Regulation of host defense and development by innate-immunity signal transduction system

在先天免疫系统中，特异性模式分子如LPS与toll样受体结合，激活涉及NF-kappaB的信号转导通路。最近我们发现了一种新的核IkB分子MAIL。在本研究中，我们重点研究了MAIL和其他NF-kappaB相关分子。在大约90%的MAIL缺陷小鼠中观察到胚胎死亡。肝脏发育不全被认为是这种胚胎死亡的可能原因。其余10%的MAIL缺陷小鼠出生时存活。这些小鼠出现了严重的特应性皮炎样疾病。我们克隆了小鼠MAIL基因上游的lps反应区，并利用一系列突变序列分析了其启动子功能。NF-kappaB结合位点位于-229 ~ -220 bp，是MAIL表达的重要靶点。过表达MAIL蛋白可抑制lps诱导的MAIL基因启动子活性。这些数据表明，NF-kappaB上调了MAIL的表达，并且至少在一定程度上受一种自动调节机制的控制。NF-kappaB靶基因产物BRCA2BRCA2是一种NF-kappaB靶分子，其DNA修复和重组功能在细胞生长和胚胎发生中起着至关重要的作用。我们证明了小鼠和狗的BRCA2蛋白与Rad51重组酶相互作用。我们在犬类BRCA2中发现了一个新的插入/删除多态性，该多态性位于一个核定位信号中。这种多态性与核定位效率和乳腺肿瘤发病率有关。

In innate immune system, specific pattern molecules such as LPS bind to Toll-like receptors and activate signal transduction pathway involving NF-kappaB. Recently we identified a novel nuclear IkB molecule, MAIL. In this study we focused on MAIL and other NF-kappaB related molecules.1. Analysis of MAIL deficient miceEmbryonic lethality was observed for about 90% of MAIL deficient mice. Hypoplasia of the liver was suggested to be a possible cause for this embryonic lethality. Remaining 10% of MAIL deficient mice were born alive. These mice developed severe atopic dermatitis-like disease.2. Analysis of transcriptional regulation of the MAIL geneWe cloned LPS-reactive upstream region of the mouse MAIL gene, and analyzed its promoter function by using a series of mutated sequences. An NF-kappaB binding site located at -229 to -220 bp was revealed to be an essential target of MAIL expression. Overexpression of MAIL protein suppressed the LPS-induced promoter activity of the MAIL gene. These data indicate that MAIL expression is upregulated by NF-kappaB, and it is controlled, at least in part, by an autoregulation mechanism.3. Analysis of an NF-kappaB target gene product, BRCA2BRCA2, an NF-kappaB target molecule, plays essential roles for cell growth and embryogenesis through its DNA repair and recombination function. We demonstrated that BRCA2 proteins from the mouse and dog interact with Rad51 recombinase. We found a novel insertion/deletion polymorphism in canine BRCA2, which is located in a nuclear localization signal. This polymorphism was associated with nuclear localization efficiency and mammary tumor morbidity.