The pleiotropic regulation of cyclin D1 by newly identified sesaminol-binding protein ANT2.
The pleiotropic regulation of cyclin D1 by newly identified sesaminol-binding protein ANT2.
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DOI：
10.1038/oncsis.2017.10
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发表时间：
2017-04-03
期刊：
影响因子：
6.2
通讯作者：
Sakai T
中科院分区：
文献类型：
--
作者：
Watanabe M;Iizumi Y;Sukeno M;Iizuka-Ohashi M;Sowa Y;Sakai T
细胞周期蛋白D1的表达在多种癌细胞中通过不同的机制上调，例如mRNA水平的增加、通过雷帕霉素复合物1（mTORC 1）信号传导的哺乳动物靶蛋白的翻译的促进和蛋白质稳定。我们在这里表明，芝麻酚，芝麻木脂素，减少细胞周期蛋白D1的表达，降低mRNA的表达水平，抑制mTORC 1信号和促进蛋白酶体降解。随后，我们产生了芝麻酚固定FG珠，以新确定芝麻酚结合蛋白。因此，我们发现腺嘌呤核苷酸转位酶2（ANT 2），线粒体内膜蛋白，直接绑定到芝麻酚。与芝麻胺醇的作用一致，ANT 2的耗竭导致细胞周期蛋白D1减少，其mRNA水平降低，mTORC 1抑制和其蛋白的蛋白酶体降解，表明芝麻胺醇负调节ANT 2的功能。此外，我们筛选了其他的ANT 2结合化合物，发现增殖物激活受体-γ激动剂曲格列酮也以多方面的方式降低细胞周期蛋白D1的表达，类似于芝麻胺醇治疗和ANT 2耗竭。因此，在本研究中使用的磁性FG珠的化学生物学方法显示，芝麻酚结合到ANT 2，这可能在mRNA水平和蛋白水平上多效性上调细胞周期蛋白D1的表达与mTORC 1激活和蛋白稳定。这些结果表明，ANT 2作为细胞周期蛋白D1过表达癌症的靶点的潜力。
The expression of cyclin D1 is upregulated in various cancer cells by diverse mechanisms, such as increases in mRNA levels, the promotion of the translation by mammalian target of rapamycin complex 1 (mTORC1) signaling and the protein stabilization. We here show that sesaminol, a sesame lignan, reduces the expression of cyclin D1 with decreasing mRNA expression levels, inhibiting mTORC1 signaling and promoting proteasomal degradation. We subsequently generated sesaminol-immobilized FG beads to newly identify sesaminol-binding proteins. As a consequence, we found that adenine nucleotide translocase 2 (ANT2), the inner mitochondrial membrane protein, directly bound to sesaminol. Consistent with the effects of sesaminol, the depletion of ANT2 caused a reduction in cyclin D1 with decreases in its mRNA levels, mTORC1 inhibition and the proteasomal degradation of its protein, suggesting that sesaminol negatively regulates the function of ANT2. Furthermore, we screened other ANT2-binding compounds and found that the proliferator-activated receptor-γ agonist troglitazone also reduced cyclin D1 expression in a multifaceted manner, analogous to that of the sesaminol treatment and ANT2 depletion. Therefore, the chemical biology approach using magnetic FG beads employed in the present study revealed that sesaminol bound to ANT2, which may pleiotropically upregulate cyclin D1 expression at the mRNA level and protein level with mTORC1 activation and protein stabilization. These results suggest the potential of ANT2 as a target against cyclin D1-overexpressing cancers.
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影响因子：
3.7
作者：
Iizumi Y;Oishi M;Taniguchi T;Goi W;Sowa Y;Sakai T
通讯作者：
Sakai T
影响因子：
3.8
作者：
Jang JY;Jeon YK;Kim CW
通讯作者：
Kim CW
影响因子：
5.7
作者：
Gao J;Wang Y;Xing Q;Yan J;Senthil M;Akmal Y;Kowolik CM;Kang J;Lu DM;Zhao M;Lin Z;Cheng CH;Yip ML;Yim JH
通讯作者：
Yim JH
影响因子：
3.6
作者：
Huang, JW;Shiau, CW;Chen, CS
通讯作者：
Chen, CS
DOI：
10.1186/bcr1857
发表时间：
2008
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Jang JY;Choi Y;Jeon YK;Kim CW
通讯作者：
Kim CW