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B Regulates BCL3 Transcription in T Lymphocytes Through an Intronic Enhancer 1
* Department of Internal Medicine, Section of Hematology/Oncology, and
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68132
Exposure to soluble protein Ags in vivo leads to abortive proliferation of responding T cells. In the absence of a danger signal, artificially provided by adjuvants, most responding cells die, and the remainder typically become anergic. The adjuvant-derived signals provided to T cells are poorly understood, but recent work has identified BCL3 as the gene, of those tested, with the greatest differential transcriptional response to adjuvant administration in vivo. As an initial step in analyzing transcriptional responses of BCL3 in T cells, we have identified candidate regulatory regions within the locus through their evolutionary conservation and by analysis of DNase hypersensitivity. An evolutionarily conserved DNase hypersensitive site (HS3) within intron 2 was found to act as a transcriptional enhancer in response to stimuli that mimic TCR activation, namely, PHA and PMA. In luciferase reporter gene constructs transiently transfected into the Jurkat T cell line, the HS3 enhancer can cooperate not only with the BCL3 promoter, but also with an exogenous promoter from herpes simplex thymidine kinase. Deletional analysis revealed that a minimal sequence of 
81 bp is required for full enhancer activity. At the 5' end of this minimal sequence is a 
B site, as confirmed by EMSAs. Mutation of this site in the context of the full-length HS3 abolished enhancer activity. Cotransfection with NF-B p65 expression constructs dramatically increased luciferase activity, even without stimulation. Conversely, cotransfection with the NF-B inhibitor IB
reduced activation. Together, these results demonstrate a critical role for NF-B in BCL3 transcriptional up-regulation by TCR-mimetic signals.
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