A peptide aptamer to antagonize BCL-6 function
A peptide aptamer to antagonize BCL-6 function
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DOI：
10.1038/sj.onc.1209252
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发表时间：
2006-04-01
期刊：
影响因子：
8
通讯作者：
Ferrigno, PK
中科院分区：
文献类型：
--
作者：
Chattopadhyay, A;Tate, SA;Ferrigno, PK
BCL-6是生发中心B细胞发育所必需的转录因子。BCL-6基因与弥漫性大细胞淋巴瘤有关，在其他类型的非霍奇金淋巴瘤和高级别乳腺癌中过表达。BCL-6是一种转录抑制因子，其N端POZ结构域介导蛋白质-蛋白质相互作用以发挥其作用。推测POZ结构域介导的相互作用的破坏可能是拮抗BCL-6在淋巴瘤中的作用的有效途径，我们筛选了特异性结合BCL-6 POZ而不是相关蛋白的POZ结构域的肽适体的文库，并在此描述了这些试剂中的第一种，Apt 48。Apt 48以不同于转录辅阻遏物SMRT的方式结合BCL-6 POZ，但发现其阻止BCL-6介导的荧光素酶报告基因的阻遏。Apt 48还再现了几种先前验证的BCL-6抑制作用。当Apt 48表达时，B细胞系中分化标志物CD 69、Blimp-1和细胞周期蛋白D2的表达增加，这是不可能的。我们还显示Apt 48的表达恢复了对BCL-6过表达细胞的精氨酸介导的生长停滞。因此，我们已经鉴定了影响BCL-6功能的肽适体，所述BCL-6功能是防止增殖B细胞分化所需的。
BCL-6 is a transcription factor essential for germinal centre B-cell development. The BCL-6 gene is involved in diffuse large-cell lymphoma and overexpressed in other types of non-Hodgkin's lymphoma and in high-grade breast cancer. BCL-6 is a transcriptional repressor whose N-terminal POZ domain mediates protein-protein interactions to exert its effects. Reasoning that disruption of POZ domain-mediated interactions may be an effective route to antagonizing the effects of BCL-6 in lymphoma, we screened a library for peptide aptamers that specifically bind to BCL-6 POZ and not the POZ domains of related proteins and describe here the first of these reagents, Apt48. Apt 48 binds BCL-6 POZ in a manner distinct from the transcriptional corepressor SMRT, yet was found to prevent BCL-6-mediated repression of a luciferase reporter gene. Apt48 also reproduced several previously validated effects of BCL-6 inhibition. Not ably, expression of the differentiation markers CD69, Blimp-1 and cyclin D2 was increased in B-cell lines when Apt48 was expressed. W e also show that expression of Apt48 restores cytokine-mediated growth arrest to BCL-6 over-expressing cells. Thus, we have identified a peptide aptamer that affects a function of BCL-6 that is required to prevent differentiation of proliferating B cells.