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Id3 inhibits B lymphocyte progenitor growth and survival in response to TGF-β

Nature Immunology volume 2, pages 242–247 (2001)Cite this article

Abstract

E proteins function in many developmental processes and are essential for the formation of lymphocyte progenitors. However, it is not known whether E proteins regulate lymphocyte survival, proliferation or differentiation or how their activity is regulated during lymphocyte development. We show here a role for Id3, an inhibitor of E protein activity, in the induction of apoptosis and growth arrest. Id3 is induced in response to transforming growth factor β (TGF-β), a pleiotropic cytokine that inhibits the growth and survival of normal and transformed lymphocyte progenitors. In the absence of Id3, the response of lymphocyte progenitors to TGF-β is perturbed, which indicates that Id3 is a mediator of this response. Our data show a key role for E proteins in lymphocyte survival and link the activity of E proteins, and their antagonists, to members of the TGF-β family of cytokines.

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Figure 1: Induction of apoptosis by retroviral-mediated expression of Id3 in BLPs.
Figure 2: Induction of growth arrest and altered gene expression in BLPs in response to TGF-β1.
Figure 3: Induction of Id3 by TGF-β1.
Figure 4: Induction of Id3 by TGF-β1 requires activation of Smad transcription factors.
Figure 5: Transduction of BLPs with TATId3 causes growth inhibition and altered gene expression similar to treatment with TGF-β1.
Figure 6: Id3 is required for normal growth inhibition by TGF-β1.

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References

  1. Murre, C. et al. Structure and function of helix-loop-helix proteins. Biochim. Biophys. Acta 1218, 129–135 (1994).

    Article  CAS  Google Scholar 

  2. Benezra, R., Davis, R. L., Lockshon, D., Turner, D. L. & Weintraub, H. The protein Id: a negative regulator of helix-loop-helix DNA binding proteins. Cell 61, 49–59 (1990).

    Article  CAS  Google Scholar 

  3. Davis, R. L., Weintraub, H. & Lassar, A. B. Expression of a single transfected cDNA converts fibroblasts to myoblasts. Cell 51, 987–1000 (1987).

    Article  CAS  Google Scholar 

  4. Lee, J. E. et al. Conversion of Xenopus ectoderm into neruons by NeuroD, a basic helix-loop-helix protein. Science 268, 836–844 (1995).

    Article  CAS  Google Scholar 

  5. Bain, G. et al. E2A proteins are required for proper B cell development and initiation of immunoglobulin gene rearrangements. Cell 79, 885–892 (1994).

    Article  CAS  Google Scholar 

  6. Zhuang, Y., Soriano, P. & Weintraub, H. The helix-loop-helix gene E2A is required for B cell formation. Cell 79, 875–884 (1994).

    Article  CAS  Google Scholar 

  7. Sun, X.-H. Constitutive expression of the Id1 gene impairs mouse B cell development. Cell 79, 893–900 (1994).

    Article  CAS  Google Scholar 

  8. Heemskerk, M. H. M. et al. Inhibition of T cell and promotion of natural killer cell development by the dominant negative helix loop helix factor Id3. J. Exp. Med. 186, 1597–1602 (1997).

    Article  CAS  Google Scholar 

  9. Bain, G. et al. E2A deficiency leads to abnormalities in β T-cell development and to rapid development of T-cell lymphomas. Mol. Cell. Biol. 17, 4782–4791 (1997).

    Article  CAS  Google Scholar 

  10. Yan, W. et al. High incidence of T-cell tumors in E2A-null mice and E2A/Id1 double-knockout mice. Mol. Cell. Biol. 17, 7317–7327 (1997).

    Article  CAS  Google Scholar 

  11. Zhuang, Y., Cheng, P. & Weintraub, H. B-Lymphocyte development is regulated by the combined dosage of three basic helix-loop-helix genes, E2A, E2-2, and HEB. Mol. Cell. Biol. 16, 2898–2905 (1996).

    Article  CAS  Google Scholar 

  12. Lee, G., Namen, A. E., Gillis, S., Ellingsworth, L. R. & Kincade, P. W. Normal B cell precursors responsive to recombinant murine IL-7 and inhibition of IL-7 activity by transforming growth factor-β. J. Immunol. 142, 3875–3883 (1989).

    CAS  PubMed  Google Scholar 

  13. Chantry, D., Turner, M. & Feldmann, M. Interleukin 7 (murine pre-B cell growth factor/lymphopoietin 1) stimulates thymocyte growth: regulation by transforming growth factor β. Eur. J. Immunol. 19, 783–786 (1989).

    Article  CAS  Google Scholar 

  14. Shull, M. M. et al. Targeted disruption of the mouse transforming growth factor-β 1 gene results in multifocal inflammatory disease. Nature 359, 693–699 (1992).

    Article  CAS  Google Scholar 

  15. Kulkarni, A. B. et al. Transforming growth factor β 1 null mutation in mice causes excessive inflammatory response and early death. Proc. Natl Acad. Sci. USA 90, 770–774 (1993).

    Article  CAS  Google Scholar 

  16. Yaswen, L. et al. Autoimmune manifestations in the transforming growth factor-β1 knockout mouse. Blood 87, 1439–1445 (1996).

    CAS  PubMed  Google Scholar 

  17. Gorelik, L. & Flavell, R. A. Abrogation of TGFβ signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease. Immunity 12, 171–181 (2000).

    Article  CAS  Google Scholar 

  18. Cazac, B. B. & Roes, J. TGF-β receptor controls B cell responsiveness and induction of IgA in vivo. Immunity 13, 443–451 (2000).

    Article  CAS  Google Scholar 

  19. Saltzman, A. et al. Transforming growth factor-β-mediated apoptosis in the Ramos B-Lymphom cell line is accompanied by caspase activation and Bcl-xL downregulation. Exp. Cell Res. 242, 244–254 (1998).

    Article  CAS  Google Scholar 

  20. Buske, C. et al. TGF-β and its receptor complex in leukemic B-cell precursors. Exp. Hematol. 26, 1155–1161 (1998).

    CAS  PubMed  Google Scholar 

  21. Lotz, M., Ranheim, E. & Kipps, T. J. Transforming growth factor β as endogenous growth inhibitor of chronic lymphocytic leukemia B cells. J. Exp. Med. 179, 999–1004 (1994).

    Article  CAS  Google Scholar 

  22. Douglas, R. S., Capocasle, R. J., Lamb, R. J., Nowell, P. C. & Moore, J. S. Chronic lymphocytic leukemia B cell are resistant to the apoptotic effects of transforming growth factor-β. Blood 89, 941–947 (1997).

    CAS  Google Scholar 

  23. Pear, W. S., Nolan, G. P., Scott, M. L. & Baltimore, D. Production of high-titer helper-free retroviruses by transient transfection. Proc. Natl Acad. Sci. USA 90, 8392–8396 (1993).

    Article  CAS  Google Scholar 

  24. Quong, M. W., Harris, D. P., Swain, S. L. & Murre, C. E2A activity is induced during B-cell activation to promote immunoglobulin class switch recombination. EMBO J. 18, 6307–6318 (1999).

    Article  CAS  Google Scholar 

  25. Vermes, I., Haanen, C., Steffens-Nakken, H. & Reutelingsperger, C. A novel assay for apoptosis. Flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein labeled Annexin V. J. Immunol. Meth. 184, 39–51 (1995).

    Article  CAS  Google Scholar 

  26. Salvesen, G. S. & Dixit, V. M. Caspases:intracellular signaling by proteolysis. Cell 91, 443–446 (1997).

    Article  CAS  Google Scholar 

  27. Whitman, M. Smads and early developmental signaling by the TGFβ superfamily. Genes Dev. 12, 2445–2462 (1998).

    Article  CAS  Google Scholar 

  28. Arsura, M., Wu, M. & Sonenshein, G. E. TGFβ1 inhibits NF-κB/Rel activity inducing apoptosis of B cells: Transcriptional actiation of IκBα. Immunity 5, 31–40 (1996).

    Article  CAS  Google Scholar 

  29. Schlissel, M., Voronova, A. & Baltimore, D. Helix-loop-helix transcription factor E47 activates germ-line immunoglobulin heavy-chain transcription and rearrangement in a pre-T-cell line. Genes Dev. 5, 1367–1376 (1991).

    Article  CAS  Google Scholar 

  30. Kee, B. L. & Murre, C. Induction of early B cell factor (EBF) and multiple B lineage genes by the basic helix-loop-helix transcription factor E12. J. Exp. Med. 188, 699–713 (1998).

    Article  CAS  Google Scholar 

  31. Lasorella, A., Noseda, M., Beyna, M. & Iavarone, A. Id2 is a retinoblastoma protein target and mediates signalling by myc oncoproteins. Nature 407, 592–598 (2000).

    Article  CAS  Google Scholar 

  32. Massague, J. TGF-β signal transduction. Annu. Rev. Biochem. 67, 753–791 (1998).

    Article  CAS  Google Scholar 

  33. Baker, J. C. & Harland, R. M. From receptor to nucleus: the Smad pathway. Curr. Opin. Gen. Dev. 7, 467–473 (1997).

    Article  CAS  Google Scholar 

  34. Nakao, A. et al. Identification of Smad7, a TGF-β-inducible antagonist of TGF-β signalling. Nature 389, 631–635 (1997).

    Article  CAS  Google Scholar 

  35. Hayashi, H. et al. The MAD-related protein Smad7 associates with the TGFβ receptor and functions as an antagonist of TGFβ signaling. Cell 89, 1165–1173 (1997).

    Article  CAS  Google Scholar 

  36. Lo, R. S. & Massague, J. Ubiquitin-dependent degradation of TGF-β-activated Smad2. Nature Cell Biol. 1, 472–478 (1999).

    Article  CAS  Google Scholar 

  37. Bain, G. et al. Regulation of the helix-loop-helix proteins, E2A and Id3, by the Ras-ERK MAPK cascade. Nature Immunol. 2, 165–171 (2001).

    Article  CAS  Google Scholar 

  38. Nagahara, H. et al. Transduction of full-length TAT fusion proteins into mammalian cell: TAT-p27Kip1 induces cell migration. Nature Med. 4, 1449–1452 (1998).

    Article  CAS  Google Scholar 

  39. Rivera, R. R., Johns, C. P., Quan, J., Johnson, R. S. & Murre, C. Thymocyte selection is regulated by the helix-loop-helix inhibitor protein, Id3. Immunity 12, 17–26 (2000).

    Article  CAS  Google Scholar 

  40. Pan, L. Sato, S. Frederick, J P., Sun, X.-H. & Zhuang, Y. Impaired immune responses and B-cell proliferation in mice lacking the Id3 gene. Mol. Cell. Biol. 19, 5969–5980 (1999).

    Article  CAS  Google Scholar 

  41. Miyazaki, M. et al. Transforming growth factor-β1 stimulates or inhibits cell growth via down- or up-regulation of p21/Waf1. Biochem. Biophy. Res. Comm. 246, 873–880 (1998).

    Article  CAS  Google Scholar 

  42. Kamesaki, H., Nishizawa, K., Michaud, G. Y., Cossman, J. & Kiyono, T. TGF-β1 induces the cyclin-dependent kinase inhibitor p27Kip1 mRNA and protein in murine B cells. J. Immunol. 160, 770–777 (1998).

    CAS  PubMed  Google Scholar 

  43. Wu, M., Bellas, R. E., Shen, J., Yang, W. & Sonenshein, G. E. Increased p27Kip1 cyclin-dependent kinase inhibitor gene expression following anti-IgM treatment promotes apoptosis of WEHI 231 B cells. J. Immunol. 163, 6530–6535 (1999).

    CAS  PubMed  Google Scholar 

  44. Hannon, G. J. & Beach, D. p15INK4B is a potential effector of TGF-β-induced cell cycle arrest. Nature 371, 257–261 (1994).

    Article  CAS  Google Scholar 

  45. Warner, B. J., Blain, S. W., Seoane, J. & Massague, J. Myc downregulation by transforming growth factor β required for activation of the p15Ink4b pathway. Mol. Cell. Biol. 19, 5913–5922 (1999).

    Article  CAS  Google Scholar 

  46. Hollnagel, A., Oehlmann, V., Heymer, J., Ulrich, R. & Nordheim, A. Id genes are direct targets of bone morphogenetic protein induction in embryonic stem cells. J. Biol. Chem. 274, 19838–19845 (1999).

    Article  CAS  Google Scholar 

  47. Heath, V. L., Murphy, E. E., Crain, C., Tomlinson, M. G. & O'Garra, A. TGF-β1 down-regulates Th2 development and results in decreased IL-4-induced STAT6 activation and GATA-3 expression. Eur. J. Immunol. 30, 2639–2649 (2000).

    Article  CAS  Google Scholar 

  48. Gorelik, L., Fields, P. E. & Flavell, R. A. TGF-β inhibits Th type 2 development through inhibition of GATA-3 expression. J. Immunol. 165, 4773–4777 (2000).

    Article  CAS  Google Scholar 

  49. Kee, B. L., Quong, M. W. & Murre, C. E2A proteins: Essential regulators at multiple stages of B-cell development. Immunol. Rev. 175, 138–149 (2000).

    Article  CAS  Google Scholar 

  50. Bain, G., Quong, M. W., Soloff, R. S., Hedrick, S. M. & Murre, C. Thymocyte maturation is regulated by the activity of the helix-loop-helix protein, E47. J. Exp. Med. 190, 1605–1616 (1999).

    Article  CAS  Google Scholar 

  51. Engel, I. & Murre, C. Ectopic expression of E47 or E12 promotes the death of E2A-deficient lymphomas. Proc. Natl Acad. Sci. USA 96, 996–1001 (1999).

    Article  CAS  Google Scholar 

  52. Bain, G. et al. Both E12 and E47 allow commitment to the B cell lineage. Immunity 6, 145–154 (1997).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank M. Becker-Hapak for suggestions on purification of TAT-fusion proteins; M. Quong for sharing preliminary data; V. Laurent for technical assistance; L. Penn and M. Montminy for suggestions and comments on the manuscript. Supported by a Special Fellowship from the Leukemia and Lymphoma Society of America (to B. L. K.) and grants from the National Institutes of Health (NIH) and the Edward Mallinckrodt Jr. Foundation (to C. M).

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  1. Department of Biology MC0366, University of California, San Diego, 9500 Gilman Drive, La Jolla, 92093, CA, USA

    Barbara L. Kee, Richard R. Rivera & Cornelis Murre

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Correspondence to Barbara L. Kee.

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Kee, B., Rivera, R. & Murre, C. Id3 inhibits B lymphocyte progenitor growth and survival in response to TGF-β. Nat Immunol 2, 242–247 (2001). https://doi.org/10.1038/85303

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