The Nuclear Import of Oncoprotein Hepatitis B X-interacting Protein Depends on Interacting with c-Fos and Phosphorylation of Both Proteins in Breast Cancer Cells
The Nuclear Import of Oncoprotein Hepatitis B X-interacting Protein Depends on Interacting with c-Fos and Phosphorylation of Both Proteins in Breast Cancer Cells
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癌蛋白乙型肝炎 X 相互作用蛋白的核输入取决于乳腺癌细胞中与 c-Fos 的相互作用以及两种蛋白的磷酸化
DOI：
10.1074/jbc.m113.458638
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发表时间：
2013-05
影响因子：
4.8
通讯作者：
Liu, Qian
中科院分区：
文献类型：
--
作者：
Cai, Xiaoli;Shen, Yu;Shen, Yu;Shi, Hui;Shi, Hui;Li, Leilei;Li, Leilei;Liu, Qian;Liu, Qian
背景：癌蛋白HBXIP在肿瘤中作为转录因子的辅助激活因子。结果：HBXIP的核输入依赖于与c-Fos、atm介导的HBXIP磷酸化和p- erk1 /2介导的c-Fos磷酸化的相互作用。结论：HBXIP的核导入是与c-Fos合作的必要条件。意义：我们为HBXIP进入乳腺癌细胞细胞核的机制提供了新的见解。致癌转录因子和辅激活因子的异常核定位总是导致癌症的发展。我们报道了肿瘤蛋白乙型肝炎x相互作用蛋白（HBXIP）作为一种新的转录辅激活因子促进乳腺癌细胞的增殖和迁移。然而，调控HBXIP核进口的机制尚不清楚。在本研究中，我们发现HBXIP在体外和体内通过c-Fos的亮氨酸拉链结构域与它们相互作用。有趣的是，HBXIP（或c-Fos）的亮氨酸拉链突变体无法与c-Fos（或HBXIP）结合，导致HBXIP的核定位消失。此外，我们发现HBXIP的核输入是ERK1/2磷酸化c-Fos的Thr232、Thr325、Thr331和Ser374位点所必需的。此外，Ser108磷酸化位点的HBXIP突变体无法导入细胞核。引人注目的是，我们发现共济失调毛细血管扩张突变激酶（ATM）在Ser108位点磷酸化HBXIP。siRNA敲除ATM显著降低丝氨酸磷酸化水平，阻断HBXIP的核输入。然后，我们确定了ATM可以与HBXIP结合。此外，我们验证了HBXIP的核导入有助于其核功能。因此，我们得出结论，癌蛋白HBXIP的核输入需要通过亮氨酸拉链结构域与c-Fos相互作用，并在乳腺癌细胞中磷酸化这两种蛋白。因此，我们的研究结果为HBXIP核输入的机制提供了新的见解。在治疗上，阻断HBXIP的核输入在乳腺癌中是显著的。
Background: The oncoprotein HBXIP acts as a coactivator of transcription factor in cancer. Results: The nuclear import of HBXIP depends on interacting with c-Fos and ATM-mediated phosphorylation of HBXIP and p-ERK1/2-mediated phosphorylation of c-Fos. Conclusion: The nuclear import of HBXIP is required for collaboration with c-Fos. Significance: We provide new insights into the mechanism that HBXIP imports into the nucleus in breast cancer cells. Aberrant nuclear localization of oncogenic transcription factors and coactivators always leads to the development of cancer. We have reported that the oncoprotein hepatitis B X-interacting protein (HBXIP) acts as a novel transcriptional coactivator to promote proliferation and migration of breast cancer cells. However, the mechanism of regulating the nuclear import of HBXIP remains unclear. In the present study, we found that HBXIP interacted with c-Fos through their leucine zipper domains in vitro and in vivo. Interestingly, the leucine zipper mutant of HBXIP (or c-Fos) was unavailable to bind to c-Fos (or HBXIP), resulting in the disappearance of nuclear localization of HBXIP. Moreover, we revealed that the nuclear import of HBXIP was required for phosphorylation of c-Fos at Thr232, Thr325, Thr331, and Ser374 by ERK1/2. In addition, the mutant of HBXIP at the Ser108 phosphorylation site failed to import into the nucleus. Strikingly, we found that the kinase ataxia telangiectasia mutated (ATM) phosphorylated HBXIP at Ser108. The knockdown of ATM by siRNA remarkably decreased the levels of serine phosphorylation and blocked the nuclear import of HBXIP. Then, we identified that ATM could bind to HBXIP. Moreover, we validated that the nuclear import of HBXIP contributed to its nuclear function. Therefore, we conclude that the nuclear import of the oncoprotein HBXIP requires interaction with c-Fos through their leucine zipper domains and phosphorylation of both proteins in breast cancer cells. Thus, our findings provide new insights into the mechanism of the nuclear import of HBXIP. Therapeutically, the block of the nuclear import of HBXIP is significant in breast cancer.
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DOI：
10.1083/jcb.201004067
发表时间：
2010-11-29
期刊：
The Journal of cell biology
影响因子：
--
作者：
Rodríguez J;Calvo F;González JM;Casar B;Andrés V;Crespo P
通讯作者：
Crespo P
影响因子：
3.6
作者：
Wenjing Cui;Yiwen Zhang;Nan Hu;Changliang Shan;Shuai Zhang;Weiying Zhang;Xiao-dong Zhang;L. Ye
通讯作者：
Wenjing Cui;Yiwen Zhang;Nan Hu;Changliang Shan;Shuai Zhang;Weiying Zhang;Xiao-dong Zhang;L. Ye
影响因子：
16.1
作者：
Sang-Hyun Lee;M. Hannink
通讯作者：
Sang-Hyun Lee;M. Hannink
ATM-Snail 通路的激活促进乳腺癌转移。
影响因子：
5.5
作者：
Sun, Mianen;Guo, Xiaojing;Xu, Bo
通讯作者：
Xu, Bo
影响因子：
8
作者：
Belguise, K.;Milord, S.;Chalbos, D.
通讯作者：
Chalbos, D.