ZNF23抑制肿瘤细胞的生长及其分子机制的研究
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摘要
KRAB锌指蛋白(KRAB-ZFP)构成转录因子的最大家族之一。该家族成员参与细胞增殖,存活和个体发育等过程。虽然目前克隆了许多KRAB-ZFP基因,但是其中的大部分成员功能很不清楚。有些KRAB-ZFP基因所定位的染色体区域在人类肿瘤中经常发生变异,被认为和某些恶性肿瘤的发生有关。本文着眼于研究一个定位于染色体16q22的一个KRAB-ZFP(ZNF23)。ZNF23蛋白定位于细胞核,在人体的各种组织中广泛分布。然而,在许多肿瘤细胞系和人类肿瘤样品包括卵巢癌、子宫内膜癌、胶质瘤和肝癌中,ZNF23蛋白明显下调或缺少。将ZNF23导入卵巢癌细胞系SKOV-3中,引起细胞周期阻滞在G1期和细胞死亡。进一步我们发现ZNF23诱导细胞周期阻滞和其增加p27表达有关,但与p53无关。而ZNF23引起细胞死亡的机制可能是抑制Bcl-xL表达,激活线粒体调亡途径。和公认的KRAB蛋白作用模式不同的是, ZNF23的生长抑制作用不依赖于KRAB结构域,而和锌指结构域有关。通过BSS技术,我们鉴定了ZNF23的DNA结合序列。因此我们发现了一个新的肿瘤相关基因ZNF23,能够调节细胞生长和调亡,我们的工作为进一步研究ZNF23功能奠定基础。
The Krupple-associated box-containing zinc-finger proteins (KRAB-ZFPs) make up one of the largest family of transcription factors. Several members of the KRAB-ZFPs modulate cell growth, survival and are implicated in malignant disorders. However, most members are not well characterized and their functions are largely unknown. Here we report that ZNF23, a member of KRAB-ZFPs, inhibits cell growth. ZNF23 protein localized to the nucleus and was ubiquitously expressed in all tested normal tissues. However, the expression levels of ZNF23 protein were lost or greatly reduced in human cancer. Ectopic expression of ZNF23 led to growth inhibition by inducing G1 arrest and cell death. ZNF23 induced cell arrest in G1 phase through up-regulation of p27kip-1, but this process was p53-independent. ZNF23 promoted mitochrondrial cell death through down-regulation of Bcl-xL. Deletion analysis revealed that the effect of ZNF23 did not rely on its KRAB domain, but on the C-terminal zinc fingers. Furthermore, DNA binding sequence of ZNF23 was identified by BSS. Thus, ZNF23 is a new tumor-associated gene with growth-inhibitory ability and our work provides the basic foundation for future studies on the function of OKL38
The Krupple-associated box-containing zinc-finger proteins (KRAB-ZFPs) make up one of the largest family of transcription factors. Several members of the KRAB-ZFPs modulate cell growth, survival and are implicated in malignant disorders. However, most members are not well characterized and their functions are largely unknown. Here we report that ZNF23, a member of KRAB-ZFPs, inhibits cell growth. ZNF23 protein localized to the nucleus and was ubiquitously expressed in all tested normal tissues. However, the expression levels of ZNF23 protein were lost or greatly reduced in human cancer. Ectopic expression of ZNF23 led to growth inhibition by inducing G1 arrest and cell death. ZNF23 induced cell arrest in G1 phase through up-regulation of p27kip-1, but this process was p53-independent. ZNF23 promoted mitochrondrial cell death through down-regulation of Bcl-xL. Deletion analysis revealed that the effect of ZNF23 did not rely on its KRAB domain, but on the C-terminal zinc fingers. Furthermore, DNA binding sequence of ZNF23 was identified by BSS. Thus, ZNF23 is a new tumor-associated gene with growth-inhibitory ability and our work provides the basic foundation for future studies on the function of OKL38
引文
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