HBXIP, a binding protein of HBx, regulates maintenance of the G2/M phase checkpoint induced by DNA damage and enhances sensitivity to doxorubicin-induced cytotoxicity
HBXIP, a binding protein of HBx, regulates maintenance of the G2/M phase checkpoint induced by DNA damage and enhances sensitivity to doxorubicin-induced cytotoxicity
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DOI：
10.1080/15384101.2017.1281482
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发表时间：
2017-01-01
期刊：
影响因子：
4.3
通讯作者：
Wang, Fengze
中科院分区：
文献类型：
--
作者：
Fei, Hongrong;Zhou, Yunsheng;Wang, Fengze
为了保持基因组的完整性，细胞需要在完成细胞分裂之前检测和修复DNA损伤。B x相互作用蛋白（HBXIP）是乙型肝炎病毒x（Hepatitis B virus x protein，HBx）的结合蛋白，在人癌细胞中异常过表达，具有促进细胞增殖和抑制细胞凋亡的作用。本研究旨在探讨HBXIP在DNA损伤反应中的作用。我们的研究结果表明，HBXIP作为一个重要的调节G2/M检查点在响应DNA损伤。HBXIP敲低增加磷酸化组蛋白H2 AX表达和电离辐射（IR）治疗后的病灶形成。HBXIP调节DNA损伤后的ATM-Chk 2通路。HBXIP的消耗消除了IR诱导的G2/M细胞周期检查点，伴随着磷酸化Cdc 25 C、磷酸化Cdc 2（Tyr 15）和p27的表达降低。我们还发现，HBXIP表达下调使癌细胞对化疗敏感，这可以通过凋亡增加和caspase-3和caspase-9的裂解来证明。我们的数据表明，HBXIP可以作为DNA损伤反应信号的介导蛋白，激活G2/M检查点，以维持基因组完整性并防止细胞死亡。
To maintain the integrity of the genome, cells need to detect and repair DNA damage before they complete cell division. Hepatitis B x-interacting protein (HBXIP), a binding protein of HBx (Hepatitis B virus x protein), is aberrantly overexpressed in human cancer cells and show to promote cell proliferation and inhibit apoptosis. The present study is designed to investigate the role of HBXIP on the DNA damage response. Our results show that HBXIP acts as an important regulator of G2/M checkpoint in response to DNA damage. HBXIP knockdown increases phospho-histone H2AX expression and foci formation after treatment with ionizing radiation (IR). HBXIP regulates the ATM-Chk2 pathway following DNA damage. Depletion of HBXIP abrogates IR-induced G2/M cell cycle checkpoints, accompanying decrease the expression of phospho-Cdc25C, phospho-Cdc2 (Tyr15) and p27. We also show that downregulation of HBXIP expression sensitizes cancer cells to chemotherapy, as evidenced by an increase in apoptosis and cleavage of caspase-3 and caspase-9. Our data suggest that HBXIP can function as a mediator protein for DNA damage response signals to activate the G2/M checkpoint to maintain genome integrity and prevent cell death.