Activation of phosphatidylinositol 3-kinase signaling promotes aberrant pituitary growth in a mouse model of thyroid-stimulating hormone-secreting pituitary tumors.
Activation of phosphatidylinositol 3-kinase signaling promotes aberrant pituitary growth in a mouse model of thyroid-stimulating hormone-secreting pituitary tumors.
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DOI：
10.1210/en.2007-1696
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发表时间：
2008-07
期刊：
影响因子：
4.8
通讯作者：
Changxue Lu;M. Willingham;F. Furuya;S. Cheng
中科院分区：
文献类型：
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作者：
Changxue Lu;M. Willingham;F. Furuya;S. Cheng
促甲状腺激素分泌型垂体瘤（TSH-secreting pituitary tumors，TSHomas）是一种组成性分泌促甲状腺激素的垂体瘤。这种异常的分子机制在很大程度上是不确定的。我们最近创建了一个在甲状腺激素受体β基因中携带突变（表示为PV）的敲入突变小鼠（TRbeta（PV/PV）小鼠）。随着这些小鼠年龄的增长，它们自发地发展TSHoma。使用该小鼠模型，我们研究了磷脂酰肌醇3-激酶（PI 3 K）-AKT信号通路在TSHoma发病机制中的作用。与垂体的异常生长同时，AKT及其下游效应物哺乳动物靶向雷帕霉素和p70（S6 K）被激活，以促进细胞增殖和垂体生长。此外，AKT的激活通过抑制Bcl-2相关死亡启动子的促凋亡活性导致凋亡减少，进一步促进异常细胞增殖。这些结果表明，活化的PI 3 K-AKT通路可能强调肿瘤发生，提高了该通路可能成为TSHomas潜在治疗靶点的可能性。事实上，用PI 3 K特异性抑制剂LY 294002处理的TRbeta（PV/PV）小鼠显示出垂体生长的显著降低。LY 294002抑制了通过AKT-哺乳动物靶向雷帕霉素-p70（S6 K）和细胞周期蛋白D1/细胞周期蛋白依赖性激酶的促生长信号传导，并增加了Bcl-2相关死亡启动子的促凋亡活性。因此，PI 3 K-AKT通路的激活至少部分介导了异常垂体生长，并且该信号通路的干预为TSHoma提供了新的治疗机会。
TSH-secreting pituitary tumors (TSHomas) are pituitary tumors that constitutively secrete TSH. Molecular mechanisms underlying this abnormality are largely undefined. We recently created a knock-in mutant mouse harboring a mutation (denoted as PV) in the thyroid hormone receptor-beta gene (TRbeta(PV/PV) mouse). As these mice age, they spontaneously develop TSHomas. Using this mouse model, we investigated the role of the phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway in the pathogenesis of TSHomas. Concurrent with aberrant growth of pituitaries, AKT and its downstream effectors, mammalian target rapamycin and p70(S6K), were activated to contribute to increased cell proliferation and pituitary growth. In addition, activation of AKT led to decreased apoptosis by inhibiting proapoptotic activity of Bcl-2-associated death promoter, further contributing to the aberrant cell proliferation. These results suggest an activated PI3K-AKT pathway could underscore tumorigenesis, raising the possibility that this pathway could be a potential therapeutic target in TSHomas. Indeed, TRbeta(PV/PV) mice treated with a PI3K-specific inhibitor, LY294002, showed a significant decrease in pituitary growth. The progrowth signaling via AKT-mammalian target rapamycin-p70(S6K) and cyclin D1/cyclin-dependent kinase were inhibited, and proapoptotic activity of Bcl-2-associated death promoter was increased by LY294002 treatment. Thus, activation of the PI3K-AKT pathway mediates, at least in part, the aberrant pituitary growth, and the intervention of this signaling pathway presents a novel therapeutic opportunity for TSHomas.