Cell growth suppression by thanatos-associated protein 11(THAP11) is mediated by transcriptional downregulation of c-Myc
Cell growth suppression by thanatos-associated protein 11(THAP11) is mediated by transcriptional downregulation of c-Myc
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DOI：
10.1038/cdd.2008.160
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发表时间：
2009-03-01
影响因子：
12.4
通讯作者：
Yang, X-M
中科院分区：
文献类型：
--
作者：
Zhu, C-Y;Li, C-Y;Yang, X-M
Thanatos相关蛋白(THAPs)是一类锌依赖、序列特异的DNA结合因子，参与细胞增殖、细胞凋亡、细胞周期、染色质修饰和转录调控。THAP11是这个人类蛋白家族中最新被描述的成员。在这项研究中，我们发现THAP11在正常组织中普遍表达，并在几种人类肿瘤组织中频繁下调。THAP11的过表达显著抑制了许多不同细胞的生长，包括癌细胞和未转化细胞。在HepG2细胞中，通过RNA干扰沉默THAP11会导致细胞生长抑制的丧失。这些结果提示，人THAP11可能是细胞增殖的内源性生理调节因子。我们还提供了证据表明，THAP11的功能是通过其抑制c-Myc转录的能力来介导的。启动子报告分析表明依赖于DNA结合的c-Myc转录抑制。染色质免疫沉淀和EMSA分析表明，THAP11与c-Myc启动子直接结合。结果表明，c-Myc的表达显著地将细胞从THAP11介导的细胞生长抑制中解救出来，而THAP11的表达仅轻微地抑制c-Myc缺失的成纤维细胞的生长，这表明THAP11通过下调c-Myc的表达来抑制细胞的生长。综上所述，这些结果表明THAP11通过负向调节c-Myc的表达而发挥细胞生长抑制的作用。
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.