Timothy P. Bender, PhD
Graduate School: University of Michigan
Primary Appointment: Professor, Microbiology, Immunology, and Cancer Biology
Regulation of gene expression during lymphocyte development
Email Address: email@example.com
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 do 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 a 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
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 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.
Perry HM, Bender TP, McNamara CA. B cell subsets in atherosclerosis. Front Immunol. 2012;3:373. doi: 10.3389/fimmu.2012.00373. Epub 2012 Dec 11.
Fulford MV, Lough AJ, Bender TP. The first report of the crystal structure of non-solvated μ-oxo boron subphthalocyanine and the crystal structures of two solvated forms. Acta Crystallogr B. 2012 Dec;68(Pt 6):636-45. doi: 10.1107/S0108768112037184. Epub 2012 Nov 16.
Paton AS, Lough AJ, Bender TP. Sulfonate pseudohalides of boron subphthalocyanine. Acta Crystallogr C. 2012 Nov;68(Pt 11):o459-64. doi: 10.1107/S0108270112040425. Epub 2012 Oct 19.
Sepehrifard A, Kamino BA, Bender TP, Morin S. Siliconized triarylamines as redox mediator in dye-sensitized solar cells. ACS Appl Mater Interfaces. 2012 Nov 28;4(11):6211-5. doi: 10.1021/am301812d. Epub 2012 Nov 7.
Tewalt EF, Cohen JN, Rouhani SJ, Guidi CJ, Qiao H, Fahl SP, Conaway MR, Bender TP, Tung KS, Vella AT, Adler AJ, Chen L, Engelhard VH. 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 Dec 6;120(24):4772-82. doi: 10.1182/blood-2012-04-427013. Epub 2012 Sep 19.
Morse GE, Bender TP. Boron subphthalocyanines as organic electronic materials. ACS Appl Mater Interfaces. 2012 Oct 24;4(10):5055-68. doi: 10.1021/am3015197. Epub 2012 Sep 27.
Morse GE, Bender TP. Aluminum chloride activation of chloro-boronsubphthalocyanine: a rapid and flexible method for axial functionalization with an expanded set of nucleophiles. Inorg Chem. 2012 Jun 18;51(12):6460-7. doi: 10.1021/ic2016935. Epub 2012 May 29.
Paton AS, Morse GE, Castelino D, Bender TP. Pseudohalides of boron subphthalocyanine. J Org Chem. 2012 Mar 2;77(5):2531-6. doi: 10.1021/jo202365x. Epub 2012 Feb 16.
Kamino BA, Mills B, Reali C, Gretton MJ, Brook MA, Bender TP. Liquid triarylamines: the scope and limitations of Piers-Rubinsztajn conditions for obtaining triarylamine-siloxane hybrid materials. J Org Chem. 2012 Feb 17;77(4):1663-74. doi: 10.1021/jo2020906. Epub 2012 Jan 31.
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