Zhu C-Y, Li C-Y, Li Y, Zhan Y-Q, Li Y-H, Xu C-W, Xu W-X, Sun H B, Yang X-M
Beijing Institute of Radiation Medicine, Beijing, China.
Cell Death Differ. 2009 Mar;16(3):395-405. doi: 10.1038/cdd.2008.160. Epub 2008 Nov 14.
Thanatos-associated proteins (THAPs) are zinc-dependent, sequence-specific DNA-binding factors involved in cell proliferation, apoptosis, cell cycle, chromatin modification and transcriptional regulation. THAP11 is the most recently described member of this human protein family. In this study, we show that THAP11 is ubiquitously expressed in normal tissues and frequently downregulated in several human tumor tissues. Overexpression of THAP11 markedly inhibits growth of a number of different cells, including cancer cells and non-transformed cells. Silencing of THAP11 by RNA interference in HepG2 cells results in loss of cell growth repression. These results suggest that human THAP11 may be an endogenous physiologic regulator of cell proliferation. We also provide evidence that the function of THAP11 is mediated by its ability to repress transcription of c-Myc. Promoter reporter assays indicate a DNA binding-dependent c-Myc transcriptional repression. Chromatin immunoprecipitations and EMSA assay suggest that THAP11 directly binds to the c-Myc promoter. The findings that expression of c-Myc rescues significantly cells from THAP11-mediated cell growth suppression and that THAP11 expression only slightly inhibits c-Myc null fibroblasts cells growth reveal that THAP11 inhibits cell growth through downregulation of c-Myc expression. Taken together, these suggest that THAP11 functions as a cell growth suppressor by negatively regulating the expression of c-Myc.
与死亡相关的蛋白（THAPs）是锌依赖性、序列特异性的DNA结合因子，参与细胞增殖、凋亡、细胞周期、染色质修饰和转录调控。THAP11是该人类蛋白家族中最新被描述的成员。在本研究中，我们发现THAP11在正常组织中广泛表达，而在多种人类肿瘤组织中经常下调。THAP11的过表达显著抑制多种不同细胞的生长，包括癌细胞和未转化细胞。在HepG2细胞中通过RNA干扰使THAP11沉默导致细胞生长抑制作用丧失。这些结果表明，人类THAP11可能是细胞增殖的内源性生理调节因子。我们还提供证据表明，THAP11的功能是由其抑制c-Myc转录的能力介导的。启动子报告基因检测表明存在依赖于DNA结合的c-Myc转录抑制。染色质免疫沉淀和电泳迁移率变动分析表明，THAP11直接结合到c-Myc启动子上。c-Myc的表达能显著挽救细胞免受THAP11介导的细胞生长抑制，以及THAP11表达仅轻微抑制c-Myc基因缺失的成纤维细胞生长的这些发现揭示，THAP11通过下调c-Myc表达来抑制细胞生长。综上所述，这些表明THAP11通过负调控c-Myc的表达而发挥细胞生长抑制因子的作用。
