional activation. Moreover, two inhibitors of PI 3-kinase, wortmannin and LY294002, inhibit the initiation of SV40 DNA replication in quiescent CV-1 cells. Taken together, these results suggest that PP2A and PI 3-kinase contribute to the ability of small t to regulate Sp1 activity, stimulate early SV40 DNA replication, and enhance the transformation of resting cells during SV40 infection.
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PMID:Protein phosphatase 2A and phosphatidylinositol 3-kinase regulate the activity of Sp1-responsive promoters. 1073 82

Epidemiological and experimental studies have suggested a protective role of phytosterols (PS) in the development of some types of cancer such as colon and prostate cancer. No work has been reported on the role of PS in the development of breast cancer, the second leading cancer in woman. The present study was designed to examine the effect of the two most common dietary PS, beta-sitosterol (SIT) and campesterol, as compared to cholesterol, the main sterol in the Western diet, on growth, apoptosis and cytotoxicity of MDA-MB-231 human breast cancer cells in culture. In addition, we investigated the possible role of protein phosphatase 2A (PP2A), an enzyme that has been shown to regulate growth and apoptosis in tumor parameters studied. Breast cancer cell growth was found to be inhibited by 66% after 3 days and 80% after 5 days with 16 microM SIT. Both campesterol and cholesterol sustained tumor growth at levels comparable to that of the vehicle control. None of the sterols tested at this level (16 microM) induced cytotoxicity as measured by lactic dehydrogenase release. SIT supplementation for 3 days at 16 microM resulted in a 6-fold increase in apoptosis in cells when compared to cholesterol treated cells. SIT treatment was found to have no effect on the level and content of tumor cell PP2A. It is concluded that SIT, by a still unknown mechanism, may offer protection from breast cancer by inhibiting growth and stimulating apoptosis.
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PMID:Inhibition of growth and stimulation of apoptosis by beta-sitosterol treatment of MDA-MB-231 human breast cancer cells in culture. 1076 59

Previous work in our laboratory using functional assays for tumorigenicity identified a tumor suppressor element on human chromosome 11q for the cutaneous squamous cell carcinoma cell line A388.6TG.c2. In this report, we screened a variety of agents for differential effects on A388.6TG.c2 compared to a growth-suppressed chromosome 11 microcell hybrid of A388.6TG.c2. One of the agents, 1, 25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3); calcitriol), exerted a growth-altering effect on A388.6TG.c2, which formed rounded cell clusters across the surface of the raft by Day 6 of treatment. In contrast, full-length chromosome 11 hybrids of A388.6TG.c2, as well as two other squamous cell carcinoma cell lines (FaDu and A431), when treated with 1,25(OH)(2)D(3), failed to demonstrate this cell-clumping phenotype. To pursue the hypothesis that the growth suppressor element is involved in altering the response to 1, 25(OH)(2)D(3), we tested microcell hybrids carrying t(X;11) chromosomes lacking large portions of 11q. Although these hybrids, like the parent A388.6TG.c2 cells, demonstrated extensive growth in organotypic cultures, they failed to form cell clusters with 1, 25(OH)(2)D(3) treatment. These results suggest that the chromosome 11 element that alters the response to 1,25(OH)(2)D(3) is distinct from the growth-suppressing element. An examination of differentiation marker expression revealed identical patterns of basal and suprabasal markers for A388.6TG.c2 and for a chromosome 11 hybrid with or without treatment with 1,25(OH)(2)D(3). Finally, characterization of candidate tumor suppressor gene PPP2R1B, which encodes for a subunit of protein phosphatase 2A (PP2A), showed seemingly insignificant alterations by cDNA sequence analysis. Collectively, the data suggest that human chromosome 11 contains two different tumor suppressor elements that may account for the two areas of loss of heterozygosity observed on the long arm of this chromosome.
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PMID:Altered response of a human squamous cell carcinoma cell line to 1, 25-dihydroxyvitamin D(3) after transfer of a normal chromosome 11. 1094 91

Binding of different regulatory subunits and methylation of the catalytic (C) subunit carboxy-terminal leucine 309 are two important mechanisms by which protein phosphatase 2A (PP2A) can be regulated. In this study, both genetic and biochemical approaches were used to investigate regulation of regulatory subunit binding by C subunit methylation. Monoclonal antibodies selectively recognizing unmethylated C subunit were used to quantitate the methylation status of wild-type and mutant C subunits. Analysis of 13 C subunit mutants showed that both carboxy-terminal and active site residues are important for maintaining methylation in vivo. Severe impairment of methylation invariably led to a dramatic decrease in Balpha subunit binding but not of striatin, SG2NA, or polyomavirus middle tumor antigen (MT) binding. In fact, most unmethylated C subunit mutants showed enhanced binding to striatin and SG2NA. Certain carboxy-terminal mutations decreased Balpha subunit binding without greatly affecting methylation, indicating that Balpha subunit binding is not required for a high steady-state level of C subunit methylation. Demethylation of PP2A in cell lysates with recombinant PP2A methylesterase greatly decreased the amount of C subunit that could be coimmunoprecipitated via the Balpha subunit but not the amount that could be coimmunoprecipitated with Aalpha subunit or MT. When C subunit methylation levels were greatly reduced in vivo, Balpha subunits were found complexed exclusively to methylated C subunits, whereas striatin and SG2NA in the same cells bound both methylated and unmethylated C subunits. Thus, C subunit methylation is critical for assembly of PP2A heterotrimers containing Balpha subunit but not for formation of heterotrimers containing MT, striatin, or SG2NA. These findings suggest that methylation may be able to selectively regulate the association of certain regulatory subunits with the A/C heterodimer.
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PMID:Methylation of the protein phosphatase 2A catalytic subunit is essential for association of Balpha regulatory subunit but not SG2NA, striatin, or polyomavirus middle tumor antigen. 1116 Aug 32

The A subunit of protein phosphatase 2A (PP2A) consists of 15 nonidentical repeats. The catalytic C subunit binds to C-terminal repeats 11 - 15 and regulatory B subunits bind to N-terminal repeats 1 - 10. Recently, four cancer-associated mutants of the A-alpha subunit have been described: Glu64-->Asp in lung carcinoma, Glu64-->Gly in breast carcinoma, Arg418-->Trp in melanoma, and Delta171 - 589 in breast carcinoma. Based on our model of PP2A, we predicted that Glu64-->Asp and Glu64-->Gly might be defective in B subunit binding, whereas Arg418-->Trp and Delta171 - 589 might bind neither B nor C subunits. We generated these mutants by site-directed mutagenesis and assayed their ability to associate with different forms of B subunits (B, B', B") or with the catalytic C subunit. The results demonstrate that all mutants are defective in binding either B or B and C subunits. Specifically, the N-terminal mutants, Glu64-->Asp and Glu64-->Gly, are defective in B' but normal in B, B", and C subunit binding, whereas the C-terminal mutants Arg418-->Trp and Delta171 - 589 bind none of the B subunits nor the C subunit. The implications of these findings with regard to the potential role of PP2A as a tumor suppressor are discussed. Oncogene (2001) 20, 10 - 15.
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PMID:Disruption of protein phosphatase 2A subunit interaction in human cancers with mutations in the A alpha subunit gene. 1124 97

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