Hzf, a p53-responsive gene, regulates maintenance of the G2 phase checkpoint induced by DNA damage
Hzf, a p53-responsive gene, regulates maintenance of the G2 phase checkpoint induced by DNA damage
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DOI：
10.1128/mcb.26.2.502-512.2006
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发表时间：
2006-01-01
影响因子：
5.3
通讯作者：
Sherr, CJ
中科院分区：
文献类型：
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作者：
Sugimoto, M;Gromley, A;Sherr, CJ
造血锌指蛋白，Hzf，是诱导基因毒性和致癌应激反应。Hzf蛋白由p53应答基因编码，其在保留或缺乏功能性53的细胞中的过度表达会阻止其增殖。Hzf的强制表达导致了具有额外中心体的四倍体细胞的出现，并最终导致细胞死亡。通过使用短发夹（sh）RNA消除Hzf mRNA表达对未应激的细胞没有明显影响，但抑制电离辐射（IR）后G 1期停滞的维持，从而使细胞对DNA损伤敏感。IR诱导Hzf shRNA处理的细胞中典型的p53应答基因产物如p21（Cip1）和Mdm 2。然而，Hzf蛋白水平的降低伴随着p21（Cip1）的多聚泛素化和周转率的增加，p21是细胞周期蛋白依赖性激酶的抑制剂，其表达有助于维持持续DNA损伤的细胞中的G，检查点的持续时间。因此，两个p53诱导的基因产物，Hzf和p21（Cip1），同时执行G，检查点。
The hematopoietic zinc finger protein, Hzf, is induced in response to genotoxic and oncogenic stress. The Hzf protein is encoded by a p53-responsive gene, and its overexpression, either in cells retaining or lacking functional 53, halts their proliferation. Enforced expression of Hzf led to the appearance of tetraploid cells with supernumerary centrosomes and, ultimately, to cell death. Eliminating Hzf mRNA expression by use of short hairpin (sh) RNAs had no overt effect on unstressed cells but inhibited the maintenance of G, phase arrest following ionizing radiation (IR), thereby sensitizing cells to DNA damage. Canonical p53-responsive gene products such as p21(Cip1) and Mdm2 were induced by IR in cells treated with Hzf shRNA. However, the reduction in the level of Hzf protein was accompanied by increased polyubiquitination and turnover of p21(Cip1), an inhibitor of cyclin-dependent kinases whose expression contributes to maintaining the duration of the G, checkpoint in cells that have sustained DNA damage. Thus, two p53-inducible gene products, Hzf and p21(Cip1), act concomitantly to enforce the G, checkpoint.