Abstract
Previous studies have indicated that the oncogene v-sis of simian sarcoma virus (SSV) encodes a growth factor that is structurally and functionally similar to platelet-derived growth factor (PDGF). In the present investigation we have analysed the phenotypic characteristics of human foreskin fibroblasts transformed by SSV. It was found that the PDGF receptors were extensively down-regulated. This finding is consistent with a high, local, extracellular concentration of a PDGF-like factor, synthesized by the transformed cell. The receptors were up-regulated by suramin, a drug that is known to dissociate PDGF and the v-sis product from the PDGF receptors. A cell-associated v-sis product of mol. wt 24,000 was identified by immunoprecipitation with PDGF antibodies; release of this component was induced by a high concentration of exogenous PDGF, indicating that a fraction of the product is associated with the PDGF receptors. SSV was not found to be an immortalizing virus; when serially passaged, SSV-transformed cells had essentially the same life-span as their non-transformed counterparts. Moreover, SSV did not induce growth in soft agar beyond the level afforded by exogenously added PDGF. Thus, the present study favors the notion that SSV transformation is mediated by a growth factor that mimics PDGF but has no further cellular effects.
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- 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]
- Betsholtz C., Heldin C. H., Nister M., Ek B., Wasteson A., Westermark B. Synthesis of a PDGF-like growth factor in human glioma and sarcoma cells suggests the expression of the cellular homologue to the transforming protein of simian sarcoma virus. Biochem Biophys Res Commun. 1983 Nov 30;117(1):176–182. doi: 10.1016/0006-291x(83)91557-7. [DOI] [PubMed] [Google Scholar]
- Betsholtz C., Westermark B. Growth factor-induced proliferation of human fibroblasts in serum-free culture depends on cell density and extracellular calcium concentration. J Cell Physiol. 1984 Feb;118(2):203–210. doi: 10.1002/jcp.1041180213. [DOI] [PubMed] [Google Scholar]
- Blobel G., Dobberstein B. Transfer of proteins across membranes. I. Presence of proteolytically processed and unprocessed nascent immunoglobulin light chains on membrane-bound ribosomes of murine myeloma. J Cell Biol. 1975 Dec;67(3):835–851. doi: 10.1083/jcb.67.3.835. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bowman P. D., Daniel C. W. Aging of human fibroblasts in vitro: surface features and behavior of aging WI 38 cells. Mech Ageing Dev. 1975 Mar-Apr;4(2):147–158. doi: 10.1016/0047-6374(75)90016-0. [DOI] [PubMed] [Google Scholar]
- Chiu I. M., Reddy E. P., Givol D., Robbins K. C., Tronick S. R., Aaronson S. A. Nucleotide sequence analysis identifies the human c-sis proto-oncogene as a structural gene for platelet-derived growth factor. Cell. 1984 May;37(1):123–129. doi: 10.1016/0092-8674(84)90307-6. [DOI] [PubMed] [Google Scholar]
- Collins T., Ginsburg D., Boss J. M., Orkin S. H., Pober J. S. Cultured human endothelial cells express platelet-derived growth factor B chain: cDNA cloning and structural analysis. Nature. 1985 Aug 22;316(6030):748–750. doi: 10.1038/316748a0. [DOI] [PubMed] [Google Scholar]
- Devare S. G., Reddy E. P., Law J. D., Robbins K. C., Aaronson S. A. Nucleotide sequence of the simian sarcoma virus genome: demonstration that its acquired cellular sequences encode the transforming gene product p28sis. Proc Natl Acad Sci U S A. 1983 Feb;80(3):731–735. doi: 10.1073/pnas.80.3.731. [DOI] [PMC free article] [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]
- Garrett J. S., Coughlin S. R., Niman H. L., Tremble P. M., Giels G. M., Williams L. T. Blockade of autocrine stimulation in simian sarcoma virus-transformed cells reverses down-regulation of platelet-derived growth factor receptors. Proc Natl Acad Sci U S A. 1984 Dec;81(23):7466–7470. doi: 10.1073/pnas.81.23.7466. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Glenn K., Bowen-Pope D. F., Ross R. Platelet-derived growth factor. III. Identification of a platelet-derived growth factor receptor by affinity labeling. J Biol Chem. 1982 May 10;257(9):5172–5176. [PubMed] [Google Scholar]
- Hannink M., Donoghue D. J. Requirement for a signal sequence in biological expression of the v-sis oncogene. Science. 1984 Dec 7;226(4679):1197–1199. doi: 10.1126/science.6095451. [DOI] [PubMed] [Google Scholar]
- Heldin C. H., Ek B., Rönnstrand L. Characterization of the receptor for platelet-derived growth factor on human fibroblasts. Demonstration of an intimate relationship with a 185,000-Dalton substrate for the platelet-derived growth factor-stimulated kinase. J Biol Chem. 1983 Aug 25;258(16):10054–10061. [PubMed] [Google Scholar]
- Heldin C. H., Wasteson A., Westermark B. Interaction of platelet-derived growth factor with its fibroblast receptor. Demonstration of ligand degradation and receptor modulation. J Biol Chem. 1982 Apr 25;257(8):4216–4221. [PubMed] [Google Scholar]
- Heldin C. H., Westermark B. Growth factors: mechanism of action and relation to oncogenes. Cell. 1984 May;37(1):9–20. doi: 10.1016/0092-8674(84)90296-4. [DOI] [PubMed] [Google Scholar]
- Heldin C. H., Westermark B., Wasteson A. Demonstration of an antibody against platelet-derived growth factor. Exp Cell Res. 1981 Dec;136(2):255–261. doi: 10.1016/0014-4827(81)90003-3. [DOI] [PubMed] [Google Scholar]
- Johnsson A., Betsholtz C., Heldin C. H., Westermark B. Antibodies against platelet-derived growth factor inhibit acute transformation by simian sarcoma virus. Nature. 1985 Oct 3;317(6036):438–440. doi: 10.1038/317438a0. [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]
- Johnsson A., Heldin C. H., Wasteson A., Westermark B., Deuel T. F., Huang J. S., Seeburg P. H., Gray A., Ullrich A., Scrace G. The c-sis gene encodes a precursor of the B chain of platelet-derived growth factor. EMBO J. 1984 May;3(5):921–928. doi: 10.1002/j.1460-2075.1984.tb01908.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Johnsson A., Heldin C. H., Westermark B., Wasteson A. Platelet-derived growth factor: identification of constituent polypeptide chains. Biochem Biophys Res Commun. 1982 Jan 15;104(1):66–74. doi: 10.1016/0006-291x(82)91941-6. [DOI] [PubMed] [Google Scholar]
- Josephs S. F., Guo C., Ratner L., Wong-Staal F. Human-proto-oncogene nucleotide sequences corresponding to the transforming region of simian sarcoma virus. Science. 1984 Feb 3;223(4635):487–491. doi: 10.1126/science.6318322. [DOI] [PubMed] [Google Scholar]
- Kaplan P. L., Ozanne B. Cellular responsiveness to growth factors correlates with a cell's ability to express the transformed phenotype. Cell. 1983 Jul;33(3):931–938. doi: 10.1016/0092-8674(83)90036-3. [DOI] [PubMed] [Google Scholar]
- King C. R., Giese N. A., Robbins K. C., Aaronson S. A. In vitro mutagenesis of the v-sis transforming gene defines functional domains of its growth factor-related product. Proc Natl Acad Sci U S A. 1985 Aug;82(16):5295–5299. doi: 10.1073/pnas.82.16.5295. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pontén J. The growth capacity of normal and Rous-virus-transformed chicken fibroblasts in vitro. Int J Cancer. 1970 Nov 15;6(3):323–332. doi: 10.1002/ijc.2910060302. [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]
- Robbins K. C., Leal F., Pierce J. H., Aaronson S. A. The v-sis/PDGF-2 transforming gene product localizes to cell membranes but is not a secretory protein. EMBO J. 1985 Jul;4(7):1783–1792. doi: 10.1002/j.1460-2075.1985.tb03851.x. [DOI] [PMC free article] [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]
- Shin S. I., Freedman V. H., Risser R., Pollack R. Tumorigenicity of virus-transformed cells in nude mice is correlated specifically with anchorage independent growth in vitro. Proc Natl Acad Sci U S A. 1975 Nov;72(11):4435–4439. doi: 10.1073/pnas.72.11.4435. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sporn M. B., Roberts A. B. Autocrine growth factors and cancer. 1985 Feb 28-Mar 6Nature. 313(6005):745–747. doi: 10.1038/313745a0. [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]
- Stoker M. G. Role of diffusion boundary layer in contact inhibition of growth. Nature. 1973 Nov 23;246(5430):200–203. doi: 10.1038/246200a0. [DOI] [PubMed] [Google Scholar]
- Stroobant P., Waterfield M. D. Purification and properties of porcine platelet-derived growth factor. EMBO J. 1984 Dec 1;3(12):2963–2967. doi: 10.1002/j.1460-2075.1984.tb02241.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]
- Williams L. T., Tremble P. M., Lavin M. F., Sunday M. E. Platelet-derived growth factor receptors form a high affinity state in membrane preparations. Kinetics and affinity cross-linking studies. J Biol Chem. 1984 Apr 25;259(8):5287–5294. [PubMed] [Google Scholar]



