Cell cycle dependence for activation of Epstein-Barr virus by inhibitors of protein synthesis or medium deficient in arginine.
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Antigens, Viral↗
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Characterization of mouse ribosomal gene fragments purified by molecular cloning.
Four mouse ribosomal gene fragments cloned in lambda gtWES were studied by restriction enzyme mapping and Southern transfer experiments. These fragments were found to contain 18S DNA and transcribed as well as non-transcribed spacer DNA. Variation in the structure of these mouse DNA inserts was limited to one region of spacer DNA. This variation may reflect real structural differences found in mouse ribosomal genes or possibly deletion events which occurred during cloning. The transcribed regions of the inserts appear identical to one antoher and restriction enzyme fragments from this region correspond to fragments observed in digests of total mouse DNA. These clones will be useful in studying the structure of transcribed spacer DNA including the ribosomal gene promoter.
Animals↗
Bovine papilloma virus: presence of virus-specific DNA sequences in naturally occurring equine tumors.
Four of five spontaneous benign equine connective tissue tumors of unknown etiology and a bovine papilloma virus (BPV)-induced equine tumor contained BPV-specific DNA sequences as determined by DNA-DNA hybridization of DNA from tumors with BPV DNA labeled in vitro. Analysis of the kinetics of reassociation indicated that 20-75% of the BPV genome was present in the various tumors. The number of partial BPV genome equivalents ranged from 60 to 500 copies per diploid quantity of cellular DNA. Thermal denaturation profiles of duplexes formed between labeled BPV DNA and DNA from tumor cells indicated two tumors contained viral DNA with base sequences identical to BPV DNA. Three tumors (including DNA from the BPV-induced tumor) contained BPV-related DNA sequences that were less thermally stable. The decrease in thermal denaturation temperature may be due to the presence of (adenine + thymine)-rich regions of the BPV genome in the tumor cells.
Animals↗
State of Epstein-Barr virus DNA in an American Burkitt's lymphoma line.
A human lymphoma cell line, positive for the Epstein-Barr virus (EBV)-associated nuclear antigen, was recently established from a North American Burkitt's lymphoma. This cell line, SU-AmB-2, contained EBV DNA both in the form of circular, nonintegrated DNA molecules of viral genome length, present in multiple copies per cell, and as integrated sequences. Having DNA present in both of these forms, it resembled cell lines established from African Burkitt's lymphomas. In studies on EBV strain differences, the episomal viral DNA in Burkitt's lymphoma cells may now be compared with viral DNA in nonmalignant cells with the use of cell lines from Burkitt's lymphoma patients of similar geographic origin.
Africa, Eastern↗
Nucleosome-like structural subunits of intranuclear parental adenovirus type 2 DNA.
The intranuclear structure of parental adenovirus 2 DNA was studied using digestion with micrococcal nuclease as a probe. When cultures were infected with 32P-labeled virions, at a multiplicity of 3,000 particles per cell, 14 to 21% of parental DNA penetrated the cell and reached the nucleus. Of this parental DNA, 60% could be solubilized by extensive digestion with micrococcal nuclease. The nuclease-resistant fraction contained viral deoxyribonucleoprotein monomers and oligomers. These nucleosome-like structures contained DNA fragments which are integral multiples of a unit-length DNA of approximately 185 base pairs. The monomeric DNA is similar in length to the unit-length DNA contained in cellular nucleosomes. However, the viral oligomers are slightly smaller than their cellular counterparts. DNA-DNA hybridization demonstrated that all segments of the viral genome, including those expressed as mRNA only at late times, are represented in the nucleosomal viral DNA. The amount of early intranuclear viral chromatin was proportional to multiplicity of infection up to multiplicities of 4,000 particles per cell. However, viral transcriptional activity did not increase in direct proportion to the amount of viral chromatin. Maximum accumulation of intranuclear viral chromatin was achieved by 3 h after infection. The intranuclear parental viral chromatin remained resistant to nuclease digestion even at late times in infection, after viral DNA replication had begun.
Adenoviruses, Human↗
Purification and mechanism of action of macromomycin.
Macromomycin (MCR), a polypeptide antibiotic previously shown to have antitumor activity in experimental tumors, has been purified into an electrophoretically homogeneous component with an approximate molecular weight of 12,500. MCR has alanine as an NH2-terminal amino acid, 4 cysteine residues, and no arginine or methionine residues. With a fluorescence assay and agarose gel electrophoresis, MCR was shown to induce strand breaks in PM2 DNA in vitro. 2-Mercaptoethanol inhibited the DNA cleavage activity of MCR. When incubated with Novikoff hepatoma ascites cells in tissue culture, MCR caused Novikoff hepatoma ascites cell DNA degradation as observed by the slower sedimentation of DNA on alkaline sucrose density gradient centrifugation when compared to untreated cell DNA. DNA synthesis in Novikoff hepatoma ascites cells was inhibited by 80% after a two-hr treatment with MCR (0.03 microgram/ml). RNA and protein syntheses were inhibited by 25 and less than 10%, respectively, at this concentration of drug. At a concentration of MCR (1.0 microgram/ml), syntheses of DNA and RNA in Novikoff hepatoma ascites cells were totally inhibited. The results of this study suggest that MCR may inhibit tumor cell growth by causing DNA breakage with subsequent inhibition of DNA and other macromolecule syntheses.
Animals↗
DNA-protein and DNA interstrand cross-linking by cis- and trans-platinum(II) diamminedichloride in L1210 mouse leukemia cells and relation to cytotoxicity.
The effects of cis- and trans-platinum(II) diamminedichloride on L1210 cells were investigated using the technique of DNA alkaline elution. Both agents produced reductions in alkaline elution rates which were partially or, in some cases, almost completely reversed by incubation of the cell lysates with proteinase K. The proteinase-sensitive component of this effect is taken to reflect DNA-protein cross-linking, while the proteinase-resistant component of this effect may include interstrand cross-links. The cytotoxicity of the two agents did not correlate with the extent of DNA-protein cross-linking but did appear to correlate with the extent of proteinase-resistant cross-linking; therefore, there may be a relationship between cytotoxicity and interstrand cross-linking.
Animals↗
[Fractionation of DNA containing single-stranded regions on a column with benzoylated DEAE-cellulose].
A possible use of a previously described method of fractionation of highly polymeric DNAs on a column with benzoylated DEAE-cellulose is discussed. The method can be used for separation of renaturated and hybrid DNA molecules as well as for detection of single-stranded structures within the DNA. Using the method in question it was shown that the DNA of hepatoma 27 contains about 6% of single-stranded DNA structures.
Animals↗
A biochemical approach to the study of the transmission of mouse mammary tumor viruses in mouse strains RIII and C3H.
Mouse mammary tumor virus (MMTV) proviral sequences were detected in the cellular DNA of mammary tumors and livers of RIII and C3H mice by molecular hybridization with radioactively labelled MMTV 60-70S RNA or tritiated MMTV complementary DNA (cDNA). By means of DNA:DNA reassociation kinetics, the DNA of the mammary tumor cells of these two mouse strains were found to contain more MMTV proviral sequences than the DNA of liver cells of these same tumor-bearing mice. Evidence is also presented that the DNA of the liver cells lacks a part (approximately 25%) of the MMTV proviral sequences found in the mammary tumor cells of these mouse strains. The relationship of the extra MMTV proviral sequences found in mammary tumor cells to the early mammary tumor-igenesis seen in these mouse strains is discussed.
Animals↗
Hepatitis B virus DNA in primary hepatocellular carcinoma tissue.
Tumour, cirrhotic, and metastatic tissues from four patients with primary hepatocellular carcinoma have been investigated for the presence of hepatitis B viral DNA by nucleic acid hybridization. Tumours from two of three patients with a current HBV infection contained 1--2 genomes per cell of unintegrated viral DNA, while tumours from the third HBs antigen-positive patient contained less than one genome equivalent per ten cells. A tumour from one patient with anti-HBs contained no detectable HBV DNA. A variety of models involving HBV as an etiologic agent may be advanced to explain the statistical correlation of HBV infection with primary hepatocellular carcinoma (PHC). The data presented here argue against the model that HBV DNA integrated into every cell is required to maintain the oncogenic transformation of hepatocytes, but they do not rule out other models.
Adult↗
Supercoiled DNA folded by nonhistone proteins in cultured mouse carcinoma cells.
Upon gentle lysis of exponentially growing mouse carcinoma cells FM3A by sodium dodecyl sulfate, DNA was released as a "DNA-protein complex" in a folded conformation. No histones could be detected in the DNA-protein complex. The proteins bound to DNA were found to be composed of several kinds of nonhistone proteins with a molecular weight range of 50,000 to 60,000; they appear to play a key role in stabilizing and maintaining the compact and folded structure of the complex. Removal of the proteins by Pronase or 2-mercaptoethanol produced a more relaxed structure sedimenting about half as fast as the original complex in a neutral sucrose gradient. DNA in the folded complex is supercoiled, as indicated by the characteristic biphasic response of its sedimentation rate to increasing concentration of various intercalating agents, actinomycin D, ethidium bromide and acriflavine, with which the cells were treated before lysis. Pronase- or 2-mercaptoethanol-treated relaxed DNA still possessed the characteristic of closed-circular structure as judged from its response to intercalating agents. Nicking with gamma-ray or 4NQO broke these superhelical turns and relaxed the folded complex to slower sedimenting forms equivalent to the relaxed DNA obtained on treatment with Pronase or 2-mercaptoethanol. Viscometric observations of DNA-protein complex were consistent with the above results. A tentative model for the structure of this DNA-protein complex is proposed in which supercoiled DNA is folded into loops by several kinds of nonhistone proteins. Autoradiographic examination of the complex appeared to support this model.
4-Nitroquinoline-1-oxide↗
Adenovirus early function required for protection of viral and cellular DNA.
Studies were done to characterize a DNA-negative temperature-sensitive (ts) mutant of human adenovirus type 2, H2 ts111. The temperature-sensitive defect, which was reversible on shift-down in the absence of protein synthesis, was expressed as early as 2 h postinfection, and the results of density-labeling experiments are in agreement with at least a DNA replication initiation block. On shift-up, after allowing viral DNA synthesis at permissive temperatures, the newly synthesized viral DNA and the mature viral DNA were cleaved into fragments which sedimented as a broad peak with a mean coefficient of 10-12S. This cleavage was more marked in the presence of hydroxyurea as the DNA synthesis inhibitor. Parental DNA in infected cells was degraded to a much lesser extent regardless of the incubation temperature. In contrast, the parental DNA was strongly degraded when early gene expression was permitted at 33 degrees C before shift-up to 39.5 degrees C. Furthermore, cellular DNA was also degraded at 39.5 degrees C in ts111-infected cells, the rate of cleavage being related to the multiplicity of infection. This cleavage effect, which did not seem to be related to penton base-associated endonuclease activity, was also enhanced when early gene expression was allowed at 33 degrees C before shift-up. The ts111 defect, which was related to an initiation block and endonucleolytic cleavage of viral and cellular DNA, seemed to correspond to a single mutation. The implication of the ts111 gene product in protection of viral and cellular DNA by way of a DNase-inhibitory function is discussed.
Adenoviruses, Human↗
[Proviral genetic material of Rous sarcoma virus in mammalian tumor cells].
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Animals↗
Structure and action of bleomycin.
The structures of bleomycins and of other bleomycin-phleomycin group of antibiotics were described. The activity of bleomycins and their derivatives in causing strand scission of SV40 viral DNA suggests that the beta-aminoalanine amide moiety and the carbamoyl group are involved in this reaction. More than one guanido group in the terminal amine of bleomycin-phleomycin group antibiotics caused irreversible renal toxicity in dogs. Pulmonary toxicity varied depending on the terminal amines. A bleomycin-inactivating enzyme which distributes widely in animal cells was shown to be a new aminopeptidase B which hydrolyzes beta-aminoalanine amide group. At least one of the reasons for activity against squamous cell carcinoma was shown to be due to the lower content of this enzyme. The inhibitor of this enzyme was synergistic to bleomycin in inhibiting growth of cells, thus suggesting the intracellular action of this enzyme. Selected for further study from the bleomycins containing various terminal amines, bleomycin 5033 which showed the same activity against squamous cell carcinoma in mouse skin as the bleomycin used at present and lower toxicity than the latter, and bleomycin A5196 which showed stronger activity and stronger toxicity but lower lung toxicity than the latter.
Aminopeptidases↗
[Viral etiology of cancer (oncogenic viruses)].
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Animals↗
Integration of the DNA of mouse mammary tumor virus in virus-infected normal and neoplastic tissue of the mouse.
We have used restriction endonucleases which cleave the DNA of mouse mammary tumor virus (MMTV) at one site (Eco RI) and several sites (Pst I, Sac I and Bam HI) to study infection and mammary tumorigenesis in mice. Proviruses acquired during infection of BALB/c mice foster-nursed by virus-producing C3H females can be distinguished from the MMTV proviruses endogenous to uninfected BALB/c mice by the nature of the fragments generated with Pst I and Bam HI. Using this assay, we show that lactating mammary glands as well as mammary tumors from BALB/cfC3H mice have acquired MMTV DNA, and that a minimum of approximately 10% of normal glandular cells can be infected. The new proviruses appear to be linked to cellular DNA of mammary tumors and infected lactating mammary glands within a limited region (0.2 x 10(6) daltons) of the viral DNA; the location of this region, based upon mapping studies with unintegrated MMTV DNA, suggests that the orientation of these proviruses is colinear with linear DNA synthesized in infected cells and thus approximately colinear with the viral RNA. Comparisons of many mammary tumors and studies of lactating mammary glands with a high proportion of independently infected cells indicate that a large number of sites in the cellular genome can accommodate a new provirus; the acquired proviruses are rarely, if ever, found in tandem with each other or with endogenous proviruses. We cannot, however, distinguish between random integration and integration into a large number of preferred sites in the host genome. Since Eco RI and Bam HI cleavage of DNA from each mammary tumor generates a unique set of viral-specific fragments, we propose that the tumors are composed principally of cells derived from a subset of the many infected cells in a mammary gland; this proposal is supported by our finding that Eco RI digestion of DNA from several transplants of a primary tumor yields the pattern characteristic of the primary tumor.
Animals↗
The influence of arginine starvation on the synthesis of virus high molecular weight DNA in HeLa cells productively infected by adenovirus type 5.
In culture cells productively infected by adenovirus a high mol. wt. form of DNA is synthesized which is known to represent, at least in part, virus DNA integrated into cellular DNA. We found that the synthesis of this high mol. wt. DNA and the other DNA size classes can strongly and differentially be influenced by altering the metabolic state of the cells. The effects of different rates of cell growth were tested in this respect as well as arginine deprivation as opposed to application of complete growth medium. Synthesis of virus high mol. wt. DNA and unit genome length DNA is enhanced in actively growing as compared to resting Ad5-infected HeLa cells. Under arginine deficiency, in resting Ad5-infected HeLa cells, integration of virus DNA sequences into cellular DNA is almost totally suppressed whereas virus unit genome length DNA is still synthesized. This differential effect is interpreted by the hypothesis that the formation of virus high mol. wt. DNA is a synthetic process that is independent of the unit size virus DNA replication, but coupled to the synthesis of a special form of a special form of cellular DNA that is less effectively shut off by the infection than cellular DNA in general.
Adenoviruses, Human↗
Effect of carbamoylation on the repair of nitrosourea-induced DNA alkylation damage in L1210 cells.
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Alkylation↗