Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of this study was to examine the activity and associated kinetic parameters of epidermal protein kinase C (PKC) following stimulation by sn-1,2-dioctanoylglycerol (DIC8) or 12-O-tetradecanoylphorbol-13-acetate (TPA) and to examine the relationship between levels of epidermal PKC activity and the induction of ornithine decarboxylase by these agents, utilizing various stocks and strains of mice. Importantly, the mouse strains and stock used in this study have known differing susceptibilities to undergo TPA-induced tumor promotion: the CD-1 stock and the DBA/2 strain (both sensitive to TPA-induced tumor promotion) and the C57BL/6 strain (resistant to TPA-induced tumor promotion). TPA-stimulated protein kinase C activity was measured in the 10(5)g supernatant fraction of epidermal homogenates using lysine-rich histone as a phosphate acceptor substrate. The maximal velocities for TPA-stimulated epidermal PKC activity in CD-1, DBA/2 and C57BL/6 were 0.28, 0.29 and 0.27 nmol PO4-histone/mg 10(5)g protein/min, respectively. TPA-stimulated epidermal PKC from CD-1, DBA/2 and C57BL/6 had similar theoretical Vmax values and the apparent concentrations of TPA yielding half-maximal stimulation of PKC were also similar. DiC8-stimulated PKC activity to a greater Vmax; however, the concentration required to yield half-maximal stimulation of PKC was one thousand times greater than that of TPA. There were no strain differences in these parameters when the enzyme was stimulated with DiC8. Thus, the levels of epidermal PKC activity in CD-1, DBA/2 and C57BL/6 mice exhibit no strain differences when stimulated by TPA or DiC8 using lysine-rich histone as a phosphate acceptor substrate. Since sn-1,2-diacylglycerols are known effective inducers of epidermal ornithine decarboxylase (ODC) activity, the induction of epidermal ODC was examined in each mouse strain 5 h after topical application of 2 nmol TPA, 5 nmol TPA or 2.5 mumol DiC8. After topical treatment with TPA, C57BL/6 demonstrated an unexpected 2- and 4-fold increase in ODC activity over CD-1 and DBA/2 mice. After treatment with DiC8, C57BL/6 demonstrated a 6- and 10-fold increase in ODC activity over CD-1 and DBA/2, respectively. Thus, the resistant strain (C57BL/6) demonstrated a 'hyperinducibility' of epidermal ODC activity by TPA or DiC8. The time course for the induction of epidermal ODC was examined in each strain, and at every time point measured (3-15 h), the C57BL/6 strain exhibited this 'hyperinducibility' of ODC relative to the other strains. Epidermal DNA synthesis was stimulated to a similar extent in C57BL/6 and CD-1 mice.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Comparison of epidermal protein kinase C activity, ornithine decarboxylase induction and DNA synthesis stimulated by TPA or dioctanoylglycerol in mouse strains with differing susceptibility to TPA-induced tumor promotion. 270 40

We investigated the ultrastructural distribution of histones within Ehrlich tumor cell nucleoli by means of three cytochemical methods and by a Lowicryl post-embedding immunogold labeling procedure involving anti-histone (H2B, H3, H4) antisera as well as antibodies to synthetic peptides of histones. With the two technical approaches, labeling was particularly concentrated over the perinucleolar chromatin and over its intranucleolar invaginations which penetrate the nucleolar body and come in close contact with the fibrillar centers. Furthermore, the high-resolution immunocytochemical technique revealed the presence of a small amount of the three histones in the fibrillar centers, preferentially located towards their peripheral regions. In addition, colocalization of DNA at all the histone-positive sites could be visualized after double immunogold staining using a monoclonal anti-DNA antibody and the anti-histone antisera. These results appear to indicate that all the DNA detected within the nucleolus was associated with histones. This finding suggests that the ribosomal DNA, including transcriptionally active genes, is bound to histones.
 ...
PMID:Ultrastructural distribution of histones within Ehrlich tumor cell nucleoli: a cytochemical and immunocytochemical study. 272 3

sn-1,2-Didecanoylglycerol, a synthetic lipid second messenger and model diacylglycerol, was evaluated as a complete skin tumor promoter in CD-1 mice. In addition, sn-1,2-dioctanoylglycerol, sn-1,2-didecanoylglycerol, the second stage tumor promoter mezerein, and the complete tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) were examined for their ability to stimulate epidermal protein kinase C activity in vitro. All four compounds stimulated epidermal protein kinase C activity utilizing lysine-rich histone as the phosphate acceptor substrate. sn-1,2-Dioctanoylglycerol and sn-1,2-didecanoylglycerol stimulated epidermal protein kinase C activity to a maximum velocity similar to that obtained when the enzyme was stimulated with TPA; however, about 1000 times greater concentration of the sn-1,2-diacylglycerols was required. sn-1,2-Didecanoylglycerol was evaluated as a complete skin tumor promoter in CD-1 mice utilizing a dosing regimen demonstrated to produce epidermal hyperplasia. Mice were initiated with 200 nmol 7,12-dimethylbenz[a]anthracene. One week later the mice received twice daily topical applications of 1 nmol TPA, 2 mumol sn-1,2-didecanoylglycerol or 5 mumol sn-1,2-didecanoylglycerol, 5 days/week. Additional initiated mice received twice weekly topical applications of 2 or 5 nmol TPA. Initiated mice treated with 5 nmol TPA twice weekly or with 1 nmol TPA twice daily for 5 days/week (cumulative weekly doses of 10 nmol TPA) responded similarly, based on the tumor incidence and the average number of tumors per mouse. Initiated mice treated with 2 or 5 mumol sn-1,2-didecanoylglycerol twice daily developed tumors in a dose-dependent manner. Initiated mice treated with 5 mumol sn-1,2-didecanoylglycerol twice daily developed many tumors, and at 20 weeks there was a 74% tumor incidence and an average of 6.0 tumors/mouse. At 20 weeks, 24% of the initiated mice treated with 2 mumol sn-1,2-didecanoylglycerol twice daily developed tumors, with an average of 1.1 tumors/mouse. Mice which were not initiated but treated twice daily with 5 mumol sn-1,2-didecanoylglycerol for 20 weeks did not develop any tumors. These data demonstrate that the representative synthetic lipid second messenger sn-1,2-didecanoylglycerol, like TPA, is a complete tumor promoter in DMBA-initiated mouse skin.
 ...
PMID:Synthetic lipid second messenger sn-1,2-didecanoylglycerol: a complete tumor promoter in mouse skin. 274 35

Serial examination of five newly derived Friend murine tumors during early subcutaneous passages showed continuing changes in chromatin composition and structure over the first 10 to 20 passages followed by a period of stabilization over the subsequent 20 passages. These changes were reflected in a decrease in two major histone variants, H2A.1 and H2B.2, with a coordinate increase in histone variants, H2A.2 and H2B.1, and a changing nucleosome repeat length (NRL). The absolute values differed among the five tumors, but all five showed the same general direction of change. There was no obvious relationship among the NRL, H2A, and H2B histone variant values. A low H2A.1/H2A.2 ratio was found in Friend tumors of high malignant potential. Cell lines derived in vitro also showed directional changes in the H2A and H2B variants similar to those of their tumor cell parents, but with different kinetics. Our findings suggest that Friend tumor establishment is accompanied by an early period of chromatin reorganization marked by changes in several parameters of chromatin structure.
 ...
PMID:Chromatin reorganization during emergence of malignant Friend tumors: early changes in H2A and H2B variants and nucleosome repeat length. 290 89

During the course of studies on protein kinases in psoriatic epidermis, a novel histone-activated protein kinase activity was identified. This activity (referred to as PK-II because it was the second peak of protein kinase activity eluted from a DEAE column) was partially purified from the supernatant of an epidermal homogenate by DEAE-cellulose column chromatography. Although histone was not a substrate for phosphorylation, in the presence of histone, endogenous proteins of Mr 105 and 95 kDa were phosphorylated. Activity was not affected by Ca2+/phospholipid, cAMP, cGMP, cAMP-dependent kinase inhibitor, spermine, spermidine, calmodulin, EGF, or phorbol ester. Phosphorylation was specific for serine and threonine residues. A major peak of PK-II activity eluted from sepharose 6B with an apparent Mr of 100 kDa, suggesting that histone may stimulate autophosphorylation. The properties of PK-II resemble those recently described for a class of polypeptide-dependent protein kinases isolated from placenta, Ehrlich ascites tumor cells, and bakers' yeast. PK-II was significantly higher in psoriatic involved epidermis (32.6 +/- 11.6 pmol/min/mg protein) compared to psoriatic uninvolved epidermis (5.7 +/- 0.6 pmol/min/mg; p = 0.03) and normal epidermis (9.5 +/- 2.2 pmol/min/mg; p = 0.05). The function of histone stimulated protein kinase in epidermal function and its role in the pathophysiology of psoriasis remain to be explored.
 ...
PMID:A novel histone-stimulated protein kinase in normal and psoriatic epidermis. 291 42

A cytosolic fraction of mouse brain gave two peaks of protein kinase activity on DEAE-cellulose column chromatography. The first peak of protein kinase corresponded to protein kinase C. The second peak contained protein kinases that were "activated" dose-dependently by the okadaic acid class tumor promoters, okadaic acid and dinophysistoxin-1. This "activation" was not achieved by other tumor promoters, such as 12-0-tetradecanoyl-phorbol-13-acetate, teleocidin, aplysiatoxin, or palytoxin. In addition, the second peak contained phosphatases. The phosphate liberation from phosphorylated histone type III-S by incubation with the second peak was inhibited by okadaic acid or dinophysistoxin-1, dose-dependently. The resulting apparent "activation" of protein kinases by okadaic acid is indicated and would imply a new pathway of tumor promotion on mouse skin.
 ...
PMID:Apparent "activation" of protein kinases by okadaic acid class tumor promoters. 293 May 74

It has recently been suggested that topoisomerases could be important targets for several DNA intercalating drugs used in cancer therapy. This prompted us to purify and characterize a type II topoisomerase in a highly tumorigenic transplantable rabbit tumor isolated from a skin carcinoma associated with cottontail rabbit papillomavirus. We have found that the decatenating activity present in tumor cells was 40-100 times higher than that in the rabbit liver, while no activity could be found in skin extracts. The type II topoisomerases purified from tumor and liver cells consist of two subunits with molecular masses of about 160 kDa. The conditions of the reactions of relaxation, unknotting and decatenation catalyzed by these topoisomerases II were found to be similar to those observed with enzymes of other eukaryotic cells. In the course of the purification of the VX2 enzyme, we isolated and characterized a protein of about 30 kDa in whose presence the topoisomerase II was able to catenate very efficiently supercoiled DNA molecules. This protein has the same electrophoretic mobility as an H1-2 histone, and cross-reacts with an anti-H1 antiserum. The VX2 topoisomerase II as well as the VX2 tumor should constitute useful models for assays of antitumoral drugs.
 ...
PMID:A type-II DNA topoisomerase and a catenating protein from the transplantable VX2 carcinoma. 298 98

We have examined the effect of the anti-tumor drug VM-26 on purified Drosophila topoisomerase II, and used this drug to map (putative) topoisomerase II cleavage sites in chromatin. These studies indicate that VM-26 interferes with the strand breakage-rejoining catalytic cycle. VM-26 appears to stabilize the topoisomerase-II-cleavable complex and markedly enhances the formation of double-strand breaks in naked DNA. VM-26 also stimulates the formation of double-strand breaks in isolated Drosophila nuclei. Analysis of the parameters of the VM-26-stimulated cleavage reaction in nuclei strongly suggests that the double-strand scissions are generated by endogenous topoisomerase II. Finally, we have examined the distribution of (putative) cleavage sites for endogenous topoisomerase II in the chromatin of the 87A7 heat shock locus and the histone repeat unit. We have found that there are prominent VM-26-induced cleavage products from the 5' ends of the 87A7, the two heat shock protein 70 genes, and in the intergenic spacer separating these genes. Moreover, the pattern of VM-26-induced cleavage products is altered in nuclei prepared from heat-shocked cells. In the case of the histone repeat unit, only minor VM-26-induced cleavage products are observed in nuclei (in spite of the fact that experiments on naked DNA indicate that the histone repeat contains many major cleavage sites for purified topoisomerase II). These findings suggest that the nucleoprotein organization of different DNA segments may be important in determining whether specific sites are accessible to endogenous topoisomerase II in nuclei.
 ...
PMID:Topoisomerase II cleavage in chromatin. 302 49

A number of environmental chemical pollutants have been reported to cause tumors or help in the propagation of tumors in experimental animals. The in-vitro effects of a few chemical contaminants were studied on the histone phosphorylation and 3H Phorbol dibutyrate (PdBu) binding of partially purified Ca2+/phospholipid dependent protein kinase c (PKC) from the brains of Fischer F344 and B6C3F1 mice. The enzyme was prepared by a modified method which gave approximately 75-fold purification. A differential effect of various compounds was observed on the phosphorylation activity and PdBu binding of PKC from rats and mice. The reported tumor promoting ability and effect on protein kinase C activity appeared to be related in the case of the rat enzyme, although causality cannot be inferred.
 ...
PMID:In-vitro modulation of protein kinase C activity by environmental chemical pollutants. 302 16

Potent tumor promoter TPA (1-100 nM) has previously been shown to induce a striking alteration of protein kinase C catalytic properties in target cells (C. Cochet et al., 1986, Biochem. Biophys. Res. Comm. 134, 1031-1037). This alteration contributes to the apparent loss of cellular protein kinase C, secondary to TPA treatment, when the enzyme is probed by its phospholipid-dependent histone kinase activity. This effect was observed as well when rat-1 cells were treated by other tumor promoters such as mezerein, teleocidin, aplysiatoxin and palytoxin, whereas inactive phorbol ester structures were ineffective. On the other hand, 1,2-dioctanoyl glycerol did not induce that effect. This protein kinase C alteration was shown to occur at the cellular membrane level. It is suggested that membrane translocation and activation of protein kinase C induced by potent tumor promoter structures are not functionally equivalent to that secondary to physiological stimuli. Although the mechanisms underlying this phenomenon remains to be understood at the molecular level, it may be of significance in the process of tumor promotion.
 ...
PMID:Phorbol ester-induced alteration of protein kinase C catalytic properties occurs at the membrane level and is not reproduced by physiological stimuli. 309 22


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>