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At least 19 recordsLinked to original sources
PubMed1978

Influence of toyocamycin on the assembly and processing of preribosomal ribonucleoproteins in the nucleolus of mammalian cells.

The adenosine analogue toyocamycin inhibits the maturation of ribosomal RNA, but permits the synthesis of other RNA species, including 45 S preribosomal RNA. In this work, the dose vs. response analysis of rRNA processing upon toyocamycin treatment of L5178Y cells is studied. It is shown that the latter steps of rRNA processing are more affected than the earlier. The mechanism responsible for the lack of conversion of toyocamycin-containing 45 S RNA into mature rRNA has not yet been elucidated. In order to investigate whether protein factors are involved in this mechanism, the effects of toyocamycin on the ability of preribosomal RNA to bind proteins and on the assembly of nucleolar preribosomes are investigated. The analogue allows the formation and the accumulation, in the nucleolus, of ribonucleoprotein complexes which contain 45 S RNA and newly synthesized proteins, but cannot be converted to mature ribosomal subunits. These complexes are not clearly distinguishable from 80 S particles synthesized in the absence of toyocamycin, with respect to their sedimentation rate in linear sucrose gradients, to their protein/RNA ratio and to their density measured in metrizamide gradients.

Antibiotics, Antineoplastic↗
PubMed1977

Toyocamycin inhibition of ribosomal ribonucleic acid processing in an osmotic-sensitive adenosine-utilizing Saccharomyces cerevisiae mutant.

An adenosine-utilizing mutant of Saccharomyces cerevisiae (SY 15 ado) is isolated after remutagenesis of an osmotic-sensitive strain, auxotrophic for adenine, with ethyl methanesulfonate. It is shown that the SY15ado mutant can be used to achieve experimental conditions under which cell growth and RNA Synthesis are directly dependent on exogenous adenosine. After starvation for adenosine, toyocamycin is incorporated into pre-rRNA chains of SY15ado cells replacing adenosine residues. The extent of this replacement depends on the concentration of added toyocamycin. Lower doses slow down processing of pre-rRNA into mature rRNA with an accumulation of 27 S and 20 S pre-rRNA. At higher concentrations toyocamycin blocks the last steps of pre-rRNA processing i.e. the conversions 27 S pre-rRNA leads to 25 S rRNA and 20 S pre-rRNA leads to 18 S rRNA. It appears that the main site of toyocamycin action is at the last steps of ribosome formation, while transcription and the early stages of pre-RNA processing are less affected.

Adenosine↗
PubMed1977

Regulation of ribosomal RNA synthesis in mammalian cells: effect of toyocamycin.

The present study shows that the antitumor agent toyocamycin (4-amino-5-cyano-7beta-D-ribofuranosylpyrrolo(2-3d)pyrimidine) affects rRNA transcription in Ehrlich ascites cells. This action of the antibiotic is dependent on the amino acid composition of the cell culture medium. In cells incubated in a medium rich in amino acids, the high transcription rate of rRNA is lowered by the addition of 2 X 10(-6) M toyocamycin, while in amino acid starved cells the decreased level of rRNA synthesis remains unaffected. Processing of the 45S rRNA precursor is markedly inhibited by toyocamycin in cells incubated in either medium, indicating that the uptake of the drug is unimpaired by amino acid starvation. Toyocamycin does not affect RNA polymerase I (RNA nucleotidyltransferase EC 2.7.7.6) activity when added to in vitro assay systems derived from cells grown in complete or in amino acid deficient media. The drug prevents the activation of rRNA synthesis following the refeeding of amino acid starved cells without affecting the stimulation of protein synthesis.

Amino Acids↗
PubMed1978

Genetic and biochemical studies with the adenosine analogs toyocamycin and tubercidin: mutation at the adenosine kinase locus in Chinese hamster cells.

The pyrrolopyrimidine nucleosides toyocamycin and tubercidin show several unique features of growth inhibition in Chinese hamster ovary (CHO) cells. Stable mutants which are more than 600-fold resistant to these drugs are obtained in CHO cells at a strikingly high frequency of approximately 10(-3), in the absence of mutagenesis. The mutants resistant to toyocamycin (Toyr) and tubercidin (Tubr) exhibit similar cross-resistance patterns to the two selective drugs as well as to adenosine and 6-methyl mercaptopurine riboside, indicating that the same lesion is probably involved in all cases. The mutants examined were found to be deficient in the enzyme adenosine kinase (AK), indicating that the phosphorylation of these analogs is an essential first step in their toxic action. The above mutants (AK-) behaved recessively in cell hybrids, and segregation studies indicate that the AK locus is not linked to the X chromosome. The frequencies of similar Toyr mutants in other Chinese hamster lines, e.g., V79, CHW, M3-1, GM7, and CHO-K1, varied from similar to more than three logs less than that observed for CHO cells, indicating that various cell lines probably differ in the number of functional gene copies for this locus.

Adenosine Kinase↗
PubMed1976

Synthesis and biological activity of pyrazolo[3,4,-d]pyrimidine nucleosides and nucleotides related to tubercidin, toyocamycin, and sangivamycin.

The 6-aza analogues of toyocamycin and sangivamycin were prepared as potential cytotoxic agents. The toyocamycin analogue (4-amino-1-(beta-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidine-3-carbonitrile) could not be obtained directly from its O-acetylated precursor but was accessible via 4-amino-1-(beta-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidine-3-thiocarboxamide. The identity of the nitrile was verified by its ultraviolet, infrared, and mass spectra, and by its conversion to the corresponding 3-carboxamide and thiocarboxamide when treated with water or hydrogen sulfide, respectively. Bioassay of the synthetic compounds in comparison with 4-amino-1-(beta-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidine (6-azatubercidin) and 4-amino-2-(beta-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidine revealed that the 3-thiocarboxamido derivative was more cytotoxic to the growth of mouse fibroblasts than 6-azatubercidin, effecting killing of 3T6 cells at less than or equal to 1 mug/ml. 4-Amino-1-(beta-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidine (but not its 2-ribofuranosyl isomer) was shown to act as a substrate for adenosine deaminase from calf intestinal mucosa with an apparent Km of 125 (vs. 20 for adenosine) and the corresponding 5'-diphosphate of 6-azatubercidin was polymerized by polynucleotide phosphorylase (Micrococcus luteus) in the presence of Mn2+ to afford a homopolymer and copolymers with adenosine. The copolymers directed the binding of [3H]lysyl-tRNA to the A-site of ribosomes from Escherichia coli, but could not be used for the synthesis of polylsine in a cellfree system. The copolymer consiting of adenosine and 6-azatubercidin in a 2:1 ratio was found to form a 1:1 complex with poly(uridylic acid) at 4degreesC.

Antibiotics, Antineoplastic↗
PubMed1979

Effect of toyocamycin on the synthesis of the 70S RNA of a murine retrovirus.

The murine Eveline cell line chronically infected by Friend virus was treated with Toyocamycin (TMC), an adenosin analog and the virions released in the presence of the drug were examined for their RNA. It was found that 70S RNA which was synthesized incorporated Toyocamycin. However, its subunit structure and its poly (A) content were apparently preserved. This incorporation may explain loss of endogenous reverse transcriptase activity.

Animals↗
PubMed1979

[Change in the envelope of a murine retrovirus produced in the presence of toyocamycin].

Toyocamycin (TMC), an adenosine analog, impairs qualitatively and quantitatively virus production in a cellular system chronically infected by Friend Virus. Viral particles released by cell cultures treated with 0.2 microgram/ml of the drug have lost most of their glycoprotein (gp 70) content. This phenomenon is likely to modify the viral envelope and could explain the loss of infectivity of the virus.

Animals↗
PubMed1979

Ribosomal proteins synthesis and exchange in the absence of 28-S and 18-S ribosomal RNA synthesis in L5178Y cells.

The effect of the adenosine analogue toyocamycin on ribosomal proteins synthesis and assembly within ribosomal particles was investigated in the murine cells, L5178Y. The analogue was used for periods not exceeding 5 h, at a concentration which permits the synthesis of ribosomal precursor RNA but inhibits the maturation process. The following observations were made: 1. Ribosomal proteins, synthesized de novo in the presence of the drug, were associated with toyocamycin-containing 45-S pre-rRNA in preribosomal-like 80-S ribonucleoproteins which accumulated in the nucleolus. Two-dimensional electrophoresis revealed a full protein complement of these particles, although minor discrepancies were observed in the relative proportions of a limited number of polypeptides. 2. In the absence of 28-S and 18-S rRNA formation, a surprisingly high proportion of newly synthesized ribosomal proteins were incorporated into high-salt washed ribosomal subunits. The extent of individual protein exchange as well as their apparent turnover rates were markedly heterogeneous. Most of these exchangeable proteins were shown to be labeled rapidly in ribosomal subunits of normal cells. Some alternative interpretations of these results are discussed.

Animals↗
PubMed1976

Biosynthesis of the modified nucleoside Q in transfer RNA.

During biosynthesis of the modified nucleoside Q, 7-(4,5-DIHYDROXYL-1-1-CYCLOPENTEN-3-YL-AMINOMETHYL)-7-DEAZAGUANOSINE, IN TRNA, the carbon atom at position 8 in precursor molecule guanine was expelled together with the nitrogen atom N-7 in a fashion similar to that in the biosynthesis of the nucleoside antibiotic toyocamycin.

Chromatography, Thin Layer↗
PubMed1976

Biochemical studies of isolated hamster tracheal epithelium.

The epithelial lining of respiratory air passageways is a primary target tissue for toxicity and carcinogenesis in man and in animal models of human disease. The importance of this target tissue was the basis for development of methods to study its biochemistry, and with this information to distinguish the unique properties of this tissue from properties common to all cell types. Biochemical methods employed labeling of macromolecules in isolated hamster treacheas during brief (less than 4 hr) incubation in vitro. Studies of RNA metabolism in isolated tracheas demonstrated a pattern of maturation of ribosomal RNA like that shown for other cell types. Alterations in RNA metabolism were observed in isolated tracheas obtained from vitamin A-deficient hamsters and hamsters previously treated by intratracheal administration of benzo[a]pyrene (BP) plus ferric oxide (Fe2O3) in vivo. Studies with toyocamycin, actinomycin D, and alpha-amanitin, all inhibitors of RNA metabolism, were performed to characterize the class of RNA molecules with a decreased proportion of labeling in tracheas from vitamin A deficient hamsters. In another series of experiments, BP was shown to bind to DNA in epithelial cells of isolated tracheas. The quantity of BP binding was increased by prior intratracheal treatment of hamsters with BP plus Fe2O3 in vivo, this induced binding was inhibited by addition of 7,8-benzoflavone to the incubation medium. Increased BP binding was also observed in isolated tracheas from hamsters believed to be in states of increased susceptibility to respiratory carcinogenesis in vivo. The results show that biochemical studies are feasible with this tissue. Furthermore, a number of questions of importance with regard to this target epithelium are best studied directly in its constituent cells.

Adenosine↗
PubMed1979

Protection of mice against lethal dosages of nebularine by nitrobenzylthioinosine, an inhibitor of nucleoside transport.

In the presence of nitrobenzylthioinosine (NBMPR) a potent inhibitor of nucleoside transport, Roswell Park Memorial Institute 6410 cells proliferating in culture were protected from otherwise inhibitory concentrations of 9-beta-D-ribofuranosylpurine (nebularine); cellular uptake of nebularine was greatly reduced under these circumstances. Initial rates of nebularine uptake by Roswell Park Memorial Institute 6410 cells were inhibited by NBMPR, indicating that the latter interfered with nebularine transport. NBMPR protected mice against potentially lethal treatment regimens with nebularine, 4-amino-7-(beta-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine (tubercidin) or 4-amino-5-cyano-7-(beta-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine (toyocamycin); protection resulted when NBMPR was administered i.p. in advance of or simultaneously with nebularine, but not when NBMPR followed nebularine by 1 hr. Both NBMPR and its 5'-monophosphate protected mice against nebularine lethality when administered s.c.

Animals↗
PubMed1977

[The structure of the nucleolus during the inhibition of RNA-and protein synthesis (author's transl)].

In cells treated with antimetabolites to inhibit RNA- and protein synthesis, electron microscopic studies reveal structural alterations of the nucleolus. The morphological appearance of the nucleolus differs depending of the inhibitor used. If transcription is prevented, segregation of nucleolar components is observed. Inhibition of processing of newly synthesized RNA results in a degranulation and an increase in the amount of nucleolar fibrils. A disturbance of the release of nucleolar ribonucleoproteins into the cytoplasm leads to an enlargement and a hypergranulation of the nucleolus. On the other hand interruption of translation of mRNAs has no immediate effect on the appearance of the nucleolar structure. Only after longer treatment of the cells with the translation inhibitor the nucleolus shrinks and becomes degranulated. The use of inhibitors with clearly defined mechanisms of action in a morphological study should make it possible to interpret similar nucleolar alterations seen in cancer cells and virus-infected cells on a molecular biological basis.

Animals↗