Abstract
Damage to the protooncogene MYC has been implicated in the genesis of diverse human tumors, but the tumorigenic potential of the isolated gene has been disputed. Here we report the use of a retroviral vector to test the potency of human MYC for neoplastic transformation in avian cells. We found that sustained and abundant expression of MYC can transform both embryonic fibroblasts and hematopoietic cells and elicit granulocytic leukemias in chickens. Transformation by MYC is accompanied by changes in diverse aspects of cellular phenotype, including morphology, ability to grow in suspension, rate of proliferation, the structure of the cytoskeleton, and the composition of the extracellular matrix. Nevertheless, the biological potency of MYC is inherently constrained when compared to that of the retroviral oncogene v-myc. Our findings enlarge on previous descriptions of neoplastic transformation by MYC and sustain the view that ungoverned expression of the gene can contribute to the genesis of human tumors.
Full text
PDF![2102](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dfe8/53634/31edc744909a/pnas01031-0064.png)
![2103](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dfe8/53634/0186e0c1ed43/pnas01031-0065.png)
![2104](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dfe8/53634/aa121381b55f/pnas01031-0066.png)
![2105](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dfe8/53634/bd9cbe5be1b0/pnas01031-0067.png)
![2106](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dfe8/53634/144edf804e6e/pnas01031-0068.png)
Images in this article
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Adams J. M., Harris A. W., Pinkert C. A., Corcoran L. M., Alexander W. S., Cory S., Palmiter R. D., Brinster R. L. The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice. Nature. 1985 Dec 12;318(6046):533–538. doi: 10.1038/318533a0. [DOI] [PubMed] [Google Scholar]
- Beug H., von Kirchbach A., Döderlein G., Conscience J. F., Graf T. Chicken hematopoietic cells transformed by seven strains of defective avian leukemia viruses display three distinct phenotypes of differentiation. Cell. 1979 Oct;18(2):375–390. doi: 10.1016/0092-8674(79)90057-6. [DOI] [PubMed] [Google Scholar]
- Bishop J. M. The molecular genetics of cancer. Science. 1987 Jan 16;235(4786):305–311. doi: 10.1126/science.3541204. [DOI] [PubMed] [Google Scholar]
- Cole M. D. The myc oncogene: its role in transformation and differentiation. Annu Rev Genet. 1986;20:361–384. doi: 10.1146/annurev.ge.20.120186.002045. [DOI] [PubMed] [Google Scholar]
- Cory S., Adams J. M. Transgenic mice and oncogenesis. Annu Rev Immunol. 1988;6:25–48. doi: 10.1146/annurev.iy.06.040188.000325. [DOI] [PubMed] [Google Scholar]
- Dougherty J. P., Temin H. M. High mutation rate of a spleen necrosis virus-based retrovirus vector. Mol Cell Biol. 1986 Dec;6(12):4387–4395. doi: 10.1128/mcb.6.12.4387. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Evan G. I., Lewis G. K., Ramsay G., Bishop J. M. Isolation of monoclonal antibodies specific for human c-myc proto-oncogene product. Mol Cell Biol. 1985 Dec;5(12):3610–3616. doi: 10.1128/mcb.5.12.3610. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Frykberg L., Graf T., Vennström B. The transforming activity of the chicken c-myc gene can be potentiated by mutations. Oncogene. 1987;1(4):415–422. [PubMed] [Google Scholar]
- Hughes S. H., Greenhouse J. J., Petropoulos C. J., Sutrave P. Adaptor plasmids simplify the insertion of foreign DNA into helper-independent retroviral vectors. J Virol. 1987 Oct;61(10):3004–3012. doi: 10.1128/jvi.61.10.3004-3012.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Iba H., Takeya T., Cross F. R., Hanafusa T., Hanafusa H. Rous sarcoma virus variants that carry the cellular src gene instead of the viral src gene cannot transform chicken embryo fibroblasts. Proc Natl Acad Sci U S A. 1984 Jul;81(14):4424–4428. doi: 10.1073/pnas.81.14.4424. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Karn J., Watson J. V., Lowe A. D., Green S. M., Vedeckis W. Regulation of cell cycle duration by c-myc levels. Oncogene. 1989 Jun;4(6):773–787. [PubMed] [Google Scholar]
- Kawai S., Nishizawa M. New procedure for DNA transfection with polycation and dimethyl sulfoxide. Mol Cell Biol. 1984 Jun;4(6):1172–1174. doi: 10.1128/mcb.4.6.1172. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Keath E. J., Caimi P. G., Cole M. D. Fibroblast lines expressing activated c-myc oncogenes are tumorigenic in nude mice and syngeneic animals. Cell. 1984 Dec;39(2 Pt 1):339–348. doi: 10.1016/0092-8674(84)90012-6. [DOI] [PubMed] [Google Scholar]
- Kelekar A., Cole M. D. Tumorigenicity of fibroblast lines expressing the adenovirus E1a, cellular p53, or normal c-myc genes. Mol Cell Biol. 1986 Jan;6(1):7–14. doi: 10.1128/mcb.6.1.7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Klempnauer K. H., Symonds G., Evan G. I., Bishop J. M. Subcellular localization of proteins encoded by oncogenes of avian myeloblastosis virus and avian leukemia virus E26 and by chicken c-myb gene. Cell. 1984 Jun;37(2):537–547. doi: 10.1016/0092-8674(84)90384-2. [DOI] [PubMed] [Google Scholar]
- Land H., Parada L. F., Weinberg R. A. Tumorigenic conversion of primary embryo fibroblasts requires at least two cooperating oncogenes. Nature. 1983 Aug 18;304(5927):596–602. doi: 10.1038/304596a0. [DOI] [PubMed] [Google Scholar]
- Martin P., Henry C., Ferre F., Duterque-Coquillaud M., Lagrou C., Ghysdael J., Debuire B., Stehelin D., Saule S. Transformation of quail embryo fibroblasts by a retrovirus carrying a normal human c-myc gene. EMBO J. 1986 Jul;5(7):1529–1533. doi: 10.1002/j.1460-2075.1986.tb04393.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mougneau E., Lemieux L., Rassoulzadegan M., Cuzin F. Biological activities of v-myc and rearranged c-myc oncogenes in rat fibroblast cells in culture. Proc Natl Acad Sci U S A. 1984 Sep;81(18):5758–5762. doi: 10.1073/pnas.81.18.5758. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Palmieri S., Kahn P., Graf T. Quail embryo fibroblasts transformed by four v-myc-containing virus isolates show enhanced proliferation but are non tumorigenic. EMBO J. 1983;2(12):2385–2389. doi: 10.1002/j.1460-2075.1983.tb01750.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Papas T. S., Lautenberger J. A. Sequence curiosity in v-myc oncogene. Nature. 1985 Nov 21;318(6043):237–237. doi: 10.1038/318237a0. [DOI] [PubMed] [Google Scholar]
- Ramsay G., Evan G. I., Bishop J. M. The protein encoded by the human proto-oncogene c-myc. Proc Natl Acad Sci U S A. 1984 Dec;81(24):7742–7746. doi: 10.1073/pnas.81.24.7742. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Roussel M., Saule S., Lagrou C., Rommens C., Beug H., Graf T., Stehelin D. Three new types of viral oncogene of cellular origin specific for haematopoietic cell transformation. Nature. 1979 Oct 11;281(5731):452–455. doi: 10.1038/281452a0. [DOI] [PubMed] [Google Scholar]
- Sheiness D., Fanshier L., Bishop J. M. Identification of nucleotide sequences which may encode the oncogenic capacity of avian retrovirus MC29. J Virol. 1978 Nov;28(2):600–610. doi: 10.1128/jvi.28.2.600-610.1978. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Small M. B., Hay N., Schwab M., Bishop J. M. Neoplastic transformation by the human gene N-myc. Mol Cell Biol. 1987 May;7(5):1638–1645. doi: 10.1128/mcb.7.5.1638. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Stewart T. A., Pattengale P. K., Leder P. Spontaneous mammary adenocarcinomas in transgenic mice that carry and express MTV/myc fusion genes. Cell. 1984 Oct;38(3):627–637. doi: 10.1016/0092-8674(84)90257-5. [DOI] [PubMed] [Google Scholar]
- Symonds G., Hartshorn A., Kennewell A., O'Mara M. A., Bruskin A., Bishop J. M. Transformation of murine myelomonocytic cells by myc: point mutations in v-myc contribute synergistically to transforming potential. Oncogene. 1989 Mar;4(3):285–294. [PubMed] [Google Scholar]
- Thompson C. B., Humphries E. H., Carlson L. M., Chen C. L., Neiman P. E. The effect of alterations in myc gene expression on B cell development in the bursa of Fabricius. Cell. 1987 Nov 6;51(3):371–381. doi: 10.1016/0092-8674(87)90633-7. [DOI] [PubMed] [Google Scholar]
- Zhou R. P., Duesberg P. H. Avian proto-myc genes promoted by defective or nondefective retroviruses are single-hit transforming genes in primary cells. Proc Natl Acad Sci U S A. 1989 Oct;86(20):7721–7725. doi: 10.1073/pnas.86.20.7721. [DOI] [PMC free article] [PubMed] [Google Scholar]