Mechanism of Carcinogenesis by RNA Tumor Viruses, I. An RNA-Dependent DNA Polymerase in Murine Sarcoma Viruses

Green, Maurice; Rokutanda, Makoto; Fujinaga, Kei; Ray, R.K.; Rokutanda, Hinae; Gurgo, Corrado

doi:10.1073/pnas.67.1.385

Cited by 85 publications

(34 citation statements)

References 15 publications

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“…Strains H and M of MSV, and FeLV were propagated in cultured cells and purified (2,5,6). AMV, kindly provided by Dr. Joseph Beard, was purified as described (7).…”

Section: Materuils and Methodsmentioning

confidence: 99%

3-Cyclic Amine Derivatives of Rifamycin: Strong Inhibitors of the DNA Polymerase Activity of RNA Tumor Viruses

Green

Bragdon

Rankin

1972

Proc. Natl. Acad. Sci. U.S.A.

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Derivatives of rifamycin-SV with substituted cyclic-amine side chains in position 3 of the ansa ring are strong inhibitors of RNA-directed DNA and DNA-directed DNA polymerase activity of RNA tumor viruses of murine, feline, and avian origin. Among 37 3-amine derivatives of rifamycin-SV that were tested, 29 3-cyclic amine derivatives were good inhibitors of the viral polymerases. Especially active were 3-piperidyl derivatives of rifamycin-SV with cyclohexyl and cyclohexylalkyl substituents. Derivatives that were effective against the viral polymerase also blocked cell transformation by the murine sarcoma virus. A DNA-directed DNA polymerase preparation from human KB cells was less sensitive to inhibition by these derivatives than the virion polymerase.Can chemotherapy of viral diseases and cancer be based on the control of replication of specific classes of nucleic acid molecules? The search for specific inhibitors of polymerase has an excellent start, for the antibiotic rifamycin-SV and several of its semisynthetic derivatives specifically bind to and block the DNA-directed RNA polymerase of bacteria. Although these derivatives do not inhibit mammalian polymerases (1), we found that lengthening the rifampicin 3-iminomethyl4-methyl-1-piperazine side chain by substitution of benzyl for methyl yields compounds ( Fig. 1, AF/ABDMP and AB/ABP) that inhibit the RNA-directed DNA polymerase (reverse transcriptase) of RNA tumor viruses; removal of the methyl group yields N-demethyl rifampicin, a weak inhibitor (2-4).To see if even more extensive inhibition is possible, we have explored further the structural requirements for antipolymerase activity. We tested the ability of rifamycin-SV derivatives that contain 3-amine, quinoxalino, and benzoxazino substituents (see Fig. 1) to inhibit RNA-directed DNA and DNA-directed DNA polymerase. For investigation of DNA-directed DNA polymerase activity, the partially purified enzyme of the Harvey strain of murine sarcoma virus (MSV strain H) was tested with poly d(A-T) as a template. For RNA-directed DNA polymerase activity, the endogenous activity of the Moloney (M) strain of MSV was used. These polymerase activities of RNA tumor viruses are especially suitable for testing, since their true function during oncogenesis is probably DNA synthesis (2-4), and, therefore, they are a natural target for possible chemotherapy. MATERUILS AND METHODSViruses. Strains H and M of MSV, and FeLV were propagated in cultured cells and purified (2, 5, 6). AMV, kindly provided by Dr. Joseph Beard, was purified as described (7).Rifamycin Derivatives. The rifamycin-SV derivatives used in this study were generously provided by Drs

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“…Strains H and M of MSV, and FeLV were propagated in cultured cells and purified (2,5,6). AMV, kindly provided by Dr. Joseph Beard, was purified as described (7).…”

Section: Materuils and Methodsmentioning

confidence: 99%

3-Cyclic Amine Derivatives of Rifamycin: Strong Inhibitors of the DNA Polymerase Activity of RNA Tumor Viruses

Green

Bragdon

Rankin

1972

Proc. Natl. Acad. Sci. U.S.A.

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“…Viral [3H]DNA was prepared by the endogenous RNA-directed DNA polymerase reaction with RaLV, R-MuLV, M-MSV(MuLV), Ki-MuLV, and the virus produced by 58-2T cells, 58-2T virus. These viruses were purified as described (11). Reaction mixtures, generally 5 ml, contained 1-2 ml of purified virus solution (0.1-1.0 mg/ml of protein), 0.1 M glycine-NaOH buffer, (pH 8.0), 10 (20), and precipitated by 2 volumes of ethanol in the presence of yeast tRNA (50.ug/ml) at -20°o vernight.…”

mentioning

confidence: 99%

Sarcoma-Virus-Related RNA Sequences in Normal Rat Cells

Tsuchida

Gilden

Hatanaka

1974

Proc. Natl. Acad. Sci. U.S.A.

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A rat type C virus spontaneously activated from the NRK (normal rat kidney) cell line was found to have two major size classes of viral RNA subunits sedimenting at 35 and 30 S. Virus-producing cells contained both RNA species, while normal "virus-free" rat cells contained primarily virus-specific 30S RNA species. A DNA transcript, specific for Kirsten sarcoma virus, pre- Three isolates, previously considered to be murine sarcoma viruses, have been studied by nucleic acid hybridization techniques during the past 2 years. Two of these isolates, the Harvey (1) and Kirsten (2) strains, arose on rat passage of mouse leukemia viruses (Moloney and Kirsten strains, respectively), and the third, the Moloney strain (3), arose on mouse passage of the Moloney leukemia virus (M-MuLV). Based on minimal hybridization between rat and mouse type C viruses (4, 5), it was possible to show that the Kirsten and Harvey sarcoma viruses derived their sarcoma-specific nucleic acid sequences from the rat type C virus (4, 6), while the Moloney strain (M-MSV) was exclusively of mouse origin (4, 5).We have previously reported preparation of KiSV-specific DNA transcripts that did not hybridize with RNA of helper mouse virus (7,27 spontaneously virus-producing rat cells has now shown KiSVspecific sequences associated with a 30S RNA in both cells, whereas virus-producing rat cells produce an additional 35S RNA subunit that is not related to KiSV. MATERIALS AND METHODSCells and Media. The following rat cell lines were used: NRK-9 (RaLV-NRK), a normal rat kidney (NRK) cell line producing endogenous rat type C virus (RaLV) (8); MSB-1 (9), a rat cell transformed by M-MSV producing M-MSV-(RaLV) (5); a Fisher rat embryo cell (5053) The following mouse cells were used: BALB/3T3 (A-31), and a derivative K-234, a BALB/3T3 cell line transformed by KiSV (NP cell) (12, 13); M-58-2, a mutant cell line derived from the NP cell after short-term treatment with 5'-bromodeoxyuridine (BrdU) (14, 15); 58-2T, a cell line established from a slowly growing tumor in a BALB/c mouse that was inoculated with M-58-2 cells (7); Ki-MuLV-producing NIH/ 3T3 cell (Ki-MuLV-NJH/3T3), obtained from Dr. V. Klement (Ki-MuLV had not been passaged in rat); and JLS-V9 infected with Rauscher strain of MuLV (R-MuLV) (16).A nonproducer hamster cell transformed by M-MSV (HT-1) was also used (17).All cells were grown in Eagle's medium with 10% (v/v) fetal bovine serum and antibiotics.Preparation of RNA. Cell RNA was prepared as described (18), by the hot phenol method. The concentration was determined by the orcinol reaction (19). Synthesis of Virus-Specific DNA. Viral [3H]DNA was prepared by the endogenous RNA-directed DNA polymerase reaction with RaLV, R-MuLV, M-MSV(MuLV), Ki-MuLV, and the virus produced by 58-2T cells, 58-2T virus. These viruses were purified as described (11). Reaction mixtures, generally 5 ml, contained 1-2 ml of purified virus solution (0.1-1.0 mg/ml of protein), 0.1 M glycine-NaOH buffer, (pH 8.0), 10 mM dithiothreitol, 0.05 mM each of dATP, dGTP, and d...

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Section: Introductionmentioning

confidence: 99%

“…ase which transcribes the viral RNA genome into DNA [1][2][3][4][5]. DNA synthesis by detergent-lysed virus particles is sensitive to ribonuclease, but in some studies was not completely depressed by ribonuclease [1,4,6]. DNAdependent DNA polymerase activity has also been detected in RNA tumor virus particles by stimulation of DNA synthesis with a variety of exogenous DNA templates [7][8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

DNA and RNA from avian myeloblastosis virus as templates for viral DNA polymerase

Kiessling¹,

Deeney²,

Beaudreau³

1972

FEBS Letters

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Mechanism of Carcinogenesis by RNA Tumor Viruses, I. An RNA-Dependent DNA Polymerase in Murine Sarcoma Viruses

Cited by 85 publications

References 15 publications

3-Cyclic Amine Derivatives of Rifamycin: Strong Inhibitors of the DNA Polymerase Activity of RNA Tumor Viruses

3-Cyclic Amine Derivatives of Rifamycin: Strong Inhibitors of the DNA Polymerase Activity of RNA Tumor Viruses

Sarcoma-Virus-Related RNA Sequences in Normal Rat Cells

DNA and RNA from avian myeloblastosis virus as templates for viral DNA polymerase

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