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Gene Review

src  -  p60-SRC phosphoprotein

Rous sarcoma virus

 
 
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Disease relevance of src

  • Hormonal regulation of the Rous sarcoma virus src gene via a heterologous promoter defines a threshold dose for cellular transformation [1].
  • Fujinami sarcoma virus (FSV), a newly characterized avian sarcoma virus, produces a protein of 140,000 daltons (p140) in infected cells. p140 is the product of a fused gene consisting of a part of the gag gene of avian retrovirus and FSV-unique sequences which are not related to the src sequences of Rous sarcoma virus [2].
  • This protein was not found in cells infected by trnasformation-defective mutants with either a partial or complete deletion of the src gene, nor in cells infected by a nontransforming avian leukosis virus [3].
  • We have derived rat cell lines producing different and regulatable amounts of pp60v-src by introducing the src gene of Rous sarcoma virus (RSV) under the control of the glucocorticoid-responsive transcriptional promoter from the mouse mammary tumor virus (MMTV) [1].
  • These results suggest that the common TSSA in the mouse and rat cells transformed by RSV or B77 ASV containing src gene is not shared with mammalian cells infected with retroviruses transducing other oncogenes of the src gene family (i.e., fps, fes, and abl) [4].
 

High impact information on src

  • The specificity, saturability, and competitive nature of pp60v-src binding provide evidence for the existence of a src receptor in the plasma membrane [5].
  • Effect of src infection on long-term marrow cultures: increased self-renewal of hemopoietic progenitor cells without leukemia [6].
  • This resulted in introduction of the src gene into the cultured cells and expression of its protein kinase function [6].
  • A mutant in src, the oncogene of Rous sarcoma virus, has been constructed in which the major phosphorylated tyrosine (Tyr-416, located in the carboxy-terminal half of the protein) has been replaced by phenylalanine [7].
  • A comparison of known protein sequences with the nucleotide sequence allows assignment of the coding regions for the gag, pol, env and src genes [8].
 

Chemical compound and disease context of src

  • Transformation of chicken cells by Fujinami sarcoma virus (FSV), PRC II or Y73 (three independently isolated avian sarcoma viruses that are replication-defective and lack the Rous sarcoma virus src gene) resulted in significant elevation (4-13 fold) of phosphotyrosine levels in cellular protein [9].
  • Here we report that purified p100gag-mil and p75gag-raf exhibit protein kinase activities in vitro which, in contrast to the src-related p130gag-fps of Fujinami sarcoma virus (FSV) and all other characterized oncogene-encoded protein kinases, phosphorylate serine and threonine but not tyrosine [10].
  • In accord with previous results recombinant RNAs contained (i) oligonucleotides characteristic of the src gene, coding for sarcoma formation, between the poly(A) end and 2000 nucleotides and (ii) olignucleotides characteristic of the env gene, coding for the envelope glycoprotein, between 2500 and 5000 nucleo tides from the poly(A) end [11].
  • The avian sarcoma virus src gene product, p60src, has been purified 650-fold from cytoplasmic extracts of the rat tumor cell line RR1022 by using ammonium sulfate fractionation, hydrophobic chromatography on omega-aminohexyl agarose, and ion exchange chromatography on phosphocellulose [12].
  • Bisulfite mutagenesis techniques have been used to introduce single-point mutations within a region of the Rous sarcoma virus src gene defined by a BglI restriction endonuclease cleavage site [13].
 

Biological context of src

  • These findings raise the possibility that phosphorylation of specific cellular targets might account for transformation of the host cell by src [14].
  • Four molecular clones containing DNA homologous to the Rous sarcoma virus transforming gene (src) have been isolated from a random library of normal chicken DNA [15].
  • The sequences in the chicken genome which have homology with the src gene of ASV are invariant from bird to bird and in this sense resemble a cellular gene rather than a viral sequence [16].
  • We have used this approach to compare 18 chicken embryos with respect to several cellular genes; endogenous viral DNA related to the replicative genes of avian sarcoma virus (ASV) or to RAV-O, an endogenous virus of chickens; and sequences related to the transforming (src) gene of ASV [16].
  • A single viral gene (src) is responsible for both the induction and maintenance of neoplastic transformation [14].
 

Anatomical context of src

  • MAG can be phosphorylated at tyrosine by the v-fps and v-src protein-tyrosine kinases in vitro and by a kinase endogenous to myelin membrane preparations [17].
  • Transformation of chicken embryo fibroblasts by Rous sarcoma virus (RSV) is caused by a single viral gene, src, which encodes a phosphoprotein, pp60src, with the enzymatic activity of a protein kinase [18].
  • The altered membrane association of these src proteins had little or no effect on the properties of chick embryo fibroblasts transformed in monolayer culture [19].
  • Here we present data on the effect of infection of PC12 cells with retroviruses carrying the src oncogene of Rous sarcoma virus [20].
  • Antibodies to pp60src, the protein encoded by the src oncogene of Rous sarcoma virus (RSV), can specifically immunoprecipitate affinity-labeled insulin receptors from cultured human lymphocytes (IM-9 cells) [21].
 

Associations of src with chemical compounds

  • An oncogenic mutant src protein, p60c-src(527F), where tyrosine 527 is substituted by phenylalanine, is also highly active in all phases of the cell cycle [22].
  • Tryptic phosphopeptide analysis demonstrated that the catalytic subunit phosphorylated a serine-containing tryptic peptide in the bacterial src protein that comigrated with the phosphoserine-containing tryptic peptide of pp60src immunoprecipitated from 32P-labeled PrA-RSV-infected chicken cells [23].
  • NH2-terminal sequences of two src proteins that cause aberrant transformation [24].
  • The phosphotyrosine content of the 115- to 120-kDa proteins was greatly reduced in chicken embryo fibroblasts infected with mutants of RSV (NY314 and SD10) encoding nonmyristoylated forms of the viral src gene product that do not associate with cellular membranes [25].
  • A distinguishing feature of src-inducible prostaglandin synthase mRNA is its low abundance in nonproliferating chicken embryo fibroblasts and its relatively high abundance in src-transformed cells [26].
 

Analytical, diagnostic and therapeutic context of src

References

  1. Hormonal regulation of the Rous sarcoma virus src gene via a heterologous promoter defines a threshold dose for cellular transformation. Jakobovits, E.B., Majors, J.E., Varmus, H.E. Cell (1984) [Pubmed]
  2. Characterization of protein kinase activity associated with the transforming gene product of Fujinami sarcoma virus. Feldman, R.A., Hanafusa, T., Hanafusa, H. Cell (1980) [Pubmed]
  3. Identification of a transformation-specific protein induced by a Rous sarcoma virus. Jay, G., Shiu, R.P., Jay, F.T., Levine, A.S., Pastan, I. Cell (1978) [Pubmed]
  4. No expression of a Rous sarcoma virus-induced tumor antigen in mammalian cells infected with retroviruses transducing other oncogenes of the src gene family. Kuzumaki, N., Yamagiwa, S., Oikawa, T. J. Natl. Cancer Inst. (1985) [Pubmed]
  5. Specific and saturable binding of pp60v-src to plasma membranes: evidence for a myristyl-src receptor. Resh, M.D. Cell (1989) [Pubmed]
  6. Effect of src infection on long-term marrow cultures: increased self-renewal of hemopoietic progenitor cells without leukemia. Boettiger, D., Anderson, S., Dexter, T.M. Cell (1984) [Pubmed]
  7. Phosphorylation of tyrosine-416 is not required for the transforming properties and kinase activity of pp60v-src. Snyder, M.A., Bishop, J.M., Colby, W.W., Levinson, A.D. Cell (1983) [Pubmed]
  8. Nucleotide sequence of Rous sarcoma virus. Schwartz, D.E., Tizard, R., Gilbert, W. Cell (1983) [Pubmed]
  9. Transforming proteins of some feline and avian sarcoma viruses are related structurally and functionally. Beemon, K. Cell (1981) [Pubmed]
  10. Serine- and threonine-specific protein kinase activities of purified gag-mil and gag-raf proteins. Moelling, K., Heimann, B., Beimling, P., Rapp, U.R., Sander, T. Nature (1984) [Pubmed]
  11. Mapping oligonucleotides of Rous sarcoma virus RNA that segregate with polymerase and group-specific antigen markers in recombinants. Wang, L., Galehouse, D., Mellon, P., Duesberg, P., Mason, W.S., Vogt, P.K. Proc. Natl. Acad. Sci. U.S.A. (1976) [Pubmed]
  12. Characterization of the protein kinase activity of avian sarcoma virus src gene product. Maness, P.F., Engeser, H., Greenberg, M.E., O'Farrell, M., Gall, W.E., Edelman, G.M. Proc. Natl. Acad. Sci. U.S.A. (1979) [Pubmed]
  13. Amino acid alterations within a highly conserved region of the Rous sarcoma virus src gene product pp60src inactivate tyrosine protein kinase activity. Bryant, D.L., Parsons, J.T. Mol. Cell. Biol. (1984) [Pubmed]
  14. Evidence that the transforming gene of avian sarcoma virus encodes a protein kinase associated with a phosphoprotein. Levinson, A.D., Oppermann, H., Levintow, L., Varmus, H.E., Bishop, J.M. Cell (1978) [Pubmed]
  15. Molecular cloning and characterization of the chicken gene homologous to the transforming gene of Rous sarcoma virus. Shalloway, D., Zelenetz, A.D., Cooper, G.M. Cell (1981) [Pubmed]
  16. Heterogeneity of genetic loci in chickens: analysis of endogenous viral and nonviral genes by cleavage of DNA with restriction endonucleases. Hughes, S.H., Payvar, F., Spector, D., Schimke, R.T., Robinson, H.L., Payne, G.S., Bishop, J.M., Varmus, H.E. Cell (1979) [Pubmed]
  17. Myelin-associated glycoprotein, a cell adhesion molecule of oligodendrocytes, is phosphorylated in brain. Edwards, A.M., Arquint, M., Braun, P.E., Roder, J.C., Dunn, R.J., Pawson, T., Bell, J.C. Mol. Cell. Biol. (1988) [Pubmed]
  18. Transformation by Rous sarcoma virus: a cellular substrate for transformation-specific protein phosphorylation contains phosphotyrosine. Radke, K., Gilmore, T., Martin, G.S. Cell (1980) [Pubmed]
  19. Changes in amino-terminal sequences of pp60src lead to decreased membrane association and decreased in vivo tumorigenicity. Krueger, J.G., Garber, E.A., Goldberg, A.R., Hanafusa, H. Cell (1982) [Pubmed]
  20. Differentiation of PC12 phaeochromocytoma cells induced by v-src oncogene. Alemà, S., Casalbore, P., Agostini, E., Tatò, F. Nature (1985) [Pubmed]
  21. Immunoprecipitation of insulin receptors from cultured human lymphocytes (IM-9 cells) by antibodies to pp60src. Perrotti, N., Taylor, S.I., Richert, N.D., Rapp, U.R., Pastan, I.H., Roth, J. Science (1985) [Pubmed]
  22. Association of p60c-src with polyoma virus middle-T antigen abrogating mitosis-specific activation. Kaech, S., Covic, L., Wyss, A., Ballmer-Hofer, K. Nature (1991) [Pubmed]
  23. Construction of plasmids for expression of Rous sarcoma virus transforming protein, p60src, in Escherichia coli. Gilmer, T.M., Parsons, J.T., Erikson, R.L. Proc. Natl. Acad. Sci. U.S.A. (1982) [Pubmed]
  24. NH2-terminal sequences of two src proteins that cause aberrant transformation. Garber, E.A., Hanafusa, H. Proc. Natl. Acad. Sci. U.S.A. (1987) [Pubmed]
  25. Nonmyristoylated p60v-src fails to phosphorylate proteins of 115-120 kDa in chicken embryo fibroblasts. Linder, M.E., Burr, J.G. Proc. Natl. Acad. Sci. U.S.A. (1988) [Pubmed]
  26. Expression of a mitogen-responsive gene encoding prostaglandin synthase is regulated by mRNA splicing. Xie, W.L., Chipman, J.G., Robertson, D.L., Erikson, R.L., Simmons, D.L. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  27. Immunofluorescence on avian sarcoma virus-transformed cells: localization of the src gene product. Rohrschneider, L.R. Cell (1979) [Pubmed]
  28. Localization of the ASV src gene product to the plasma membrane of transformed cells by electron microscopic immunocytochemistry. Willingham, M.C., Jay, G., Pastan, I. Cell (1979) [Pubmed]
  29. Purification of the Rous sarcoma virus src kinase by casein-agarose and tyrosine-agarose affinity chromatography. Fukami, Y., Lipmann, F. Proc. Natl. Acad. Sci. U.S.A. (1985) [Pubmed]
  30. Comparison between the viral transforming gene (src) of recovered avian sarcoma virus and its cellular homolog. Takeya, T., Hanafusa, H., Junghans, R.P., Ju, G., Skalka, A.M. Mol. Cell. Biol. (1981) [Pubmed]
 
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