Hzf determines cell survival upon genotoxic stress by modulating p53 transactivation
Hzf determines cell survival upon genotoxic stress by modulating p53 transactivation
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DOI：
10.1016/j.cell.2007.06.013
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发表时间：
2007-08-24
期刊：
影响因子：
64.5
通讯作者：
Lee, Sam W.
中科院分区：
文献类型：
--
作者：
Das, Sanjeev;Raj, Lakshmi;Lee, Sam W.
关于基因毒性应激反应的一个尚未解决的关键问题是 p53 肿瘤抑制因子的激活如何导致细胞周期停滞和 DNA 修复或细胞凋亡。我们在这里展示了造血锌指 (Hzf)，一种含有锌指的 p53 靶基因，在自动调节反馈环路中调节 p53 反式激活功能。 Hzf 受 p53 诱导并与其 DNA 结合域结合，导致 proarrest p53 靶基因相对于其促凋亡靶基因优先反式激活。因此，p53 激活导致 Hzf 野生型 MEF 细胞周期停滞，而在 Hzf(-/-) MEF 中，诱导细胞凋亡。与野生型小鼠相比，Hzf 缺失小鼠暴露于电离辐射导致多个器官的细胞凋亡增强。这些发现为 p53 反式激活功能的调节提供了新的见解，并表明 Hzf 在调节细胞命运决策以应对基因毒性应激方面发挥着关键作用。
A critical unresolved issue about the genotoxic stress response is how the resulting activation of the p53 tumor suppressor can lead either to cell-cycle arrest and DNA repair or to apoptosis. We show here that hematopoietic zinc finger ( Hzf), a zinc-finger-containing p53 target gene, modulates p53 transactivation functions in an autoregulatory feedback loop. Hzf is induced by p53 and binds to its DNA-binding domain, resulting in preferential transactivation of proarrest p53 target genes over its proapoptotic target genes. Thus, p53 activation results in cell-cycle arrest in Hzf wild-type MEFs, while in Hzf(-/-) MEFs, apoptosis is induced. Exposure of Hzf null mice to ionizing radiation resulted in enhanced apoptosis in several organs, as compared to in wild-type mice. These findings provide novel insights into the regulation of p53 transactivation function and suggest that Hzf functions as a key player in regulating cell fate decisions in response to genotoxic stress.