The long term goal of this work is to understand the entire regulatory program of IgH gene expression in B cells including early processes which activate transcription and target rearrangement, how growth and maturation signals are transduced to affect gene expression, the mechanism and factors which initiate transcription at different developmental stages, the nature of post-transcriptional regulatory mechanisms and how various regulatory networks interact. This knowledge will reveal general principles of tissue-specific and developmentally regulated gene expression, suggest molecular defects which may cause autoimmune and immune deficiency disease and identify unique regulatory features associated with gene rearrangement that may provide insight into other complex systems which generate information by combinatorial mechanisms. Based on our past work, there is a good understanding of the DNA sequences and cellular proteins which are important in IgH gene transcription. The current proposal is to clone cDNAs for transcription factors which bind to IgH promoter and enhancer sequences. Expression of cDNAs will provide chemical amounts of purified transcription factors for ; 1) structural and functional analyses of factor domains, ii) production of antibodies to the factors for use in assessing the levels and subcellular localization of the factors. iii) isolation of non-DNA binding proteins which interact with DNA-binding factors and iv) studies on regulation of transcription factors during B-cell development. IgH mRNA stability during B-cell development will also be studied. If, as preliminary data suggest, differential mRNa stability is observed, the RNA sequences and cellular proteins which determined this stability will be identified and characterized.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM029361-11
Application #
3276944
Study Section
Mammalian Genetics Study Section (MGN)
Project Start
1988-12-01
Project End
1993-11-30
Budget Start
1989-12-01
Budget End
1990-11-30
Support Year
11
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Type
Schools of Medicine
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10027
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Lin, Kuo-I; Angelin-Duclos, Cristina; Kuo, Tracy C et al. (2002) Blimp-1-dependent repression of Pax-5 is required for differentiation of B cells to immunoglobulin M-secreting plasma cells. Mol Cell Biol 22:4771-80
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Angelin-Duclos, Cristina; Johnson, Kristen; Liao, Jerry et al. (2002) An interfering form of Blimp-1 increases IgM secreting plasma cells and blocks maturation of peripheral B cells. Eur J Immunol 32:3765-75
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Piskurich, J F; Lin, K I; Lin, Y et al. (2000) BLIMP-I mediates extinction of major histocompatibility class II transactivator expression in plasma cells. Nat Immunol 1:526-32
Lin, K I; Lin, Y; Calame, K (2000) Repression of c-myc is necessary but not sufficient for terminal differentiation of B lymphocytes in vitro. Mol Cell Biol 20:8684-95
Berrier, A; Siu, G; Calame, K (1998) Transcription of a minimal promoter from the NF-IL6 gene is regulated by CREB/ATF and SP1 proteins in U937 promonocytic cells. J Immunol 161:2267-75
Angelin-Duclos, C; Calame, K (1998) Evidence that immunoglobulin VH-DJ recombination does not require germ line transcription of the recombining variable gene segment. Mol Cell Biol 18:6253-64

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