Study on transcriptional regulation in CD40 signaling.

点击翻译按钮获取中文摘要

CD40 signaling plays an essential role in immune responses. CD40 signaling activates various signaling molecules such as the transcription factor NF-kB. However, it is not yet elucidated how these signaling molecules regulate the target genes. It is also not yet clear how the products of the target genes are involved in immune responses. Previously, we demonstrated that CD40 signaling reduces the mRNA level of the cell cycle inhibitor kip1. First, we addressed the molecular mechanisms for the repression of kip1 by CD40 signaling. We assessed the promoter activity of the kip1 gene by luciferace assay using 3T3 cells, and demonstrated that NF-kB repress the kip1 promoter. Further the region containing -581 to -348 in the kip1 promoter carry two NF-kB recognition sequences and the promoter activity in this region is suppressed by NF-kB. This suggests that this region may play a role in CD40-mediated suppression of the kip1 level. However, NF-kB-mediated suppression still occurs even if the NF-kB site is mutated. Thus, how NF-kB represses the promoter activity in this region is still unclear. Next, we assessed the role of kip1 repression in CD40-mediated B cell proliferation and survival. Since p27kip1 inhibits CDKs essential fur cell cycle progression, kip1 repression may play a role in B cell proliferation induced by CD40 signaling. CD40 signaling induces survival of the B cells including the B cell line WEHI-231 by abrogating antigen receptor-mediated apoptosis. When we expressed kip1 in WEHI-231 cells using a retrovirus vector, survival of antigen receptor-ligated WEHI-231 cells is partially impaired. This indicates that kip1 suppression is required for fully restore antigen receptor-induced apoptosis by CD40 signaling. Taken together kip1 repression appears to involve NF-kB and play a role in proliferation and survival of B cells.