PI3K-PTEN dysregulation leads to mTOR-driven upregulation of the core clock gene BMAL1 in normal and malignant epithelial cells.
PI3K-PTEN dysregulation leads to mTOR-driven upregulation of the core clock gene BMAL1 in normal and malignant epithelial cells.
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DOI：
10.18632/oncotarget.9877
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发表时间：
2016-07-05
期刊：
影响因子：
--
通讯作者：
Squarize CH
中科院分区：
文献类型：
--
作者：
Matsumoto CS;Almeida LO;Guimarães DM;Martins MD;Papagerakis P;Papagerakis S;Leopoldino AM;Castilho RM;Squarize CH
在各种病理条件下观察到功能失调的时钟信号传导。时钟基因家族的许多成员在肿瘤细胞中上调。在这里，我们探讨了头颈癌中一种常见的信号通路被破坏对生物钟基因调节的影响。PTEN是PI3K信号传导的关键分子控制器，并且在多种癌症中经常观察到PTEN功能的丧失。我们的主要目标是确定PTEN是否调节生物钟信号。我们发现，氧化驱动的PTEN功能丧失导致mTOR信号传导的激活和核心时钟蛋白BMAL1（也称为ARNTL）的激活。使用靶向PTEN的小干扰RNA和从表皮中的PTEN的体内条件性消耗进一步证实了PTEN诱导的BMAL1上调。我们观察到，PTEN驱动的BMAL1积累是mTOR介导的，并且给予雷帕霉素（一种特异性mTOR抑制剂）导致BMAL1正常水平的体内拯救。在体内施用mTOR抑制剂后，通过缺失PER2（周期家族基因）也挽救了BMAL1的积累。值得注意的是，BMAL1调节需要mTOR调节蛋白Raptor和Rictor。这些发现表明mTORC 1和mTORC 2复合物在控制BMAL 1中起关键作用，建立PI3K信号传导和昼夜节律调节之间的联系，最终导致PI3K信号传导中断的肿瘤细胞中BMAL 1失调。
Dysfunctional clock signaling is observed in a variety of pathological conditions. Many members of the clock gene family are upregulated in tumor cells. Here, we explored the consequences of a commonly disrupted signaling pathway in head and neck cancer on the regulation of circadian clock genes. PTEN is a key molecular controller of the PI3K signaling, and loss of PTEN function is often observed in a variety of cancers. Our main goal was to determine whether PTEN regulates circadian clock signaling. We found that oxidation-driven loss of PTEN function resulted in the activation of mTOR signaling and activation of the core clock protein BMAL1 (also known as ARNTL). The PTEN-induced BMAL1 upregulation was further confirmed using small interference RNA targeting PTEN, and in vivo conditional depletion of PTEN from the epidermis. We observed that PTEN-driven accumulation of BMAL1 was mTOR-mediated and that administration of Rapamycin, a specific mTOR inhibitor, resulted in in vivo rescue of normal levels of BMAL1. Accumulation of BMAL1 by deletion of PER2, a Period family gene, was also rescued upon in vivo administration of mTOR inhibitor. Notably, BMAL1 regulation requires mTOR regulatory protein Raptor and Rictor. These findings indicate that mTORC1 and mTORC2 complex plays a critical role in controlling BMAL1, establishing a connection between PI3K signaling and the regulation of circadian rhythm, ultimately resulting in deregulated BMAL1 in tumor cells with disrupted PI3K signaling.
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DOI：
10.1002/hed.10274
发表时间：
2003-08-01
影响因子：
2.9
作者：
Bradford, CR;Zhu, SB;Carey, TE
通讯作者：
Carey, TE
影响因子：
4.7
作者：
Chen, ST;Choo, KB;Chang, JG
通讯作者：
Chang, JG
影响因子：
6.6
作者：
Alvarez-Nuñez, F;Bussaglia, E;Matias-Guju, X
通讯作者：
Matias-Guju, X
夜间暴露在光线下造成的昼夜节律和褪黑激素的破坏会导致乳腺癌对他莫昔芬治疗产生内在耐药性。
影响因子：
11.2
作者：
Dauchy RT;Xiang S;Mao L;Brimer S;Wren MA;Yuan L;Anbalagan M;Hauch A;Frasch T;Rowan BG;Blask DE;Hill SM
通讯作者：
Hill SM
影响因子：
3.7
作者：
Castilho RM;Squarize CH;Leelahavanichkul K;Zheng Y;Bugge T;Gutkind JS
通讯作者：
Gutkind JS