HSF4 promotes G1/S arrest in human lens epithelial cells by stabilizing p53
HSF4 promotes G1/S arrest in human lens epithelial cells by stabilizing p53
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HSF4 通过稳定 p53 促进人晶状体上皮细胞 G1/S 停滞
DOI：
10.1016/j.bbamcr.2015.04.018
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发表时间：
2015-08-01
影响因子：
5.1
通讯作者：
Liu, Mugen
中科院分区：
文献类型：
--
作者：
Huang, Mi;Li, Duanzhuo;Liu, Mugen
在透镜的发育过程中，上皮细胞不断分裂分化为次生纤维细胞是关键的一步。这一过程的失败，需要细胞增殖抑制和细胞周期退出，导致白内障形成。热休克转录因子4（Heat Shock Transcription Factor 4，HSF 4）基因突变可导致先天性白内障和老年性白内障。然而，HSF 4突变如何诱导白内障形成仍不清楚。在这项研究中，我们证明，HSF 4可以抑制人透镜上皮细胞（HLECs）的增殖，促进G1/S阻滞在p53依赖的方式。相比之下，具有白内障致病突变的HSF 4不能引起细胞周期停滞，并且对细胞增殖没有明显影响。我们进一步确定HSF 4在细胞核中募集p53并促进其转录活性，导致其靶基因p21在HLEC中表达。HSF 4，而不是其引起白内障的突变体，稳定p53蛋白并抑制其泛素降解。我们的数据显示，HSF 4可能作为透镜上皮细胞增殖和次级纤维细胞分化之间的开关，这一过程主要取决于p53。通过对HSF 4下游通路的研究，我们的研究结果有助于揭示HSF 4突变引起的致病机制。(C)2015 Elsevier B. V.版权所有。
The differentiation from constantly dividing epithelial cells into secondary fiber cells is a key step during lens development. Failure in this process, which requires cell proliferation inhibition and cell cycle exit, causes cataract formation. HSF4 (Heat Shock Transcription Factor 4) gene mutations may lead to both congenital and senile cataract. However, how HSF4 mutations induce cataract formation remains obscure. In this study, we demonstrate that HSF4 can suppress the proliferation of human lens epithelial cells (HLECs) by promoting G1/S arrest in a p53-dependent manner. In contrast, HSF4 with cataract causative mutations fail to cause cell cycle arrest and have no obvious effect on cell proliferation. We further identify that HSF4 recruits p53 in the nucleus and promotes its transcriptional activity, leading to the expression of its target gene p21 in HLECs. HSF4, but not its cataract-causing mutants, stabilizes p53 protein and inhibits its ubiquitin degradation. Our data reveal that HSF4 may work as a switch between lens epithelial cell proliferation and secondary fiber cell differentiation, a process which mainly depends on p53. Through demonstration of this novel downstream pathway of HSF4, our results help uncover the pathogenic mechanisms caused by HSF4 mutations. (C) 2015 Elsevier B.V. All rights reserved.