Abstract

We are investigating the mechanisms of action and regulation of the immunoglobulin heavy chain constant region gene switch recombinase as a function of B cell physiology and development. Switch substrate retroviruses (SSRs) will be introduced into cultures of mature murine and human B lymphocytes, purified subsets of human B cells and murine pre-B cells to assess the activation, regulation and developmental timing of switch-recombinase activity. Model B cell lines responsive to CD40 and cytokine signaling will be employed to discriminate between extracellular signals that initiate and/or potentiate switch-recombinase activity. Sensitive PCR assays will be performed to reveal the consequences for SSR recombination as these cells are exposed to CD40 receptor signaling, cytokines, and dendritic cells known to affect endogenous antibody class switching. SSR harboring CH locus regulatory elements and RNA maturation signals will be employed to determine their putative role(s) in targeting CH gene segments for switch recombination.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM026939-20
Application #
6180482
Study Section
Allergy and Immunology Study Section (ALY)
Program Officer
Wolfe, Paul B
Project Start
1979-07-01
Project End
2003-06-30
Budget Start
2000-07-01
Budget End
2001-06-30
Support Year
20
Fiscal Year
2000
Total Cost
$256,185
Indirect Cost

  Institution

Name
State University New York Stony Brook
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794

  Publications

Krause, Kristina; Marcu, Kenneth B; Greeve, Jobst (2006) The cytidine deaminases AID and APOBEC-1 exhibit distinct functional properties in a novel yeast selectable system. Mol Immunol 43:295-307
Greeve, Jobst; Philipsen, Antje; Krause, Kristina et al. (2003) Expression of activation-induced cytidine deaminase in human B-cell non-Hodgkin lymphomas. Blood 101:3574-80
Li, Xiang; Massa, Paul E; Hanidu, Adedayo et al. (2002) IKKalpha, IKKbeta, and NEMO/IKKgamma are each required for the NF-kappa B-mediated inflammatory response program. J Biol Chem 277:45129-40
McKenzie, F R; Connelly, M A; Balzarano, D et al. (2000) Functional isoforms of IkappaB kinase alpha (IKKalpha) lacking leucine zipper and helix-loop-helix domains reveal that IKKalpha and IKKbeta have different activation requirements. Mol Cell Biol 20:2635-49
Brondello, J M; Pouyssegur, J; McKenzie, F R (1999) Reduced MAP kinase phosphatase-1 degradation after p42/p44MAPK-dependent phosphorylation. Science 286:2514-7
Ballantyne, J; Henry, D L; Muller, J R et al. (1998) Efficient recombination of a switch substrate retrovector in CD40-activated B lymphocytes: implications for the control of CH gene switch recombination. J Immunol 161:1336-47
Muller, J R; Marcu, K B (1998) Stimulation of murine B lymphocytes induces a DNA exonuclease whose activity on switch-mu DNA is specifically inhibited by other germ-line switch region RNAs. J Immunol 160:3337-41
Muller, J R; Giese, T; Henry, D L et al. (1998) Generation of switch hybrid DNA between Ig heavy chain-mu and downstream switch regions in B lymphocytes. J Immunol 161:1354-62
Ballantyne, J; Henry, D L; Marcu, K B (1997) Antibody class switch recombinase activity is B cell stage specific and functions stochastically in the absence of 'targeted accessibility' control. Int Immunol 9:963-74
Ballantyne, J; Ozsvath, L; Bondarchuk, K et al. (1995) Chromosomally integrated retroviral substrates are sensitive indicators of an antibody class switch recombinase-like activity. Curr Top Microbiol Immunol 194:439-48

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