SIGNALING THROUGH CD27, A MEMBER OF THE TNFR FAMILY

CD 27属于TNF-受体（TNFR）家族，其成员 调节细胞生长或死亡的倾向。 CD 27的配体 是CD 70，其属于TNF配体家族。完成的大量工作 几个研究小组的研究表明，CD 27/CD 70相互作用提供了 T细胞生长的共刺激信号并增强B细胞 分化和IG合成。 CD 27的调节表达 成熟的胸腺细胞意味着它在胸腺分化中的作用。 一 可溶性形式的受体（sCD 27）已被检测到的血清中， 正常人和它的水平被发现在患者升高 自身免疫性疾病和某些B细胞癌症。 在我们 试图了解CD 27信号转导的潜在机制， 出乎意料地，我们发现通过CD 70转染子连接CD 27 导致B细胞系Raji和拉莫斯的凋亡。 自CD 27 显然参与了共刺激和细胞信号传导， 在体内仔细调节表达，我们认为CD 27诱导 细胞凋亡在活化的T或B细胞的清除中起主要作用 克隆 在自身免疫性疾病患者中观察到的sCD 27升高 疾病和B细胞癌可能很好地促成病理性 通过干扰CD 27诱导的细胞凋亡来进行这一过程。 细胞质 TNFR 1和Fas的尾部（而不是CD 27）具有“死亡结构域”， 对于通过这些受体诱导细胞凋亡是必不可少的。 如何 那么CD 27是否能够诱导细胞凋亡呢？它是否发生在 Fas无效吗？ 为了了解这些分子机制 在这种新的凋亡途径的基础上，使用CD 27胞质尾作为 在酵母双杂交系统中，我们克隆了一个新的CD 27 细胞质尾结合蛋白Siva-1，当在各种细胞中表达时， 哺乳动物细胞可以诱导凋亡。因此，我们建议， Siva-1介导CD 27的凋亡作用。 的结构特征 Siva-1包括一个死亡结构域同源区（DDHR）、盒B样环、 指状结构域和Zn指状结构域。 我们还找到了一个替代者 Siva-1（Siva-2）的剪接形式，缺乏大部分DDHR， 诱导细胞凋亡，支持我们的建议，即Siva-1的DDHR是 CD 27的促凋亡功能的下游管道。我们建议 充分定义Siva-1和-2在CD 27诱导的细胞凋亡中的作用， Siva-1和Siva-2的功能域，并确定Siva-1是否 和Siva-2协同工作以调节CD 27的凋亡功能。 这些研究应该为监管作用提供重要见解 T和B细胞功能的细胞表面分子。

CD27 belongs to the TNF-Receptor (TNFR) family, members of which regulate the propensity of a cell to grow or die. The ligand for CD27 is CD70, which belongs to the TNF family of ligands. Extensive work done by several groups have shown that CD27/CD70 interaction provides costimulatory signals for T cell growth and enhances B cell differentiation and Ig synthesis. Regulated expression of CD27 in mature thymocytes implies a role for it in thymic differentiation. A soluble form of the receptor (sCD27) has been detected in the serum of normal individuals and its levels were found to be elevated in patients with autoimmune disorders and certain B cell cancers. During our attempts to understand mechanisms underlying CD27 signaling, unexpectedly, we found that ligation of CD27 by CD70 transfectants resulted in apoptosis in the B cell lines Raji and Ramos. Since CD27 is clearly involved in costimulation and cell signaling with carefully regulated expression in vivo, we believe that CD27 induced apoptosis plays a major role in the clearance of activated T or B cell clones. The elevated sCD27 observed in patients with autoimmune disorders and B cell cancers may well contribute to the pathologic process by interfering with CD27 induced apoptosis. The cytoplasmic tails of TNFR1 and Fas (but not CD27) have the 'death domain' which is indispensable for induction of apoptosis through these receptors. How then is CD27 able to induce apoptosis? and does it occur in cells where Fas is ineffective? In order to understand the molecular mechanisms underlying this novel apoptotic pathway, using CD27 cytoplasmic tail as the bait in the yeast two hybrid system, we cloned a novel CD27 cytoplasmic tail binding protein Siva-1 which when expressed in various mammalian cells can induce apoptosis. Accordingly, we propose that Siva-1 mediates the apoptotic effects of CD27. Structural features of Siva-1 include a death domain homology region (DDHR), box-B like ring finger and a Zn finger like domain. We also identified an alternate splice form of Siva-1 (Siva-2) which lacks most of the DDHR and does not induce apoptosis, supporting our proposal that the DDHR of Siva-1 is the downstream conduit of the proapoptotic function of CD27. We propose to fully define the roles of Siva-1 and -2 in CD27 induced apoptosis, map the functional domains of Siva-1 and Siva-2 and determine whether Siva-1 and Siva-2 work in concert to regulate the apoptotic function of CD27. These studies should provide important insights into the regulatory role of cell surface molecules in T and B cell function.