Timothy P. Bender

Education

  • BA, Albion College, Albion, MI
  • MS, The University of Michigan, Ann Arbor, MI
  • PhD, The University of Michigan, Ann Arbor, MI

Primary Appointment

  • Professor, Microbiology, Immunology, and Cancer Biology

Contact

Research Interest(s)

Regulation of gene expression during lymphocyte development

Research Description

The process of lymphocyte development is regulated by the complex interplay of signaling pathways and changing sets of transcription factors that are present in maturing lymphocytes. We are currently interested in the role played by the Myb family of transcription factors, particularly c-myb, in regulating T and B-lymphocyte development. Proper expression of the c-myb locus is crucial for normal adult hematopoiesis and traditional null mutations are embryonic lethal. c-myb null embryos die between day 14 and 15 of embryogenesis due to severe anemia. In addition to the crucial role played by c-myb during hematopoiesis c-myb also appears to play a significant role in the transformation of hematopoietic cells and has recently been implicated in tumors of the breast and gut epithelium as well as tumors of the nervous system. The c-myb locus encodes a highly conserved transcription factor that is highly expressed in immature hematopoietic cells and expression is turned off during the maturation of each hematopoietic lineage. During lymphocyte development, c-myb is highly expressed during the immature stages of lymphocyte development but is down regulated at or near the point of repertoire selection. Interestingly, c-myb activity increases in mature B and T lymphocytes following activation in response to antigen. Due to the embryonic lethality of the c-myb null mutation we have developed conditional mutants at the c-myb locus using the cre/loxP technology. With these mice, we are able induce deletion at the c-myb locus at specific times during lymphocyte development that allow us to study c-myb function both during antigen independent development and during differentiation of mature effector function in response to antigen. We are currently focused on determining the key points during lymphocyte development that are dependent on c-myb activity as well as the role of c-myb in regulating the population dynamics of mature B and T cell populations. In addition, these mice provide models to examine the regulation of c-myb activity by physiologically relevant signaling pathways, to determine the structural features on c-myb that are important at different times during lymphocyte development and to identify downstream effectors of c-myb function. Given the importance of appropriately regulated c-myb expression, our laboratory has been interested in determining the mechanisms that regulate c-myb expression and activity. We have demonstrated the primary mechanism that regulates expression of c-myb mRNA is a conditional block to transcription elongation (attenuation) that occurs in the first intron of the c-myb locus. We are particularly interested in characterizing signaling pathways that impact on the efficiency of this block to transcription elongation during lymphocyte development and induction of effector function. As potential targets of c-myb activity have been identified it has become apparent that c-myb is involved in the regulation of lineage and stage specific genes as well as genes that are expressed in most cell types. Thus, identifying mechanisms that regulate c-myb activity poses an interesting problem. We have identified and characterized a major site of phosphorylation on c-myb. Significantly, this site is located in a region of the c-myb protein that is deleted in transforming forms of c-myb and serves to differentially regulate c-myb on some target promoters but not others. We will examine the potential role of this phosphorylation site in activating c-myb transforming potential as well as in regulating c-myb activity during hematopoiesis. Phosphorylation does not modulate the ability of c-myb to bind DNA and we postulate that it likely regulates interaction between c-myb and other proteins that serve to modulate c-myb activity. We have identified several candidate interaction partners and are in the process of characterizing them.

Selected Publications

  • Perry H, Oldham S, Fahl S, Que X, Gonen A, Harmon D, Tsimikas S, Witztum J, Bender T, McNamara C. Helix-loop-helix factor inhibitor of differentiation 3 regulates interleukin-5 expression and B-1a B cell proliferation. Arteriosclerosis, thrombosis, and vascular biology. 2013;33(12): 2771-9. PMID: 24115031 | PMCID: PMC4003558
  • Perry H, Bender T, McNamara C. B cell subsets in atherosclerosis. Frontiers in immunology. 2012;3 373. PMID: 23248624 | PMCID: PMC3518786
  • Tewalt E, Cohen J, Rouhani S, Guidi C, Qiao H, Fahl S, Conaway M, Bender T, Tung K, Vella A, Adler A, Chen L, Engelhard V. Lymphatic endothelial cells induce tolerance via PD-L1 and lack of costimulation leading to high-level PD-1 expression on CD8 T cells. Blood. 2012. PMID: 22993390 | PMCID: PMC3520619
  • Doran A, Lipinski M, Oldham S, Garmey J, Campbell K, Skaflen M, Cutchins A, Lee D, Glover D, Kelly K, Galkina E, Ley K, Witztum J, Tsimikas S, Bender T, McNamara C. B-cell aortic homing and atheroprotection depend on Id3. Circulation research. 2011;110(1): e1-12. PMID: 22034493 | PMCID: PMC3253259
  • Gimferrer I, Hu T, Simmons A, Wang C, Souabni A, Busslinger M, Bender T, Hernandez-Hoyos G, Alberola-Ila J. Regulation of GATA-3 expression during CD4 lineage differentiation. Journal of immunology (Baltimore, Md. : 1950). 2011;186(7): 3892-8. PMID: 21357543 | PMCID: PMC3074202
  • Waldron T, De Dominici M, Soliera A, Audia A, Iacobucci I, Lonetti A, Martinelli G, Zhang Y, Martinez R, Hyslop T, Bender T, Calabretta B. c-Myb and its target Bmi1 are required for p190BCR/ABL leukemogenesis in mouse and human cells. Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2011;26(4): 644-53. PMID: 21960247 | PMCID: PMC3252490
  • A new window on c-Myb function. Blood. 2010;116(8): 1190-1. PMID: 20798239
  • Hu T, Simmons A, Yuan J, Bender T, Alberola-Ila J. The transcription factor c-Myb primes CD4+CD8+ immature thymocytes for selection into the iNKT lineage. Nature immunology. 2010;11(5): 435-41. PMID: 20383148 | PMCID: PMC2857587
  • Yuan J, Crittenden R, Bender T. c-Myb promotes the survival of CD4+CD8+ double-positive thymocytes through upregulation of Bcl-xL. Journal of immunology (Baltimore, Md. : 1950). 2010;184(6): 2793-804. PMID: 20142358 | PMCID: PMC2856624
  • Fahl S, Crittenden R, Allman D, Bender T. c-Myb is required for pro-B cell differentiation. Journal of immunology (Baltimore, Md. : 1950). 2009;183(9): 5582-92. PMID: 19843942 | PMCID: PMC2785544
  • Giles A, Bender T, Ravichandran K. The adaptor protein Shc plays a key role during early B cell development. Journal of immunology (Baltimore, Md. : 1950). 2009;183(9): 5468-76. PMID: 19828641 | PMCID: PMC2847786
  • Smith E, von Vietinghoff S, Stark M, Zarbock A, Sanders J, Duley A, Rivera-Nieves J, Bender T, Ley K. T-lineage cells require the thymus but not VDJ recombination to produce IL-17A and regulate granulopoiesis in vivo. Journal of immunology (Baltimore, Md. : 1950). 2009;183(9): 5685-93. PMID: 19843951 | PMCID: PMC2893017
  • Trampont P, Tosello-Trampont A, Shen Y, Duley A, Sutherland A, Bender T, Littman D, Ravichandran K. CXCR4 acts as a costimulator during thymic beta-selection. Nature immunology. 2009;11(2): 162-70. PMID: 20010845 | PMCID: PMC2808461
  • Lidonnici M, Corradini F, Waldron T, Bender T, Calabretta B. Requirement of c-Myb for p210(BCR/ABL)-dependent transformation of hematopoietic progenitors and leukemogenesis. Blood. 2008;111(9): 4771-9. PMID: 18227349 | PMCID: PMC2343605
  • Xiao C, Calado D, Galler G, Thai T, Patterson H, Wang J, Rajewsky N, Bender T, Rajewsky K. MiR-150 controls B cell differentiation by targeting the transcription factor c-Myb. Cell. 2007;131(1): 146-59. PMID: 17923094
  • Chen J, Kremer C, Bender T. The carbonic anhydrase I locus contains a c-Myb target promoter and modulates differentiation of murine erythroleukemia cells. Oncogene. 2006;25(19): 2758-72. PMID: 16407849
  • Thomas M, Kremer C, Ravichandran K, Rajewsky K, Bender T. c-Myb is critical for B cell development and maintenance of follicular B cells. Immunity. 2005;23(3): 275-86. PMID: 16169500
  • Bender T, Kremer C, Kraus M, Buch T, Rajewsky K. Critical functions for c-Myb at three checkpoints during thymocyte development. Nature immunology. 2004;5(7): 721-9. PMID: 15195090
  • Chen J, Kremer C, Bender T. A Myb dependent pathway maintains Friend murine erythroleukemia cells in an immature and proliferating state. Oncogene. 2002;21(12): 1859-69. PMID: 11896618
  • Zhang L, Camerini V, Bender T, Ravichandran K. A nonredundant role for the adapter protein Shc in thymic T cell development. Nature immunology. 2002;3(8): 749-55. PMID: 12101399
  • Chen J, Bender T. A novel system to identify Myb target promoters in friend murine erythroleukemia cells. Blood cells, molecules & diseases. 2001;27(2): 429-36. PMID: 11500057
  • Allen R, Bender T, Siu G. c-Myb is essential for early T cell development. Genes & development. 1999;13(9): 1073-8. PMID: 10323859 | PMCID: PMC316940
  • Jeng M, Shupnik M, Bender T, Westin E, Bandyopadhyay D, Kumar R, Masamura S, Santen R. Estrogen receptor expression and function in long-term estrogen-deprived human breast cancer cells. Endocrinology. 1998;139(10): 4164-74. PMID: 9751496
  • Miglarese M, Richardson A, Aziz N, Bender T. Differential regulation of c-Myb-induced transcription activation by a phosphorylation site in the negative regulatory domain. The Journal of biological chemistry. 1996;271(37): 22697-705. PMID: 8798443
  • Aziz N, Miglarese M, Hendrickson R, Shabanowitz J, Sturgill T, Hunt D, Bender T. Modulation of c-Myb-induced transcription activation by a phosphorylation site near the negative regulatory domain. Proceedings of the National Academy of Sciences of the United States of America. 1995;92(14): 6429-33. PMID: 7604007 | PMCID: PMC41531
  • Miglarese M, Mannion-Henderson J, Wu H, Parsons J, Bender T. The protein tyrosine kinase substrate cortactin is differentially expressed in murine B lymphoid tumors. Oncogene. 1994;9(7): 1989-97. PMID: 7516062
  • Cuddihy A, Brents L, Aziz N, Bender T, Kuehl W. Only the DNA binding and transactivation domains of c-Myb are required to block terminal differentiation of murine erythroleukemia cells. Molecular and cellular biology. 1993;13(6): 3505-13. PMID: 8497265 | PMCID: PMC359820
  • Isakson P, Purkerson J, Catron K, Bender T. A novel method for synchronizing a B cell lymphoma. Journal of immunological methods. 1991;145(1): 137-42. PMID: 1765644
  • McClinton D, Stafford J, Brents L, Bender T, Kuehl W. Differentiation of mouse erythroleukemia cells is blocked by late up-regulation of a c-myb transgene. Molecular and cellular biology. 1990;10(2): 705-10. PMID: 2405253 | PMCID: PMC360869
  • Bender T, Catron K, Kuehl W, Thompson C. Sense and anti-sense transcription in the murine c-myb attenuator region. Current topics in microbiology and immunology. 1988;141 324-9. PMID: 2463898
  • Bender T, Thompson C, Kuehl W. Differential expression of c-myb mRNA in murine B lymphomas by a block to transcription elongation. Science (New York, N.Y.). 1987;237(4821): 1473-6. PMID: 3498214
  • Bender T, Kuehl W. Murine myb protooncogene mRNA: cDNA sequence and evidence for 5' heterogeneity. Proceedings of the National Academy of Sciences of the United States of America. 1986;83(10): 3204-8. PMID: 3010282 | PMCID: PMC323481
  • Dmitrovsky E, Kuehl W, Hollis G, Kirsch I, Bender T, Segal S. Expression of a transfected human c-myc oncogene inhibits differentiation of a mouse erythroleukaemia cell line. Nature. 1986;322(6081): 748-50. PMID: 3528861
  • Bender T, Schroer J. Site specific monoclonal antibodies to insulin. Methods in enzymology. 1985;109 704-21. PMID: 2581114
  • Sher M, Bender T, Niederhuber J. Two Ia.17-specific monoclonal antibodies detect the same epitope but do not share idiotype. Journal of immunology (Baltimore, Md. : 1950). 1984;133(1): 338-44. PMID: 6202786
  • Bender T, Schroer J, Claflin J. Idiotypes on monoclonal antibodies to bovine insulin. I. Two public idiotypes on anti-bovine insulin hybridomas define idiotypically distinct families of hybridomas. Journal of immunology (Baltimore, Md. : 1950). 1983;131(6): 2882-9. PMID: 6358355