Nongenomic activation of phosphatidylinositol 3-kinase signaling by thyroid hormone receptors.
Nongenomic activation of phosphatidylinositol 3-kinase signaling by thyroid hormone receptors.
复制标题
DOI：
10.1016/j.steroids.2008.10.009
复制
发表时间：
2009-07
期刊：
影响因子：
2.7
通讯作者：
Cheng, Sheue-Yann
中科院分区：
文献类型：
--
作者：
Furuya, Fumihiko;Lu, Changxue;Guigon, Celine J.;Cheng, Sheue-Yann
关键词：
甲状腺激素（T3）对于生长、发育、分化和代谢稳态的维持至关重要。最近的研究表明，甲状腺激素受体（TRs）不仅通过核启动转录介导T3的生物学活性，而且还可以通过非基因组途径发挥作用。携带显性阴性TRβ突变体的敲入突变小鼠（TRβPV/PV小鼠）表现出的甲状腺癌的显著表型允许阐明TRβ突变体（PV）通过核外作用的新致癌活性。PV与磷脂酰肌醇3-激酶（PI 3 K）的调节性p85α亚基发生物理相互作用，激活下游AKT-哺乳动物雷帕霉素靶蛋白（mTOR）和p70 S6 K和PI 3 K-整合素相关激酶-基质金属蛋白酶-2信号通路。PV介导的PI 3 K活化导致细胞增殖、运动、迁移和转移增加。值得注意的是，核受体辅阻遏物（NCoR）被发现通过与PV竞争结合p85α的C末端SH 2结构域来调节PV激活的PI 3 K信号传导。TRβPV/PV小鼠甲状腺肿瘤细胞中NCoR的过表达降低了AKT-mTOR-p70 S6 K信号传导。相反，通过siRNA敲低降低肿瘤细胞中的细胞NCoR导致过度活化的PI 3 K-AKT信号传导以增加细胞增殖和运动性。此外，甲状腺肿瘤细胞中的NCoR蛋白水平显著低于野生型甲状腺细胞，使PV与p85α更有效地结合以激活PI 3 K信号传导，从而促进肿瘤进展。因此，PV，一种apo-TRβ，可以通过直接的蛋白质-蛋白质相互作用来介导关键的致癌作用。这些研究还揭示了NCoR在调节突变TRβ控制甲状腺癌发生的非基因组作用中的新的核外作用。
Thyroid hormone (T3) is critical in growth, development, differentiation, and maintenance of metabolic homeostasis. Recent studies suggest that thyroid hormone receptors (TRs) not only mediate the biological activities of T3 via nucleus-initiated transcription, but also could act via nongenomic pathways. The striking phenotype of thyroid cancer exhibited by a knockin mutant mouse that harbors a dominant negative TRβ mutant (TRβPV/PV mouse) allows the elucidation of novel oncogenic activity of a TRβ mutant (PV) via extra-nuclear actions. PV physically interacts with the regulatory p85α subunit of phosphatidylinositol 3-kinase (PI3K) to activate the downstream AKT-mammalian target of rapamycin (mTOR) and p70S6K and PI3K-integrin-linked kinase-matrix metalloproteinase-2 signaling pathways. The PV-mediated PI3K activation results in increased cell proliferation, motility, migration, and metastasis. Remarkably, a nuclear receptor corepressor (NCoR) was found to regulate the PV-activated PI3K signaling by competing with PV for binding to the C-terminal SH2 domain of p85α. Overexpression of NCoR in thyroid tumor cells of TRβPV/PV mice reduces AKT-mTOR- p70S6K signaling. Conversely, lowering cellular NCoR by siRNA knockdown in tumor cells leads to over-activated PI3K-AKT signaling to increase cell proliferation and motility. Furthermore, NCoR protein levels are significantly lower in thyroid tumor cells than in wild type thyrocytes, allowing more effective binding of PV to p85α to activate PI3K signaling, thereby contributing to tumor progression. Thus, PV, an apo-TRβ, could act via direct protein-protein interaction to mediate critical oncogenic actions. These studies also uncovered a novel extra-nuclear role of NCoR in modulating the nongenomic actions of a mutated TRβ in controlling thyroid carcinogenesis.
登录
查看更多内容
影响因子：
15.9
作者：
PARRILLA, R;MIXSON, AJ;WEINTRAUB, BD
通讯作者：
WEINTRAUB, BD
影响因子：
5.8
作者：
Liu, Zhi;Hou, Peng;Xing, Mingzhao
通讯作者：
Xing, Mingzhao
影响因子：
4.8
作者：
Pedram, Ali;Razandi, Mahnaz;Levin, Ellis R.
通讯作者：
Levin, Ellis R.
影响因子：
4.8
作者：
Kang, Q;Cao, Y;Zolkiewska, A
通讯作者：
Zolkiewska, A
影响因子：
--
作者：
MEIER, CA;DICKSTEIN, BM;WEINTRAUB, BD
通讯作者：
WEINTRAUB, BD