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)

Pancreatic islet homogenates display protein kinase C activity. Although the rate of histone phosphorylation by islet homogenates is not enhanced by Ca2+ alone, the Ca2+ ion markedly augments reaction velocity in the presence of phosphatidylserine and at low concentrations (20 nM--0.2 microM) of the tumor-promoting agent 12-0-tetradecanoylphorbol-13-acetate (TPA). At a higher concentration (2.0 microM), TPA stimulates histone phosphorylation even in the absence of Ca2+. Ca-calmodulin also stimulates protein phosphorylation but the latter effect is apparently mediated by a Ca-calmodulin-responsive protein kinase distinct from the protein kinase C. In the presence of phosphatidylserine, retinoic acid (0.1 microM) fails to cause any obvious change in protein kinase C activity. However, in the 0.1-100.0 microM range, retinoic acid confers a limited responsiveness to TPA in the absence of phosphatidylserine. These findings support the view that Ca2+ may regulate protein phosphorylation in the pancreatic B-cell through several distinct pathways.
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PMID:Protein kinase C activity in pancreatic islets: effects of Ca2+, calmodulin and retinoic acid. 316 13

A nonhistone chromatin protein (NHCP) has been purified to homogeneity from a 0.5 M NaCl extract of Ehrlich ascites tumor cell (EAT cell) nuclei as a phosphate acceptor for casein kinase II using ion-exchange column chromatographies and Sephacryl S300 gel filtration. The purified NHCP (approximate Mr = 400,000) was found to be a tetramer of an Mr = 98,000 polypeptide (pI = 6.9) and to have high contents of glycine (15%) and serine (11.6%). This protein (designated as 400-kDa NHCP) was highly phosphorylated by casein kinase II (Mr = 130,000), but not by histone kinase. Casein kinase II phosphorylated only seryl residues of the purified 400-kDa NHCP. The NHCP bound with DNA, but not with RNAs, and the DNA binding ability of the protein was reduced when it was phosphorylated by casein kinase II. Moreover, we found that (a) the 400-kDa NHCP is present in large quantities in malignant mouse cells, such as EAT, EL-4, and Meth-A cells, but only slightly in normal tissues and cells; (b) the protein level is rapidly increased when mouse lymphocytes are treated with recombinant interleukin 2 (T cell growth factor) or concanavalin A; and (c) the kinase responsible for the 400-kDa NHCP phosphorylation in the chromatin of various mouse cells is a casein kinase II. These experimental results suggest that the 400-kDa NHCP acts as an effective phosphate acceptor for casein kinase II at the chromatin level and that an increased phosphorylation of the protein by the kinase may be implicated in the progress of cell differentiation and proliferation.
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PMID:Purification and characterization of a 400-kDa nonhistone chromatin protein that serves as an effective phosphate acceptor for casein kinase II from Ehrlich ascites tumor cells. 317 May 22

Cultivation of Ehrlich-ascites tumor cells in the presence of N-mustard leads to a selection of cells with a defective choline carrier. As N-mustard employs the choline carrier for transport, this results in reduced drug uptake and in a decrease in drug sensitivity which is specific for N-mustard. Walker carcinoma cells with a stable pleiotropic resistance to a variety of alkylating agents and adriamycin exhibit no evidence for an impaired drug transport and show the same frequency of DNA-interstrand cross-links as the sensitive parental line. Both sensitive and resistant Walker cells exhibit equal capacities for repair of N-mustard induced DNA-interstrand cross-links. The inhibition of histone acetylation by N-mustard, however, was found to be significantly lower in the resistant Walker or Ehrlich cells compared to sensitive counterparts. Although the difference between N-mustard concentrations leading to half maximal inhibition of histone acetylation in sensitive and resistant cells is considerably smaller than the difference between N-mustard doses required for half maximal inhibition of cell proliferation the data suggest that--besides DNA-DNA cross-linking--the inhibition of histone acetylation has to be considered as an important alternative mechanism responsible for the cytotoxic activity of alkylating agents. Inhibition of histone acetylation is not due an accelerated deacetylation and is predominantly expressed in chromatin fractions soluble in 0.1 M NaCl after digestion with micrococcal nuclease.
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PMID:Differential sensitivity of histone acetylation in nitrogen-mustard sensitive and resistant cells. Relation to drug uptake, formation and repair of DNA-interstrand cross-links. 322 83

The patterns of chromosomal proteins reflect in many cases the functional state of the respective cell type. The H1 histone group is particularly important in this respect, since these histones are involved in the higher order chromatin organization above the level of chains of nucleosomes. In mammals, the H1 histone family comprises at least five main subtypes (H1a-H1e), a testicular variant (H1t) and, thirdly, a subtype H1(0), which is found only in terminally differentiated cells. The H1(0) variant is structurally related to the avian red blood cell specific histone H5, which was the basis for our recent isolation of the human H1(0) gene. Changes of H1 histone patterns may be crucial events in modulating local chromatin arrangements, since the formation of higher order chromatin structures depends on a cooperative interaction of the H1 histones. Variations in their patterns can be studied in vivo during several developmental processes (such as spermatogenesis, erythropoiesis, maturation of several cell types) or in vitro in several tumor cell lines upon treatment with several inducers or upon inhibition of cell division. The differential regulation of the individual H1 subtypes is reflected in the gene and mRNA structures coding for the respective proteins. The cell cycle regulated histones are mostly encoded by non-polyadenylated mRNAs, whereas H5 as well as H1(0) mRNA shows a poly(A) tail at its 3' end. In conclusion, gene activity may not only be controlled at the level of RNA polymerases and their regulatory transcription factors. The varied patterns of chromosomal proteins at different stages during development and differentiation suggest that the local or overall organization of chromatin plays an additional role in these regulatory programs. Hence, the analysis of variations in patterns of chromosomal proteins is an integral part of the investigation of gene regulation mechanisms.
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PMID:The H1 and core histone subtypes: differential gene expression and varied primary structures. 325 Feb 26

The H1(0) histone was first described by Panyim and Chalkley in 1969 as a new electrophoretic band found with histones of non-replicating tissues. Tissues which are active in DNA replication such as ascites tumor cells or thymus cells were reported to lack this band. In this respect the H1(0) histone differs from the bulk of histones which are generally maintained in a constant ratio with respect to each other and to DNA. An inverse relationship between H1(0) histone levels and growth rate was suggested by the decrease in H1(0) histone concentration during regeneration of the pancreas and liver. The synthesis of H1(0) is unusual but not unique in that, unlike the major histone species, it is not restricted to the S phase of the cell cycle. Although there is a general trend for the levels of H1(0) histone to be lower in neoplastic than normal tissues, exceptions have been observed. Compounds such as sodium butyrate and dimethylsulfoxide, which can induce differentiated properties in neoplastic cells, can bring about the accumulation of increased amounts of H1(0) histones. The relative magnitude of these effects exhibits cell-type specificity. There are two H1(0) histone subtypes (a and b) with ratios which differ according to the tissue examined and whose relative importance is not known. The levels of H1(0) histone appear to be more closely related to the degree of differentiation than to the proliferative activity of cells.
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PMID:Relationship of H1(0) histone to differentiation and cancer. 332 65

It has been described that phosphorylation, and dephosphorylation, of specific proteins is associated with key events of the cell cycle and is likely to be due to activation of kinase(s). From our results, the presence of calcium-phospholipid-dependent protein kinase (PKC) was clearly demonstrated in both the cytosolic and particulate fractions of immature Xenopus laevis oocytes and in the cytosolic fraction of mature oocytes. However, it was less active in metaphase II- than in prophase I-arrested oocytes. The enzyme was partially purified by DEAE-cellulose and phenyl-Sepharose chromatography. It was activated in vitro by the tumor-promoting phorbol ester, 12-O-tetradecanoyl phorbol 13-acetate (TPA) as already described for PKC from other tissues. On the other hand, a calcium-phospholipid-independent histone kinase activity 4-fold higher in metaphase II- than in prophase I-arrested oocytes was detected. The possible role of PKC and phospholipid-independent histone kinase in the maturation process is discussed.
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PMID:Involvement of a calcium-phospholipid-dependent protein kinase in the maturation of Xenopus laevis oocytes. 333 63

Calcium- and phospholipid-dependent protein kinase C activity and substrates were characterized in cell lysates of preneoplastic JB6 cells, a model system of genetic variants for sensitivity to tumor promoter-induced neoplastic transformation. Protein kinase C activity was similar for sensitive and resistant variants, as measured by calcium- and phospholipid-dependent phosphorylation of an exogenous substrate (histone HIII). Of 13 endogenous protein kinase C substrates, identified by labeling proteins with [gamma-32P] ATP, at least two (80 and 23 kDa) are potential candidates for mediating events on the pathway for promotion of transformation. 32P incorporation into the 80-kDa protein kinase C substrate was stimulated by tetradecanoylphorbol acetate and correlated with phenotype: the highest incorporation was found in promotion-insensitive cells, an intermediate level in promotion-sensitive cells and the lowest in the transformed cells. The phosphorylation of an 80-kDa protein, found by labeling intact cells in monolayer growth with [32P]orthophosphate, was also stimulated by tetradecanoylphorbol acetate and correlated inversely with phenotype. The 80 kDa protein kinase C substrate from cell lysates and the 80-kDa phosphoprotein from intact cells appear to be identical, as indicated by peptide mapping with protease V8 from Staphylococcus aureus. This finding suggests that the 80-kDa substrate is relevant to promoter-induced signal transduction in the intact cell. The 23-kDa protein kinase C substrate exhibited a band shift in sodium dodecyl sulfate gels in response to another transformation promoter in JB6 cells, the calcium analog, lanthanum (Smith, B. M., Gindhart, T. D., and Colburn, N. H. (1986) Carcinogenesis 7, 1949-1956). In summary, there are no unique substrates that distinguish the variants. Quantitative differences in certain substrates or their phosphorylation may, however, account for the difference in promotion sensitivity among the variants.
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PMID:Protein kinase C and its substrates in tumor promoter-sensitive and -resistant cells. 336 Jul 87

Elastoviscosimetric examination was carried out to study the structure of supramolecular DNA complexes obtained from transplantable tumor strain cells and those of the same strains showing pronounced growth in synthetic culture media. The supramolecular DNA complex was isolated as a nucleoid and examined by ethidium bromide elastoviscosimetric titration method. Levels of supercoiled DNA were found to be significantly lower in the chromatin of cells of in vitro growing strains, as compared to parental strain cells where the said type of DNA predominated. Two patterns of DNA compact packing--supercoiled-domain and one characterized by a faster bond between DNA and non-histone proteins, and single-stranded DNA areas preexisting in domains--were suggested.
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PMID:[Structural differences of the supramolecular DNA complex from tumor strain cells]. 342 Aug 26

Monoclonal antibodies (8/1, 10/10, and 25/3) against rat brain type II protein kinase C were used for the immunochemical characterization of this kinase. These antibodies immunoprecipitated the type II protein kinase C in a dose-dependent manner but did neither to the type I nor III isozyme. Immunoblot analysis of the tryptic fragments from protein kinase C revealed that all three antibodies recognized the 27-38-kDa fragments, the phospholipid/phorbol ester-binding domain, but not the 45-48-kDa fragments, the kinase catalytic domain. The immune complexes of the kinase and the antibodies retained 70-80% of the kinase activity which was dependent on Ca2+ and phosphatidylserine and further activated by diacylglycerol or tumor-promoting phorbol ester. With antibody 8/1, the kinetic parameters with respect to Km for ATP and histone and K alpha for phosphatidylserine and phorbol 12,13-dibutyrate were not significantly influenced. However, the antibody causes variable effects on the K alpha for Ca2+ under different assay conditions. When determined in the presence of phosphatidylserine, the K alpha for Ca2+ was reduced by an order of magnitude (37 +/- 8 to 2.0 +/- 1.8 microM); in the presence of phosphatidylserine and phorbol 12,13-dibutyrate, the K alpha for Ca2+ was not significantly altered; and in the presence of phosphatidylserine and dioleoylglycerol, the kinase became an apparently Ca2+-independent enzyme. The effects of antibody 8/1 on the kinetic parameters of the enzyme for phorbol ester binding were different from those for kinase activity. This antibody causes a 20-30% reduction in phorbol ester binding and a 2-fold increase (1.9 +/- 0.2 to 3.9 +/- 0.3 micrograms/ml) in the concentration of phosphatidylserine required for half-maximal binding, but is without significant influence on those parameters for Ca2+ and phorbol 12,13-dibutyrate. The differential effects of antibody 8/1 on kinase activity and phorbol ester binding with respect to the kinetic parameter of phosphatidylserine suggest that the roles of this phospholipid in supporting phorbol ester binding and kinase activation are different. In the presence of the antibody, the autophosphorylations of the phospholipid/phorbol ester-binding domain and the kinase domain were reduced; the reduction was more pronounced for the former than for the latter. These results suggest that the epitope for antibody 8/1 is localized within the phospholipid/phorbol ester-binding domain at the region adjacent to the kinase domain so that the autophosphorylations of both domains are affected.
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PMID:Monoclonal antibodies against type II rat brain protein kinase C. 342 75

Histones isolated from Reuber H35 rat hepatoma cells treated with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) were examined for possible alterations in phosphorylation. Incorporation of 32P orthophosphate into individual acid-extracted histones was monitored by autoradiography and scintillation counting of polyacrylamide gels or by reverse-phase high performance liquid chromatography. Treatment of quiescent H35 cells (arrested by serum starvation) with submicromolar doses of TPA resulted in a rapid and specific increase in phosphorylation of histones H2B and H1(0). Smaller increases in phosphorylation were observed for H4. No significant change in phosphorylation of the major H1 histones or H2A were observed after 1 h of treatment. The phosphorylation was TPA dose-dependent, with a maximum increase of approximately 14-fold for H2B, 11-fold for H1(0), and 2-fold for H4 achieved at 0.8 M TPA. The nonpromoting parent compound phorbol did not induce any of these changes. Furthermore, the mitogenic hormone insulin did not cause a similar pattern of histone phosphorylation, suggesting that the effect observed was not due to a general mitogenic response in the H35 hepatoma cells. Addition of 8-Br-cAMP also failed to reproduce the effect of TPA on histone phosphorylation, suggesting that cAMP-dependent protein kinases are not likely to be involved in mediating this response to TPA.
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PMID:Phosphorylation of histones is stimulated by phorbol esters in quiescent Reuber H35 hepatoma cells. 352 91


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