Skip to main content
NCBI home page
Molecular and Cellular Biology logoLink to Molecular and Cellular Biology
. 1989 Jun;9(6):2493–2499. doi: 10.1128/mcb.9.6.2493

Gene regulation by tyrosine kinases: src protein activates various promoters, including c-fos.

M Fujii 1, D Shalloway 1, I M Verma 1
PMCID: PMC362322  PMID: 2474755

Abstract

A promoter of the nuclear proto-oncogene fos was activated by cotransfection with the viral src gene. Ability to transactivate the c-fos promoter was dependent on tyrosine kinase activity, because (i) src mutants which have reduced tyrosine kinase activity due to mutation of Tyr-416 to Phe showed lower promoter activation, (ii) pp60c-src mutants which have increased tyrosine kinase activity due to mutation of Tyr-527 to Phe also augmented c-fos promoter induction, and (iii) mutation in the ATP-binding site of pp60v-src strongly suppressed c-fos promoter activation. Tyrosine kinase activity alone, however, was not sufficient for promoter activation, because of pp60v-src mutant which lacked its myristylation site and consequently membrane association showed no increased c-fos promoter activation. Both the tyrosine kinase- and membrane-association-defective mutants were also unable to induce transformation. Therefore, phosphorylation of membrane-associated substrates appears to be required for both gene expression and cellular transformation by the src protein. Two regions of the c-fos promoter located between positions -362 and -324 and positions -323 and -294 were responsive to src stimulation. We believe that protein tyrosine phosphorylation represents an important step of signal transduction from the membrane to the nucleus.

Full text

PDF
2493

Images in this article

2495Image
on p.2495
2495Image
on p.2495
2496Image
on p.2496
2496Image
on p.2496

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alemà S., Casalbore P., Agostini E., Tatò F. Differentiation of PC12 phaeochromocytoma cells induced by v-src oncogene. Nature. 1985 Aug 8;316(6028):557–559. doi: 10.1038/316557a0. [DOI] [PubMed] [Google Scholar]
  2. Anderson S. M., Klinken S. P., Hankins W. D. A murine recombinant retrovirus containing the src oncogene transforms erythroid precursor cells in vitro. Mol Cell Biol. 1985 Dec;5(12):3369–3375. doi: 10.1128/mcb.5.12.3369. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bohmann D., Bos T. J., Admon A., Nishimura T., Vogt P. K., Tjian R. Human proto-oncogene c-jun encodes a DNA binding protein with structural and functional properties of transcription factor AP-1. Science. 1987 Dec 4;238(4832):1386–1392. doi: 10.1126/science.2825349. [DOI] [PubMed] [Google Scholar]
  4. Brugge J. S., Cotton P. C., Queral A. E., Barrett J. N., Nonner D., Keane R. W. Neurones express high levels of a structurally modified, activated form of pp60c-src. Nature. 1985 Aug 8;316(6028):554–557. doi: 10.1038/316554a0. [DOI] [PubMed] [Google Scholar]
  5. Böhnlein E., Lowenthal J. W., Siekevitz M., Ballard D. W., Franza B. R., Greene W. C. The same inducible nuclear proteins regulates mitogen activation of both the interleukin-2 receptor-alpha gene and type 1 HIV. Cell. 1988 Jun 3;53(5):827–836. doi: 10.1016/0092-8674(88)90099-2. [DOI] [PubMed] [Google Scholar]
  6. Calothy G., Laugier D., Cross F. R., Jove R., Hanafusa T., Hanafusa H. The membrane-binding domain and myristylation of p60v-src are not essential for stimulation of cell proliferation. J Virol. 1987 May;61(5):1678–1681. doi: 10.1128/jvi.61.5.1678-1681.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Chackalaparampil I., Shalloway D. Altered phosphorylation and activation of pp60c-src during fibroblast mitosis. Cell. 1988 Mar 25;52(6):801–810. doi: 10.1016/0092-8674(88)90422-9. [DOI] [PubMed] [Google Scholar]
  8. Chiu R., Boyle W. J., Meek J., Smeal T., Hunter T., Karin M. The c-Fos protein interacts with c-Jun/AP-1 to stimulate transcription of AP-1 responsive genes. Cell. 1988 Aug 12;54(4):541–552. doi: 10.1016/0092-8674(88)90076-1. [DOI] [PubMed] [Google Scholar]
  9. Courtneidge S. A., Heber A. An 81 kd protein complexed with middle T antigen and pp60c-src: a possible phosphatidylinositol kinase. Cell. 1987 Sep 25;50(7):1031–1037. doi: 10.1016/0092-8674(87)90169-3. [DOI] [PubMed] [Google Scholar]
  10. Deschamps J., Meijlink F., Verma I. M. Identification of a transcriptional enhancer element upstream from the proto-oncogene fos. Science. 1985 Dec 6;230(4730):1174–1177. doi: 10.1126/science.3865371. [DOI] [PubMed] [Google Scholar]
  11. Donner L., Fedele L. A., Garon C. F., Anderson S. J., Sherr C. J. McDonough feline sarcoma virus: characterization of the molecularly cloned provirus and its feline oncogene (v-fms). J Virol. 1982 Feb;41(2):489–500. doi: 10.1128/jvi.41.2.489-500.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Fagan J. B., Sobel M. E., Yamada K. M., de Crombrugghe B., Pastan I. Effects of transformation on fibronectin gene expression using cloned fibronectin cDNA. J Biol Chem. 1981 Jan 10;256(1):520–525. [PubMed] [Google Scholar]
  13. Fujii M., Nakamura M., Ohtani K., Sugamura K., Hinuma Y. 12-O-tetradecanoylphorbol-13-acetate induces the enhancer function of human T-cell leukemia virus type I. FEBS Lett. 1987 Nov 2;223(2):299–303. doi: 10.1016/0014-5793(87)80308-3. [DOI] [PubMed] [Google Scholar]
  14. Fujii M., Sassone-Corsi P., Verma I. M. c-fos promoter trans-activation by the tax1 protein of human T-cell leukemia virus type I. Proc Natl Acad Sci U S A. 1988 Nov;85(22):8526–8530. doi: 10.1073/pnas.85.22.8526. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Gazin C., Dupont de Dinechin S., Hampe A., Masson J. M., Martin P., Stehelin D., Galibert F. Nucleotide sequence of the human c-myc locus: provocative open reading frame within the first exon. EMBO J. 1984 Feb;3(2):383–387. doi: 10.1002/j.1460-2075.1984.tb01816.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Gogusev J., Teutsch B., Morin M. T., Mongiat F., Haguenau F., Suskind G., Rabotti G. F. Inhibition of HLA class I antigen and mRNA expression induced by Rous sarcoma virus in transformed human fibroblasts. Proc Natl Acad Sci U S A. 1988 Jan;85(1):203–207. doi: 10.1073/pnas.85.1.203. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Gorman C. M., Moffat L. F., Howard B. H. Recombinant genomes which express chloramphenicol acetyltransferase in mammalian cells. Mol Cell Biol. 1982 Sep;2(9):1044–1051. doi: 10.1128/mcb.2.9.1044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. 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]
  19. Groudine M., Weintraub H. Activation of cellular genes by avian RNA tumor viruses. Proc Natl Acad Sci U S A. 1980 Sep;77(9):5351–5354. doi: 10.1073/pnas.77.9.5351. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Hamaguchi M., Hanafusa H. Association of p60src with Triton X-100-resistant cellular structure correlates with morphological transformation. Proc Natl Acad Sci U S A. 1987 Apr;84(8):2312–2316. doi: 10.1073/pnas.84.8.2312. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Hayes T. E., Kitchen A. M., Cochran B. H. Inducible binding of a factor to the c-fos regulatory region. Proc Natl Acad Sci U S A. 1987 Mar;84(5):1272–1276. doi: 10.1073/pnas.84.5.1272. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Hendricks M., Weintraub H. Multiple tropomyosin polypeptides in chicken embryo fibroblasts: differential repression of transcription by Rous sarcoma virus transformation. Mol Cell Biol. 1984 Sep;4(9):1823–1833. doi: 10.1128/mcb.4.9.1823. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Hunter T., Cooper J. A. Protein-tyrosine kinases. Annu Rev Biochem. 1985;54:897–930. doi: 10.1146/annurev.bi.54.070185.004341. [DOI] [PubMed] [Google Scholar]
  24. Ishii S., Merlino G. T., Pastan I. Promoter region of the human Harvey ras proto-oncogene: similarity to the EGF receptor proto-oncogene promoter. Science. 1985 Dec 20;230(4732):1378–1381. doi: 10.1126/science.2999983. [DOI] [PubMed] [Google Scholar]
  25. Kamps M. P., Buss J. E., Sefton B. M. Rous sarcoma virus transforming protein lacking myristic acid phosphorylates known polypeptide substrates without inducing transformation. Cell. 1986 Apr 11;45(1):105–112. doi: 10.1016/0092-8674(86)90542-8. [DOI] [PubMed] [Google Scholar]
  26. Kamps M. P., Sefton B. M. Neither arginine nor histidine can carry out the function of lysine-295 in the ATP-binding site of p60src. Mol Cell Biol. 1986 Mar;6(3):751–757. doi: 10.1128/mcb.6.3.751. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Kaplan D. R., Whitman M., Schaffhausen B., Pallas D. C., White M., Cantley L., Roberts T. M. Common elements in growth factor stimulation and oncogenic transformation: 85 kd phosphoprotein and phosphatidylinositol kinase activity. Cell. 1987 Sep 25;50(7):1021–1029. doi: 10.1016/0092-8674(87)90168-1. [DOI] [PubMed] [Google Scholar]
  28. Katz R. A., Omer C. A., Weis J. H., Mitsialis S. A., Faras A. J., Guntaka R. V. Restriction endonuclease and nucleotide sequence analyses of molecularly cloned unintegrated avian tumor virus DNA: structure of large terminal repeats in circle junctions. J Virol. 1982 Apr;42(1):346–351. doi: 10.1128/jvi.42.1.346-351.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. 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]
  30. Kmiecik T. E., Shalloway D. Activation and suppression of pp60c-src transforming ability by mutation of its primary sites of tyrosine phosphorylation. Cell. 1987 Apr 10;49(1):65–73. doi: 10.1016/0092-8674(87)90756-2. [DOI] [PubMed] [Google Scholar]
  31. Lamph W. W., Wamsley P., Sassone-Corsi P., Verma I. M. Induction of proto-oncogene JUN/AP-1 by serum and TPA. Nature. 1988 Aug 18;334(6183):629–631. doi: 10.1038/334629a0. [DOI] [PubMed] [Google Scholar]
  32. Linder M. E., Burr J. G. Nonmyristoylated p60v-src fails to phosphorylate proteins of 115-120 kDa in chicken embryo fibroblasts. Proc Natl Acad Sci U S A. 1988 Apr;85(8):2608–2612. doi: 10.1073/pnas.85.8.2608. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Macara I. G., Marinetti G. V., Balduzzi P. C. Transforming protein of avian sarcoma virus UR2 is associated with phosphatidylinositol kinase activity: possible role in tumorigenesis. Proc Natl Acad Sci U S A. 1984 May;81(9):2728–2732. doi: 10.1073/pnas.81.9.2728. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Matrisian L. M., Glaichenhaus N., Gesnel M. C., Breathnach R. Epidermal growth factor and oncogenes induce transcription of the same cellular mRNA in rat fibroblasts. EMBO J. 1985 Jun;4(6):1435–1440. doi: 10.1002/j.1460-2075.1985.tb03799.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Matrisian L. M., Leroy P., Ruhlmann C., Gesnel M. C., Breathnach R. Isolation of the oncogene and epidermal growth factor-induced transin gene: complex control in rat fibroblasts. Mol Cell Biol. 1986 May;6(5):1679–1686. doi: 10.1128/mcb.6.5.1679. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Mitchell R. L., Henning-Chubb C., Huberman E., Verma I. M. c-fos expression is neither sufficient nor obligatory for differentiation of monomyelocytes to macrophages. Cell. 1986 May 23;45(4):497–504. doi: 10.1016/0092-8674(86)90281-3. [DOI] [PubMed] [Google Scholar]
  37. Nabel G., Baltimore D. An inducible transcription factor activates expression of human immunodeficiency virus in T cells. Nature. 1987 Apr 16;326(6114):711–713. doi: 10.1038/326711a0. [DOI] [PubMed] [Google Scholar]
  38. Nishizuka Y. The role of protein kinase C in cell surface signal transduction and tumour promotion. Nature. 1984 Apr 19;308(5961):693–698. doi: 10.1038/308693a0. [DOI] [PubMed] [Google Scholar]
  39. Ohtani K., Nakamura M., Saito S., Noda T., Ito Y., Sugamura K., Hinuma Y. Identification of two distinct elements in the long terminal repeat of HTLV-I responsible for maximum gene expression. EMBO J. 1987 Feb;6(2):389–395. doi: 10.1002/j.1460-2075.1987.tb04767.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Peterlin B. M., Luciw P. A., Barr P. J., Walker M. D. Elevated levels of mRNA can account for the trans-activation of human immunodeficiency virus. Proc Natl Acad Sci U S A. 1986 Dec;83(24):9734–9738. doi: 10.1073/pnas.83.24.9734. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Piette J., Yaniv M. Two different factors bind to the alpha-domain of the polyoma virus enhancer, one of which also interacts with the SV40 and c-fos enhancers. EMBO J. 1987 May;6(5):1331–1337. doi: 10.1002/j.1460-2075.1987.tb02372.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Quantin B., Breathnach R. Epidermal growth factor stimulates transcription of the c-jun proto-oncogene in rat fibroblasts. Nature. 1988 Aug 11;334(6182):538–539. doi: 10.1038/334538a0. [DOI] [PubMed] [Google Scholar]
  43. Ralston R., Bishop J. M. The product of the protooncogene c-src is modified during the cellular response to platelet-derived growth factor. Proc Natl Acad Sci U S A. 1985 Dec;82(23):7845–7849. doi: 10.1073/pnas.82.23.7845. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Ryseck R. P., Hirai S. I., Yaniv M., Bravo R. Transcriptional activation of c-jun during the G0/G1 transition in mouse fibroblasts. Nature. 1988 Aug 11;334(6182):535–537. doi: 10.1038/334535a0. [DOI] [PubMed] [Google Scholar]
  45. Sassone-Corsi P., Lamph W. W., Kamps M., Verma I. M. fos-associated cellular p39 is related to nuclear transcription factor AP-1. Cell. 1988 Aug 12;54(4):553–560. doi: 10.1016/0092-8674(88)90077-3. [DOI] [PubMed] [Google Scholar]
  46. Sassone-Corsi P., Ransone L. J., Lamph W. W., Verma I. M. Direct interaction between fos and jun nuclear oncoproteins: role of the 'leucine zipper' domain. Nature. 1988 Dec 15;336(6200):692–695. doi: 10.1038/336692a0. [DOI] [PubMed] [Google Scholar]
  47. Sassone-Corsi P., Sisson J. C., Verma I. M. Transcriptional autoregulation of the proto-oncogene fos. Nature. 1988 Jul 28;334(6180):314–319. doi: 10.1038/334314a0. [DOI] [PubMed] [Google Scholar]
  48. Sassone-Corsi P., Wildeman A., Chambon P. A trans-acting factor is responsible for the simian virus 40 enhancer activity in vitro. Nature. 1985 Feb 7;313(6002):458–463. doi: 10.1038/313458a0. [DOI] [PubMed] [Google Scholar]
  49. Sawyer S. T., Cohen S. Enhancement of calcium uptake and phosphatidylinositol turnover by epidermal growth factor in A-431 cells. Biochemistry. 1981 Oct 13;20(21):6280–6286. doi: 10.1021/bi00524a057. [DOI] [PubMed] [Google Scholar]
  50. Sugano S., Stoeckle M. Y., Hanafusa H. Transformation by Rous sarcoma virus induces a novel gene with homology to a mitogenic platelet protein. Cell. 1987 May 8;49(3):321–328. doi: 10.1016/0092-8674(87)90284-4. [DOI] [PubMed] [Google Scholar]
  51. Sugimoto Y., Whitman M., Cantley L. C., Erikson R. L. Evidence that the Rous sarcoma virus transforming gene product phosphorylates phosphatidylinositol and diacylglycerol. Proc Natl Acad Sci U S A. 1984 Apr;81(7):2117–2121. doi: 10.1073/pnas.81.7.2117. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Unkeless J., Dano K., Kellerman G. M., Reich E. Fibrinolysis associated with oncogenic transformation. Partial purification and characterization of the cell factor, a plasminogen activator. J Biol Chem. 1974 Jul 10;249(13):4295–4305. [PubMed] [Google Scholar]
  53. Verma I. M., Sassone-Corsi P. Proto-oncogene fos: complex but versatile regulation. Cell. 1987 Nov 20;51(4):513–514. doi: 10.1016/0092-8674(87)90115-2. [DOI] [PubMed] [Google Scholar]
  54. Weinberg R. A. The action of oncogenes in the cytoplasm and nucleus. Science. 1985 Nov 15;230(4727):770–776. doi: 10.1126/science.2997917. [DOI] [PubMed] [Google Scholar]
  55. Whitman M., Kaplan D. R., Schaffhausen B., Cantley L., Roberts T. M. Association of phosphatidylinositol kinase activity with polyoma middle-T competent for transformation. Nature. 1985 May 16;315(6016):239–242. doi: 10.1038/315239a0. [DOI] [PubMed] [Google Scholar]
  56. Zinn K., DiMaio D., Maniatis T. Identification of two distinct regulatory regions adjacent to the human beta-interferon gene. Cell. 1983 Oct;34(3):865–879. doi: 10.1016/0092-8674(83)90544-5. [DOI] [PubMed] [Google Scholar]

Articles from Molecular and Cellular Biology are provided here courtesy of Taylor & Francis

RESOURCES