Abstract
To identify functional relationships between oncogenes and growth factors, we compared the effects of transfected myc and ras oncogenes on the responsiveness of Fischer rat 3T3 cells to three growth factors: epidermal growth factor (EGF), platelet-derived growth factor (PDGF), and transforming growth factor-beta (TGF-beta). Control cells did not grow in soft agar under any conditions. ras-Transfected cells grew in soft agar under all conditions tested and were insensitive to the stimulatory effects of exogenous growth factors. These cells secreted elevated levels of both EGF-like factors and TGF-beta, suggesting that the lack of responsiveness of these cells to exogenous growth factors arose from autocrine stimulation. myc-Transfected cells displayed conditional anchorage-independent growth: they formed numerous colonies in soft agar in the presence of EGF but relatively few colonies in the presence of PDGF or TGF-beta. Secretion of EGF-like factors and TGF-beta by these cells was not elevated above that of control cells. These results suggest a model for the mechanism of cooperation between myc and ras oncogenes in which ras-like genes induce growth factor production, while myc-like genes increase the responsiveness of cells to these factors.
Full text
PDFSelected References
These references are in PubMed. This may not be the complete list of references from this article.
- Abrams H. D., Rohrschneider L. R., Eisenman R. N. Nuclear location of the putative transforming protein of avian myelocytomatosis virus. Cell. 1982 Jun;29(2):427–439. doi: 10.1016/0092-8674(82)90159-3. [DOI] [PubMed] [Google Scholar]
- Anzano M. A., Roberts A. B., De Larco J. E., Wakefield L. M., Assoian R. K., Roche N. S., Smith J. M., Lazarus J. E., Sporn M. B. Increased secretion of type beta transforming growth factor accompanies viral transformation of cells. Mol Cell Biol. 1985 Jan;5(1):242–247. doi: 10.1128/mcb.5.1.242. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Armelin H. A., Armelin M. C., Kelly K., Stewart T., Leder P., Cochran B. H., Stiles C. D. Functional role for c-myc in mitogenic response to platelet-derived growth factor. Nature. 1984 Aug 23;310(5979):655–660. doi: 10.1038/310655a0. [DOI] [PubMed] [Google Scholar]
- Assoian R. K., Frolik C. A., Roberts A. B., Miller D. M., Sporn M. B. Transforming growth factor-beta controls receptor levels for epidermal growth factor in NRK fibroblasts. Cell. 1984 Jan;36(1):35–41. doi: 10.1016/0092-8674(84)90071-0. [DOI] [PubMed] [Google Scholar]
- Assoian R. K., Grotendorst G. R., Miller D. M., Sporn M. B. Cellular transformation by coordinated action of three peptide growth factors from human platelets. 1984 Jun 28-Jul 4Nature. 309(5971):804–806. doi: 10.1038/309804a0. [DOI] [PubMed] [Google Scholar]
- Assoian R. K., Komoriya A., Meyers C. A., Miller D. M., Sporn M. B. Transforming growth factor-beta in human platelets. Identification of a major storage site, purification, and characterization. J Biol Chem. 1983 Jun 10;258(11):7155–7160. [PubMed] [Google Scholar]
- Balk S. D., Riley T. M., Gunther H. S., Morisi A. Heparin-treated, v-myc-transformed chicken heart mesenchymal cells assume a normal morphology but are hypersensitive to epidermal growth factor (EGF) and brain fibroblast growth factor (bFGF); cells transformed by the v-Ha-ras oncogene are refractory to EGF and bFGF but are hypersensitive to insulin-like growth factors. Proc Natl Acad Sci U S A. 1985 Sep;82(17):5781–5785. doi: 10.1073/pnas.82.17.5781. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bishop J. M. Viral oncogenes. Cell. 1985 Aug;42(1):23–38. doi: 10.1016/s0092-8674(85)80098-2. [DOI] [PubMed] [Google Scholar]
- Bowen-Pope D. F., Vogel A., Ross R. Production of platelet-derived growth factor-like molecules and reduced expression of platelet-derived growth factor receptors accompany transformation by a wide spectrum of agents. Proc Natl Acad Sci U S A. 1984 Apr;81(8):2396–2400. doi: 10.1073/pnas.81.8.2396. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cifone M. A., Fidler I. J. Correlation of patterns of anchorage-independent growth with in vivo behavior of cells from a murine fibrosarcoma. Proc Natl Acad Sci U S A. 1980 Feb;77(2):1039–1043. doi: 10.1073/pnas.77.2.1039. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cochran B. H., Zullo J., Verma I. M., Stiles C. D. Expression of the c-fos gene and of an fos-related gene is stimulated by platelet-derived growth factor. Science. 1984 Nov 30;226(4678):1080–1082. doi: 10.1126/science.6093261. [DOI] [PubMed] [Google Scholar]
- De Larco J. E., Preston Y. A., Todaro G. J. Properties of a sarcoma-growth-factor-like peptide from cells transformed by a temperature-sensitive sarcoma virus. J Cell Physiol. 1981 Oct;109(1):143–152. doi: 10.1002/jcp.1041090116. [DOI] [PubMed] [Google Scholar]
- Deuel T. F., Huang J. S., Huang S. S., Stroobant P., Waterfield M. D. Expression of a platelet-derived growth factor-like protein in simian sarcoma virus transformed cells. Science. 1983 Sep 30;221(4618):1348–1350. doi: 10.1126/science.6310754. [DOI] [PubMed] [Google Scholar]
- Doolittle R. F., Hunkapiller M. W., Hood L. E., Devare S. G., Robbins K. C., Aaronson S. A., Antoniades H. N. Simian sarcoma virus onc gene, v-sis, is derived from the gene (or genes) encoding a platelet-derived growth factor. Science. 1983 Jul 15;221(4607):275–277. doi: 10.1126/science.6304883. [DOI] [PubMed] [Google Scholar]
- Downward J., Yarden Y., Mayes E., Scrace G., Totty N., Stockwell P., Ullrich A., Schlessinger J., Waterfield M. D. Close similarity of epidermal growth factor receptor and v-erb-B oncogene protein sequences. Nature. 1984 Feb 9;307(5951):521–527. doi: 10.1038/307521a0. [DOI] [PubMed] [Google Scholar]
- Frolik C. A., Wakefield L. M., Smith D. M., Sporn M. B. Characterization of a membrane receptor for transforming growth factor-beta in normal rat kidney fibroblasts. J Biol Chem. 1984 Sep 10;259(17):10995–11000. [PubMed] [Google Scholar]
- Greenberg M. E., Ziff E. B. Stimulation of 3T3 cells induces transcription of the c-fos proto-oncogene. Nature. 1984 Oct 4;311(5985):433–438. doi: 10.1038/311433a0. [DOI] [PubMed] [Google Scholar]
- Hurley J. B., Simon M. I., Teplow D. B., Robishaw J. D., Gilman A. G. Homologies between signal transducing G proteins and ras gene products. Science. 1984 Nov 16;226(4676):860–862. doi: 10.1126/science.6436980. [DOI] [PubMed] [Google Scholar]
- Johnsson A., Betsholtz C., von der Helm K., Heldin C. H., Westermark B. Platelet-derived growth factor agonist activity of a secreted form of the v-sis oncogene product. Proc Natl Acad Sci U S A. 1985 Mar;82(6):1721–1725. doi: 10.1073/pnas.82.6.1721. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kaczmarek L., Hyland J. K., Watt R., Rosenberg M., Baserga R. Microinjected c-myc as a competence factor. Science. 1985 Jun 14;228(4705):1313–1315. doi: 10.1126/science.4001943. [DOI] [PubMed] [Google Scholar]
- Kahn P., Shin S. I. Cellular tumorigenicity in nude mice. Test of associations among loss of cell-surface fibronectin, anchorage independence, and tumor-forming ability. J Cell Biol. 1979 Jul;82(1):1–16. doi: 10.1083/jcb.82.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kamata T., Feramisco J. R. Epidermal growth factor stimulates guanine nucleotide binding activity and phosphorylation of ras oncogene proteins. Nature. 1984 Jul 12;310(5973):147–150. doi: 10.1038/310147a0. [DOI] [PubMed] [Google Scholar]
- Kaplan P. L., Anderson M., Ozanne B. Transforming growth factor(s) production enables cells to grow in the absence of serum: an autocrine system. Proc Natl Acad Sci U S A. 1982 Jan;79(2):485–489. doi: 10.1073/pnas.79.2.485. [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]
- Kelly K., Cochran B. H., Stiles C. D., Leder P. Cell-specific regulation of the c-myc gene by lymphocyte mitogens and platelet-derived growth factor. Cell. 1983 Dec;35(3 Pt 2):603–610. doi: 10.1016/0092-8674(83)90092-2. [DOI] [PubMed] [Google Scholar]
- Kingston R. E., Baldwin A. S., Jr, Sharp P. A. Regulation of heat shock protein 70 gene expression by c-myc. Nature. 1984 Nov 15;312(5991):280–282. doi: 10.1038/312280a0. [DOI] [PubMed] [Google Scholar]
- Kingston R. E., Baldwin A. S., Sharp P. A. Transcription control by oncogenes. Cell. 1985 May;41(1):3–5. doi: 10.1016/0092-8674(85)90049-2. [DOI] [PubMed] [Google Scholar]
- Kruijer W., Cooper J. A., Hunter T., Verma I. M. Platelet-derived growth factor induces rapid but transient expression of the c-fos gene and protein. Nature. 1984 Dec 20;312(5996):711–716. doi: 10.1038/312711a0. [DOI] [PubMed] [Google Scholar]
- Land H., Parada L. F., Weinberg R. A. Cellular oncogenes and multistep carcinogenesis. Science. 1983 Nov 18;222(4625):771–778. doi: 10.1126/science.6356358. [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]
- McGrath J. P., Capon D. J., Goeddel D. V., Levinson A. D. Comparative biochemical properties of normal and activated human ras p21 protein. Nature. 1984 Aug 23;310(5979):644–649. doi: 10.1038/310644a0. [DOI] [PubMed] [Google Scholar]
- Melton D. A., Krieg P. A., Rebagliati M. R., Maniatis T., Zinn K., Green M. R. Efficient in vitro synthesis of biologically active RNA and RNA hybridization probes from plasmids containing a bacteriophage SP6 promoter. Nucleic Acids Res. 1984 Sep 25;12(18):7035–7056. doi: 10.1093/nar/12.18.7035. [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]
- Müller R., Bravo R., Burckhardt J., Curran T. Induction of c-fos gene and protein by growth factors precedes activation of c-myc. Nature. 1984 Dec 20;312(5996):716–720. doi: 10.1038/312716a0. [DOI] [PubMed] [Google Scholar]
- Ozanne B., Fulton R. J., Kaplan P. L. Kirsten murine sarcoma virus transformed cell lines and a spontaneously transformed rat cell-line produce transforming factors. J Cell Physiol. 1980 Oct;105(1):163–180. doi: 10.1002/jcp.1041050118. [DOI] [PubMed] [Google Scholar]
- Rassoulzadegan M., Cowie A., Carr A., Glaichenhaus N., Kamen R., Cuzin F. The roles of individual polyoma virus early proteins in oncogenic transformation. Nature. 1982 Dec 23;300(5894):713–718. doi: 10.1038/300713a0. [DOI] [PubMed] [Google Scholar]
- Robbins K. C., Antoniades H. N., Devare S. G., Hunkapiller M. W., Aaronson S. A. Structural and immunological similarities between simian sarcoma virus gene product(s) and human platelet-derived growth factor. Nature. 1983 Oct 13;305(5935):605–608. doi: 10.1038/305605a0. [DOI] [PubMed] [Google Scholar]
- Roberts A. B., Anzano M. A., Lamb L. C., Smith J. M., Sporn M. B. New class of transforming growth factors potentiated by epidermal growth factor: isolation from non-neoplastic tissues. Proc Natl Acad Sci U S A. 1981 Sep;78(9):5339–5343. doi: 10.1073/pnas.78.9.5339. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Roberts A. B., Anzano M. A., Wakefield L. M., Roche N. S., Stern D. F., Sporn M. B. Type beta transforming growth factor: a bifunctional regulator of cellular growth. Proc Natl Acad Sci U S A. 1985 Jan;82(1):119–123. doi: 10.1073/pnas.82.1.119. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Roberts A. B., Frolik C. A., Anzano M. A., Sporn M. B. Transforming growth factors from neoplastic and nonneoplastic tissues. Fed Proc. 1983 Jun;42(9):2621–2626. [PubMed] [Google Scholar]
- Roberts A. B., Lamb L. C., Newton D. L., Sporn M. B., De Larco J. E., Todaro G. J. Transforming growth factors: isolation of polypeptides from virally and chemically transformed cells by acid/ethanol extraction. Proc Natl Acad Sci U S A. 1980 Jun;77(6):3494–3498. doi: 10.1073/pnas.77.6.3494. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Roberts A. B., Roche N. S., Sporn M. B. Selective inhibition of the anchorage-independent growth of myc-transfected fibroblasts by retinoic acid. Nature. 1985 May 16;315(6016):237–239. doi: 10.1038/315237a0. [DOI] [PubMed] [Google Scholar]
- Ruley H. E. Adenovirus early region 1A enables viral and cellular transforming genes to transform primary cells in culture. Nature. 1983 Aug 18;304(5927):602–606. doi: 10.1038/304602a0. [DOI] [PubMed] [Google Scholar]
- Scher C. D., Shepard R. C., Antoniades H. N., Stiles C. D. Platelet-derived growth factor and the regulation of the mammalian fibroblast cell cycle. Biochim Biophys Acta. 1979 Aug 10;560(2):217–241. doi: 10.1016/0304-419x(79)90020-9. [DOI] [PubMed] [Google Scholar]
- Sherr C. J., Rettenmier C. W., Sacca R., Roussel M. F., Look A. T., Stanley E. R. The c-fms proto-oncogene product is related to the receptor for the mononuclear phagocyte growth factor, CSF-1. Cell. 1985 Jul;41(3):665–676. doi: 10.1016/s0092-8674(85)80047-7. [DOI] [PubMed] [Google Scholar]
- Shih C., Weinberg R. A. Isolation of a transforming sequence from a human bladder carcinoma cell line. Cell. 1982 May;29(1):161–169. doi: 10.1016/0092-8674(82)90100-3. [DOI] [PubMed] [Google Scholar]
- Sporn M. B., Todaro G. J. Autocrine secretion and malignant transformation of cells. N Engl J Med. 1980 Oct 9;303(15):878–880. doi: 10.1056/NEJM198010093031511. [DOI] [PubMed] [Google Scholar]
- Sweet R. W., Yokoyama S., Kamata T., Feramisco J. R., Rosenberg M., Gross M. The product of ras is a GTPase and the T24 oncogenic mutant is deficient in this activity. Nature. 1984 Sep 20;311(5983):273–275. doi: 10.1038/311273a0. [DOI] [PubMed] [Google Scholar]
- Ullrich A., Coussens L., Hayflick J. S., Dull T. J., Gray A., Tam A. W., Lee J., Yarden Y., Libermann T. A., Schlessinger J. Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells. 1984 May 31-Jun 6Nature. 309(5967):418–425. doi: 10.1038/309418a0. [DOI] [PubMed] [Google Scholar]
- Vennström B., Kahn P., Adkins B., Enrietto P., Hayman M. J., Graf T., Luciw P. Transformation of mammalian fibroblasts and macrophages in vitro by a murine retrovirus encoding an avian v-myc oncogene. EMBO J. 1984 Dec 20;3(13):3223–3229. doi: 10.1002/j.1460-2075.1984.tb02282.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Waterfield M. D., Scrace G. T., Whittle N., Stroobant P., Johnsson A., Wasteson A., Westermark B., Heldin C. H., Huang J. S., Deuel T. F. Platelet-derived growth factor is structurally related to the putative transforming protein p28sis of simian sarcoma virus. Nature. 1983 Jul 7;304(5921):35–39. doi: 10.1038/304035a0. [DOI] [PubMed] [Google Scholar]
- Willingham M. C., Pastan I., Shih T. Y., Scolnick E. M. Localization of the src gene product of the Harvey strain of MSV to plasma membrane of transformed cells by electron microscopic immunocytochemistry. Cell. 1980 Apr;19(4):1005–1014. doi: 10.1016/0092-8674(80)90091-4. [DOI] [PubMed] [Google Scholar]
- de Larco J. E., Todaro G. J. Growth factors from murine sarcoma virus-transformed cells. Proc Natl Acad Sci U S A. 1978 Aug;75(8):4001–4005. doi: 10.1073/pnas.75.8.4001. [DOI] [PMC free article] [PubMed] [Google Scholar]