During fiscal year 2010 we accomplished the following: 1) We used Bim-deficient B cells to further distinguish transcriptional and post-transcriptional regulation of p100 protein production in response to acute and tonic BCR stimulation. These studies substantiated the idea of PI3K-dependent translational control of p100 production. 2) We used NFκB2-deficient mice to establish unequivocally that p100 is essential for BAFF-dependent survival of B cells in vitro. It is interesting to note that p100-deficient mice have reasonable numbers of mature B cells, whereas BAFF- or BAFF-R- deficient mice do not. Our results suggest that BAFF-dependent survival in vivo can be mediated by pathways other than p100. Since BCR is essential for survival of mature B cells in vivo, these other pathways must also be initiated at the BCR. We initiated studies of Mcl-1 regulation by BCR to determine if this anti-apoptotic protein is responsible in part for p100 independent B cell survival in vivo. 3) Downstream of PI3K activation we found that suppression of mTOR by rapamycin did not abolish p100 up-regulation in response to tonic or acute BCR signaling. However, rapamycin treatment of Pim2-deficient B cells abolished BCR-induced p100 up-regulation. We infer that Pim 2 and mTOR provide redundant pathways to p100 induction.
| Castro, Iris; Wright, Jacqueline A; Damdinsuren, Bazarragchaa et al. (2009) B cell receptor-mediated sustained c-Rel activation facilitates late transitional B cell survival through control of B cell activating factor receptor and NF-kappaB2. J Immunol 182:7729-37 |
| Stadanlick, Jason E; Kaileh, Mary; Karnell, Fredrick G et al. (2008) Tonic B cell antigen receptor signals supply an NF-kappaB substrate for prosurvival BLyS signaling. Nat Immunol 9:1379-87 |
