Changes that take place during cell differentiation often involve the activation and repression of specific genes. The common origin of B and T lymphocytes suggests the possibility of overlap in the transcriptional regulation of their genes, particularly those expressed soon after divergence of the two lineages. This idea is supported by the observation that the immunoglobulin mu heavy chain gene is active in some T cells whereas the later activated kappa light chain gene is not. Thus, comparison of the transcriptional regulation of early B and T cell genes (and the factors that control them) may to provide insights into the signals initiating lymphocyte. The T cell receptor (TCR) beta chain gene and the interleukin-2 receptor alpha chain gene (IL-2Ralpha) are both expressed early in the course of T cell ontogeny. Experiments outlined in this proposal seek to identify the cis-acting sequence elements (by transfection assays and analysis of transgenic mice) and the corresponding trans-acting factors that specify the developmentally correct activation of the TCR genes. This will allow future studies on the regulation of the factors themselves, presumably in response to environmental cues. IL-2Ralpha is further inducible upon T cell activation and recent reports suggest that this might be true of the TRC genes as well. IL-2Ralpha gene induction is dependent upon a sequence motif that binds the inducible factor NF-KB. Curiously, a similar motif is located in the TCR locus as well, suggesting that both genes may be regulated by the same factor. Transfections into B and T cell lines is expected to not only clarify the functional role of this site but to also reveal other regulatory circuits that prevent constitutive expression of these genes in B cells where NR-KB is constituitively present.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM043874-01
Application #
3302972
Study Section
Allergy and Immunology Study Section (ALY)
Project Start
1990-04-01
Project End
1995-03-31
Budget Start
1990-04-01
Budget End
1991-03-31
Support Year
1
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Brandeis University
Department
Type
Schools of Arts and Sciences
DUNS #
616845814
City
Waltham
State
MA
Country
United States
Zip Code
02454
Carvajal, I M; Sen, R (2000) Functional analysis of the murine TCR beta-chain gene enhancer. J Immunol 164:6332-9
Wang, W; Wykrzykowska, J; Johnson, T et al. (1999) A NF-kappa B/c-myc-dependent survival pathway is targeted by corticosteroids in immature thymocytes. J Immunol 162:314-22
Sen, J; Kapeller, R; Fragoso, R et al. (1996) Intrathymic signals in thymocytes are mediated by p38 mitogen-activated protein kinase. J Immunol 156:4535-8
Sen, J; Venkataraman, L; Shinkai, Y et al. (1995) Expression and induction of nuclear factor-kappa B-related proteins in thymocytes. J Immunol 154:3213-21
Sen, J; Shinkai, Y; Alt, F W et al. (1994) Nuclear factors that mediate intrathymic signals are developmentally regulated. J Exp Med 180:2321-7
Landry, D B; Engel, J D; Sen, R (1993) Functional GATA-3 binding sites within murine CD8 alpha upstream regulatory sequences. J Exp Med 178:941-9
Pierce, J W; Gifford, A M; Baltimore, D (1991) Silencing of the expression of the immunoglobulin kappa gene in non-B cells. Mol Cell Biol 11:1431-7