During FY17 we accomplished the following: 1) Attempted to confirm the model that survivin/Cdk4 interaction provides the basis for G1 progression during signal-independent B cell proliferation. Co-immunoprecipitation studies from G1 phase of the cell-cycle proved more complex than anticipated and are being re-designed. We also attempted to determine the molecular mechanism underlying cell survival mediated by very low (non-mitogenic) doses of anti-CD40. A manuscript describing the basic property of signal-independent proliferation is being written. 2) Used dominant negative IB (dn-IB) expressing cell lines to identify true targets of NF-B during cell activation. We conclusively demonstrated that NF-B binding and inducible transcription were insufficient criteria to identify NF-B target genes. Using more stringent criteria we identified 130 direct NF-B target genes in activated B cells. The majority of these genes have not been linked to NF-B in earlier studies, indicating that they are novel targets of this transcription factor. We also determined that NF-B activation leads to gene repression and thereby provided evidence that NF-B affects responses in complex and unanticipated ways. Finally, we identified indirect targets of NF-B that were suppressed by dn-IB, but did not bind NF-B. We provided evidence that these genes were regulated by NF-B-dependent transcription factors, and represent the second wave of a cascade of gene expression changes initiated by NF-B. A manuscript is being written 3) GtfIIif/f mice were bred to CD19-cre strain to obtain B cells deficient in this transcription factor. GtfIIi-deficient B cells were activated with anti-Ig or LPS and RNA extracted at various times post-activation. RNA-Seq was carried out and the data are being computationally interrogated. To extend these studies, we initiated breeding of GtfIIif/f mice to CD4-cre to obtain T cells that lack this transcription factor. This strain will be ready for RNA analysis in FY18. A manuscript describing B cells studies is being written.
| Lee-Chang, Catalina; Bodogai, Monica; Moritoh, Kanako et al. (2016) Aging Converts Innate B1a Cells into Potent CD8+ T Cell Inducers. J Immunol 196:3385-97 |
| Kaileh, Mary; Vazquez, Estefania; MacFarlane 4th, Alexander W et al. (2016) mTOR-Dependent and Independent Survival Signaling by PI3K in B Lymphocytes. PLoS One 11:e0146955 |
| Fowler, Trent; Garruss, Alexander S; Ghosh, Amalendu et al. (2015) Divergence of transcriptional landscape occurs early in B cell activation. Epigenetics Chromatin 8:20 |
| Maul, Robert W; Cao, Zheng; Venkataraman, Lakshmi et al. (2014) Spt5 accumulation at variable genes distinguishes somatic hypermutation in germinal center B cells from ex vivo-activated cells. J Exp Med 211:2297-306 |
| Kaileh, Mary; Sen, Ranjan (2012) NF-ýýB function in B lymphocytes. Immunol Rev 246:254-71 |
| Sen, Ranjan (2011) The origins of NF-?B. Nat Immunol 12:686-8 |
| Olkhanud, Purevdorj B; Damdinsuren, Bazarragchaa; Bodogai, Monica et al. (2011) Tumor-evoked regulatory B cells promote breast cancer metastasis by converting resting CD4? T cells to T-regulatory cells. Cancer Res 71:3505-15 |
| Fowler, Trent; Sen, Ranjan; Roy, Ananda L (2011) Regulation of primary response genes. Mol Cell 44:348-60 |
| Damdinsuren, Bazarragchaa; Zhang, Yongqing; Khalil, Ashraf et al. (2010) Single round of antigen receptor signaling programs naive B cells to receive T cell help. Immunity 32:355-66 |
| Sen, Ranjan; Smale, Stephen T (2010) Selectivity of the NF-{kappa}B response. Cold Spring Harb Perspect Biol 2:a000257 |
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