Cell Transformation by Viruses

Dulbecco, Renato

doi:10.1126/science.166.3908.962

Cited by 120 publications

(21 citation statements)

References 50 publications

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“…The ability to overcome this inhibition of growth is regarded as characteristic of transformed cells (4) and is related to an increase in tumorigenicity (3).…”

mentioning

confidence: 99%

Restoration of Contact-Inhibited Growth to Transformed Cells by Dibutyryl Adenosine 3′:5′-Cyclic Monophosphate

Sheppard

1971

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

296

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Spontaneously transformed and virallytransformed cells are restored to contact-inhibited growth by the addition of dibutyryl cyclic AMP to the nutrient medium. Theophylline, an inhibitor of the phosphodiesterase that degrades cyclic nucleotides, must also be present for maximal effect. Once the transformed cells reach a saturation density in the presence of the additives, release from the contact-inhibited state occurs upon removal of the dibutyryl cyclic AMP and theophylline from the medium. Agglutinability of the transformed cells by wheat-germ agglutinin (a monitor of architectural changes in the plasma membrane) is decreased by dibutyryl cyclic AMP-theophylline treatment, but increases again upon removal of the additives.

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“…The ability to overcome this inhibition of growth is regarded as characteristic of transformed cells (4) and is related to an increase in tumorigenicity (3).…”

mentioning

confidence: 99%

Restoration of Contact-Inhibited Growth to Transformed Cells by Dibutyryl Adenosine 3′:5′-Cyclic Monophosphate

Sheppard

1971

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

296

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“…Elucidation of the function of each of the proteins coded by the virus would be a great stride toward an understanding of the molecular basis of cancer (1)(2)(3). However, the problem becomes more complex when we consider the fact that polyoma infection stimulates cells to synthesize various enzymes and basic proteins that were repressed prior to infection (4)(5)(6)(7).…”

mentioning

confidence: 99%

Isolation of a Polyoma-Nucleoprotein Complex from Infected Mouse-Cell Cultures

Green

Miller

Hendler

1971

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

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A complex containing polyoma (py) DNA and protein (py complex) was isolated from polyomainfected mouse-cell cultures. The The small size of the polyoma virus genome (about 3 X 106 daltons) makes it an ideal prototype for studies on the mechanism of viral-induced tumorigenesis. Elucidation of the function of each of the proteins coded by the virus would be a great stride toward an understanding of the molecular basis of cancer (1-3). However, the problem becomes more complex when we consider the fact that polyoma infection stimulates cells to synthesize various enzymes and basic proteins that were repressed prior to infection (4-7). These proteins, as well as those coded by the virus, may play a role in the type of response of the cell to infection; i.e., in determining whether the cell is killed or becomes transformed.In an effort to gain information regarding the mechanism of polyoma replication and development, we have taken the approach of isolating those proteins that remain associated with the viral DNA upon extraction from infected mouse-cell cultures. A modified Hirt procedure (8), employing a neutral detergent (Triton X-100) and low salt concentration, is used to separate a polyoma nucleoprotein complex from cellular DNA. The method is quite similar to our method for the isolation of XDNA-RNA polymerase complex from Escherichia coli (9). MATERIALS AND METHODS Infection of cell culturesLarge-plaque polyoma (py) virus stocks were prepared by infection of secondary mouse embryo (ME) or mouse kidney cells growing in tissue culture (10 ,1 1). Non-purified virus was used for most of the experiments. ME, 3T3 Balb/C, or Ts-a-3T3 cells were used as hosts for polyoma virus. They were grown as monolayers in 100-mm plastic tissue-culture plates in Dulbecco's modification of Eagle's medium containing 10% calf serum, except for the 3T3 Balb/C cells, which were grown with 20% calf serum. Plates were seeded such that confluence was reached within 30 hr after seeding.Cells were infected soon after confluence by adding 0.4 ml of virus [10 plaque-forming units (PFU) per cell] to the cell cultures drained free of medium. After incubation (1 hr) at 37°C for adsorption, the cultures were covered with 5 ml of fresh growth medium that contained 1% horse serum. DNA was labeled with [3H]thymidine (5 .sCi/ml, 12-15 Ci/mmol) at the times designated. from Rohm & Haas], 1 ml/plate, was added at room temperature. The plates were gently swirled for 10 min and NaCl was added to a final concentration of 0.2 M. The salt produced noticeable lysis of the cells. The lysate was poured or scraped with a Teflon "policeman" into a polyallomer centrifuge tube and cleared bycentrifugation in the SW39 rotor (Spinco) at 4°C for 30 min at 20,000 rpm in order to pellet the cellular DNA. The supernatant, containing the py DNA, was decanted and stored in a glass vial at 4°C. It is important not to subject the lysate to shearing forces at any stage in order to prevent the release of cellular DNA into the supernatant.In recent experiments, centr...

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“…On the other hand, the view that cancer is caused by viruses or abnormal cellular differentiation has been more rigorously tested experimentally (Dulbecco, 1969;Cold Spring Harbor Symp., 1974;Pitot and Heidelberger, 1963;Heidelberger, 1975). This difference may simply reflect the fact that our knowledge of animal viruses and cellular differentiation in mammals is more advanced than that on mutation in mammals.…”

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confidence: 99%

A test for mutation theory of cancer: Carcinogenesis by misrepair of DNA damaged by 4-nitroquinoline 1-oxide

Kondo¹

1977

Br J Cancer

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Summary.-Evidence for a mutation theory of cancer is presented by reviewing the experimental work on 4-nitroquinoline 1-oxide (4NQO) carcinogenesis. 4NQO almost completely mimics u.v. light and produces 4NQO-purine adducts on DNA. When 4NQO-treated cells are held in liquid medium under appropriate conditions, the 4NQO adducts disappear from DNA, in parallel to decrease of premutational damage in Escherichia coli, or pretransformational damage in cultured mouse cells. Post-treatment with caffeine greatly diminishes the yields by 4NQO of mutants in E. coli, malignant transformants in cultured mouse cells and tumour nodules in the lung of mice. Potentially tumourigenized stem cells in the lung remain sensitive to selective killing by caffeine for at least 5 days after 4NQO treatment, in spite of their DNA being apparently replicated, an indication that carcinogen-damaged DNA in the stem cell can be transmitted to its successive daughter stem cells for many generations. This peculiar characteristic is discussed as a possible lead to the crux of the mutation theory of cancer in vivo, and a model for carcinogenesis is proposed.

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Cell Transformation by Viruses

Cited by 120 publications

References 50 publications

Restoration of Contact-Inhibited Growth to Transformed Cells by Dibutyryl Adenosine 3′:5′-Cyclic Monophosphate

Restoration of Contact-Inhibited Growth to Transformed Cells by Dibutyryl Adenosine 3′:5′-Cyclic Monophosphate

Isolation of a Polyoma-Nucleoprotein Complex from Infected Mouse-Cell Cultures

A test for mutation theory of cancer: Carcinogenesis by misrepair of DNA damaged by 4-nitroquinoline 1-oxide

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