Aberrant accumulation of PTTG1 induced by a mutated thyroid hormone β receptor inhibits mitotic progression
Aberrant accumulation of PTTG1 induced by a mutated thyroid hormone β receptor inhibits mitotic progression
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DOI：
10.1172/jci28598
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发表时间：
2006-11-01
影响因子：
15.9
通讯作者：
Cheng, Sheue-yann
中科院分区：
文献类型：
--
作者：
Ying, Hao;Furuya, Fumihiko;Cheng, Sheue-yann
垂体肿瘤转化蛋白1（PTTG 1）的过度表达与甲状腺癌相关。我们在滤泡性甲状腺癌小鼠模型（TR β（PV/PV）小鼠）的甲状腺肿瘤中发现PTTG 1水平升高。在这里，我们研究了PTTG 1水平升高的分子机制，以及PTTG 1增加对甲状腺癌发生的贡献。我们发现，PTTG I与甲状腺激素0受体（TR β）及其突变体PV有物理联系。伴随甲状腺激素诱导的TR β降解，PTTG 1蛋白被蛋白酶体机制降解，但当PTTG 1与PV相关时，没有发生这种降解。PTTG 1/TRP的降解通过配体TR β与类固醇受体辅激活因子3（SRC-3）的直接相互作用而被激活，所述类固醇受体辅激活因子3招募蛋白酶体激活因子PA 28 γ。PV不结合T3，不能直接与SRC-3/PA 28 γ相互作用以激活蛋白酶体降解，导致PTTG 1水平升高。在表达PV的细胞中，积累的PTTG 1阻碍有丝分裂进程。我们的研究结果揭示了我们认为是一种新的机制，通过这种机制，PTTG 1是一种癌基因，由配体TR β调节。PV中这种调节功能的丧失导致PTTG 1的异常积累，破坏有丝分裂进程，这可能有助于甲状腺癌的发生。
Overexpression of pituitary tumor-transforming 1 (PTTG1) is associated with thyroid cancer. We found elevated PTTG 1 levels in the thyroid tumors of a mouse model of follicular thyroid carcinoma (TR beta(PV/PV) mice). Here we examined the molecular mechanisms underlying elevated PTTG1 levels and the contribution of increased PTTG1 to thyroid carcinogenesis. We showed that PTTG I was physically associated with thyroid hormone 0 receptor (TR beta) as well as its mutant, designated PV. Concomitant with thyroid hormone-induced (T3-induced) degradation of TR beta, PTTG1 proteins were degraded by the proteasomal machinery, but no such degradation occurred when PTTG1 was associated with PV. The degradation of PTTG1/TRP was activated by the direct interaction of the liganded TR beta with steroid receptor coactivator 3 (SRC-3), which recruits proteasome activator PA28 gamma. PV, which does not bind T3, could not interact directly with SRC-3/PA28 gamma to activate proteasome degradation, resulting in elevated PTTG1 levels. The accumulated PTTG1 impeded mitotic progression in cells expressing PV. Our results unveil what we believe to be a novel mechanism by which PTTG1, an oncogene, is regulated by the liganded TR beta. The loss of this regulatory function in PV led to an aberrant accumulation of PTTG1 disrupting mitotic progression that could contribute to thyroid carcinogenesis.