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Mol Med. 1997 January; 3(1): 72–81.
PMCID: PMC2230102

CD3-epsilon overexpressed in prothymocytes acts as an oncogene.

Abstract

BACKGROUND: Upon engagement of the T cell receptor for antigen, its associated CD3 proteins recruit signal transduction molecules, which in turn regulate T lymphocyte proliferation, apoptosis, and thymocyte development. Because some signal transducing molecules recruited by CD3-epsilon, i.e., p56lck and p59fyn, are oncogenic and since we previously found that overexpression of CD3-epsilon transgenes causes a block in T lymphocyte and NK cell development, we tested the hypothesis that aberrant CD3-epsilon signaling leads both to abnormal T lymphocyte death and lymphomagenesis. MATERIALS AND METHODS: Ten independently derived transgenic mouse lines were generated with four different genomic CD3-epsilon constructs. Mice either homozygous or hemizygous for each transgene were analyzed for an arrest in T lymphocyte development and for the occurrence of T cell lymphomas. RESULTS: Aggressive clonal T cell lymphomas developed at very high frequencies in seven mouse lines with intermediate levels of copies of CD3-epsilon derived transgenes. However, these lymphomas were not found when high copy numbers of CD3-epsilon transgenes caused a complete block in early thymic development or when a transgene was used in which the exons coding for the CD3-epsilon protein were deleted. Analyses of a series of double mutant mice, tgCD3-epsilon x RAG-2null, indicated that lymphomagenesis was initiated in lineage-committed prothymocytes, i.e., before rearrangement of the T cell receptor genes. In addition, the transgene coding for the CD3-epsilon cytoplasmic domain and its transmembrane region induced a T cell differentiation signal in premalignant tgCD3-epsilon x RAG-2null mice. CONCLUSION: The nonenzymatic CD3-epsilon protein acted as a potent oncogene when overexpressed early in T lymphocyte development. Lymphomagenesis was dependent on signal transduction events initiated by the cytoplasmic domain of CD3-epsilon.

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Selected References

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  • Korsmeyer SJ. Programmed cell death: Bcl-2. Important Adv Oncol. 1993:19–28. [PubMed]
  • Vogelstein B, Kinzler KW. The multistep nature of cancer. Trends Genet. 1993 Apr;9(4):138–141. [PubMed]
  • Boettiger D. Interaction of oncogenes with differentiation programs. Curr Top Microbiol Immunol. 1989;147:31–78. [PubMed]
  • Selivanova G, Wiman KG. p53: a cell cycle regulator activated by DNA damage. Adv Cancer Res. 1995;66:143–180. [PubMed]
  • Leonard CJ, Canman CE, Kastan MB. The role of p53 in cell-cycle control and apoptosis: implications for cancer. Important Adv Oncol. 1995:33–42. [PubMed]
  • Wang JY, Knudsen ES, Welch PJ. The retinoblastoma tumor suppressor protein. Adv Cancer Res. 1994;64:25–85. [PubMed]
  • Fisher RJ, Bader JP, Papas TS. Oncogenes and the mitogenic signal pathway. Important Adv Oncol. 1989:3–27. [PubMed]
  • Balmain A, Brown K. Oncogene activation in chemical carcinogenesis. Adv Cancer Res. 1988;51:147–182. [PubMed]
  • Dilworth SM, Brewster CE, Jones MD, Lanfrancone L, Pelicci G, Pelicci PG. Transformation by polyoma virus middle T-antigen involves the binding and tyrosine phosphorylation of Shc. Nature. 1994 Jan 6;367(6458):87–90. [PubMed]
  • Crowe AJ, McGlade J, Pawson T, Hayman MJ. Phosphorylation of the SHC proteins on tyrosine correlates with the transformation of fibroblasts and erythroblasts by the v-sea tyrosine kinase. Oncogene. 1994 Feb;9(2):537–544. [PubMed]
  • Harrison-Findik D, Susa M, Varticovski L. Association of phosphatidylinositol 3-kinase with SHC in chronic myelogeneous leukemia cells. Oncogene. 1995 Apr 6;10(7):1385–1391. [PubMed]
  • Pelicci G, Lanfrancone L, Grignani F, McGlade J, Cavallo F, Forni G, Nicoletti I, Grignani F, Pawson T, Pelicci PG. A novel transforming protein (SHC) with an SH2 domain is implicated in mitogenic signal transduction. Cell. 1992 Jul 10;70(1):93–104. [PubMed]
  • Pelicci G, Lanfrancone L, Salcini AE, Romano A, Mele S, Grazia Borrello M, Segatto O, Di Fiore PP, Pelicci PG. Constitutive phosphorylation of Shc proteins in human tumors. Oncogene. 1995 Sep 7;11(5):899–907. [PubMed]
  • Salcini AE, McGlade J, Pelicci G, Nicoletti I, Pawson T, Pelicci PG. Formation of Shc-Grb2 complexes is necessary to induce neoplastic transformation by overexpression of Shc proteins. Oncogene. 1994 Oct;9(10):2827–2836. [PubMed]
  • Clevers H, Alarcon B, Wileman T, Terhorst C. The T cell receptor/CD3 complex: a dynamic protein ensemble. Annu Rev Immunol. 1988;6:629–662. [PubMed]
  • Ashwell JD, Klusner RD. Genetic and mutational analysis of the T-cell antigen receptor. Annu Rev Immunol. 1990;8:139–167. [PubMed]
  • Letourneur F, Klausner RD. Activation of T cells by a tyrosine kinase activation domain in the cytoplasmic tail of CD3 epsilon. Science. 1992 Jan 3;255(5040):79–82. [PubMed]
  • Wegener AM, Letourneur F, Hoeveler A, Brocker T, Luton F, Malissen B. The T cell receptor/CD3 complex is composed of at least two autonomous transduction modules. Cell. 1992 Jan 10;68(1):83–95. [PubMed]
  • Owen JJ, Owen MJ, Williams GT, Kingston R, Jenkinson EJ. The effects of anti-CD3 antibodies on the development of T-cell receptor alpha beta + lymphocytes in embryonic thymus organ cultures. Immunology. 1988 Apr;63(4):639–642. [PubMed]
  • Bentin J, Vaughan JH, Tsoukas CD. T cell proliferation induced by anti-CD3 antibodies: requirement for a T-T cell interaction. Eur J Immunol. 1988 Apr;18(4):627–632. [PubMed]
  • Levelt CN, Mombaerts P, Wang B, Kohler H, Tonegawa S, Eichmann K, Terhorst C. Regulation of thymocyte development through CD3: functional dissociation between p56lck and CD3 sigma in early thymic selection. Immunity. 1995 Aug;3(2):215–222. [PubMed]
  • Malissen M, Gillet A, Ardouin L, Bouvier G, Trucy J, Ferrier P, Vivier E, Malissen B. Altered T cell development in mice with a targeted mutation of the CD3-epsilon gene. EMBO J. 1995 Oct 2;14(19):4641–4653. [PubMed]
  • Shinkai Y, Ma A, Cheng HL, Alt FW. CD3 epsilon and CD3 zeta cytoplasmic domains can independently generate signals for T cell development and function. Immunity. 1995 Apr;2(4):401–411. [PubMed]
  • Anderson SJ, Levin SD, Perlmutter RM. Involvement of the protein tyrosine kinase p56lck in T cell signaling and thymocyte development. Adv Immunol. 1994;56:151–178. [PubMed]
  • Wang B, Biron C, She J, Higgins K, Sunshine MJ, Lacy E, Lonberg N, Terhorst C. A block in both early T lymphocyte and natural killer cell development in transgenic mice with high-copy numbers of the human CD3E gene. Proc Natl Acad Sci U S A. 1994 Sep 27;91(20):9402–9406. [PubMed]
  • Wang B, Levelt C, Salio M, Zheng D, Sancho J, Liu CP, She J, Huang M, Higgins K, Sunshine MJ, et al. Over-expression of CD3 epsilon transgenes blocks T lymphocyte development. Int Immunol. 1995 Mar;7(3):435–448. [PubMed]
  • Molina TJ, Kishihara K, Siderovski DP, van Ewijk W, Narendran A, Timms E, Wakeham A, Paige CJ, Hartmann KU, Veillette A, et al. Profound block in thymocyte development in mice lacking p56lck. Nature. 1992 May 14;357(6374):161–164. [PubMed]
  • Levelt CN, Mombaerts P, Iglesias A, Tonegawa S, Eichmann K. Restoration of early thymocyte differentiation in T-cell receptor beta-chain-deficient mutant mice by transmembrane signaling through CD3 epsilon. Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):11401–11405. [PubMed]
  • Shinkai Y, Rathbun G, Lam KP, Oltz EM, Stewart V, Mendelsohn M, Charron J, Datta M, Young F, Stall AM, et al. RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell. 1992 Mar 6;68(5):855–867. [PubMed]
  • Godfrey DI, Zlotnik A. Control points in early T-cell development. Immunol Today. 1993 Nov;14(11):547–553. [PubMed]
  • Scollay R, Wilson A, D'Amico A, Kelly K, Egerton M, Pearse M, Wu L, Shortman K. Developmental status and reconstitution potential of subpopulations of murine thymocytes. Immunol Rev. 1988 Aug;104:81–120. [PubMed]
  • Shinkai Y, Alt FW. CD3 epsilon-mediated signals rescue the development of CD4+CD8+ thymocytes in RAG-2-/- mice in the absence of TCR beta chain expression. Int Immunol. 1994 Jul;6(7):995–1001. [PubMed]
  • Levelt CN, Wang B, Ehrfeld A, Terhorst C, Eichmann K. Regulation of T cell receptor (TCR)-beta locus allelic exclusion and initiation of TCR-alpha locus rearrangement in immature thymocytes by signaling through the CD3 complex. Eur J Immunol. 1995 May;25(5):1257–1261. [PubMed]
  • Dedera DA, Waller EK, LeBrun DP, Sen-Majumdar A, Stevens ME, Barsh GS, Cleary ML. Chimeric homeobox gene E2A-PBX1 induces proliferation, apoptosis, and malignant lymphomas in transgenic mice. Cell. 1993 Sep 10;74(5):833–843. [PubMed]
  • Winandy S, Wu P, Georgopoulos K. A dominant mutation in the Ikaros gene leads to rapid development of leukemia and lymphoma. Cell. 1995 Oct 20;83(2):289–299. [PubMed]
  • O'Neill HC, McGrath MS, Allison JP, Weissman IL. A subset of T cell receptors associated with L3T4 molecules mediates C6VL leukemia cell binding of its cognate retrovirus. Cell. 1987 Apr 10;49(1):143–151. [PubMed]
  • McGrath MS, Pillemer E, Weissman IL. Murine leukaemogenesis: monoclonal antibodies to T-cell determinants arrest T-lymphoma cell proliferation. Nature. 1980 May 22;285(5762):259–261. [PubMed]
  • Anderson SJ, Perlmutter RM. A signaling pathway governing early thymocyte maturation. Immunol Today. 1995 Feb;16(2):99–105. [PubMed]
  • Weiss A, Littman DR. Signal transduction by lymphocyte antigen receptors. Cell. 1994 Jan 28;76(2):263–274. [PubMed]

Articles from Molecular Medicine are provided here courtesy of The Feinstein Institute for Medical Research at North Shore LIJ