Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo, Japan.
Eur J Immunol. 2012 Dec;42(12):3405-15. doi: 10.1002/eji.201242530. Epub 2012 Oct 16.
We previously identified zinc finger (ZF) protein ZNF385B as a molecule specifically expressed in Burkitt's lymphoma (BL) among hematologic malignancies. Here, we investigated ZNF385B expression in healthy B cells in a variety of hematological tissues by RT-PCR and immunohistochemistry. ZNF385B expression was found to be limited to a subset of GC B cells, the healthy counterpart to BL B cells. To elucidate the function of ZNF385B in healthy B cells, we established a tetracycline-controlled protein-inducible system in B-cell lines and observed that ectopic expression of the longest transcript variant of ZNF385B, possessing four ZF domains, induced upregulation of PERP and FAS/CD95, a downstream target of p53, and activation of caspase, resulting in apoptosis induction. However, a ZNF385B deletion mutant with three ZF domains corresponding to shorter isoforms, did not induce upregulation; rather it inhibited apoptosis induced by CD20 cross-linking and BCR stimulation. The direct binding of ZNF385B with p53 has suggested the involvement of ZNF385B in B-cell apoptosis via modulation of p53 transactivation; our data indicate that ZNF385B characteristically expressed in GC B cells has both proapoptotic and antiapoptotic activities depending on the type of isoform and should be a novel player in GC B-cell selection.
我们之前发现锌指（ZF）蛋白 ZNF385B 是一种在血液恶性肿瘤中特异性表达于 Burkitt 淋巴瘤（BL）的分子。在这里，我们通过 RT-PCR 和免疫组织化学研究了 ZNF385B 在各种血液组织中的健康 B 细胞中的表达。发现 ZNF385B 表达仅限于 GC B 细胞亚群，即 BL B 细胞的健康对应物。为了阐明 ZNF385B 在健康 B 细胞中的功能，我们在 B 细胞系中建立了四环素控制的蛋白诱导系统，并观察到最长转录变体的异位表达 ZNF385B，具有四个 ZF 结构域，诱导 PERP 和 FAS/CD95 的上调，p53 的下游靶标，并激活 caspase，导致凋亡诱导。然而，具有三个 ZF 结构域的 ZNF385B 缺失突变体对应于较短的亚型，不会诱导上调；相反，它抑制 CD20 交联和 BCR 刺激诱导的凋亡。ZNF385B 与 p53 的直接结合表明 ZNF385B 通过调节 p53 反式激活参与 B 细胞凋亡；我们的数据表明，GC B 细胞中特征性表达的 ZNF385B 根据同工型的类型具有促凋亡和抗凋亡活性，应该是 GC B 细胞选择中的一个新参与者。
