Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA.
Cancer Res. 2011 Oct 15;71(20):6524-34. doi: 10.1158/0008-5472.CAN-11-0853. Epub 2011 Aug 18.
Genome-wide sequencing studies in breast cancer have recently identified frequent mutations in the zinc finger protein 668 (ZNF668), the function of which is undefined. Here, we report that ZNF668 is a nucleolar protein that physically interacts with and regulates p53 and its negative regulator MDM2. Through MDM2 binding, ZNF668 regulated autoubiquitination of MDM2 and its ability to mediate p53 ubiquitination and degradation. ZNF668 deficiency also impaired DNA damage-induced stabilization of p53. RNA interference-mediated knockdown of ZNF668 was sufficient to transform normal mammary epithelial cells. ZNF668 effectively suppressed breast cancer cell proliferation in vitro and tumorigenicity in vivo. Taken together, our studies identify ZNF668 as a novel breast tumor suppressor gene that functions in regulating p53 stability.
最近在乳腺癌的全基因组测序研究中发现，锌指蛋白 668（ZNF668）频繁发生突变，但其功能尚未确定。在这里，我们报告 ZNF668 是一种核仁蛋白，它与 p53 及其负调节因子 MDM2 相互作用并调节其功能。通过与 MDM2 结合，ZNF668 调节了 MDM2 的自泛素化及其介导 p53 泛素化和降解的能力。ZNF668 缺陷也会损害 DNA 损伤诱导的 p53 稳定。RNA 干扰介导的 ZNF668 敲低足以使正常乳腺上皮细胞发生转化。ZNF668 有效地抑制了体外乳腺癌细胞的增殖和体内的致瘤性。总之，我们的研究确定 ZNF668 是一种新的乳腺癌肿瘤抑制基因，它在调节 p53 稳定性方面发挥作用。
