Thalidomide Induces Limb Anomalies by PTEN Stabilization, Akt Suppression, and Stimulation of Caspase-Dependent Cell Death
Thalidomide Induces Limb Anomalies by PTEN Stabilization, Akt Suppression, and Stimulation of Caspase-Dependent Cell Death
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DOI：
10.1128/mcb.00553-07
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发表时间：
2007-11
影响因子：
5.3
通讯作者：
J. Knobloch;I. Schmitz;Katrin Götz;K. Schulze-Osthoff;U. Rüther
中科院分区：
文献类型：
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作者：
J. Knobloch;I. Schmitz;Katrin Götz;K. Schulze-Osthoff;U. Rüther
沙利度胺是一种用于治疗多发性骨髓瘤和炎症性疾病的药物，也是一种致畸剂，可导致人类的出生缺陷，如肢体截断和小眼球。沙利度胺诱导的肢体截短是由于胚胎肢体发育过程中细胞死亡增加和随后肢体生长障碍所致。在这里，我们证明了在原代人胚胎细胞和鸡胚胎中，沙利度胺诱导的信号通过骨形态发生蛋白（Bmps）保护活性PTEN蛋白酶体降解，导致Akt信号的抑制。因此，半胱天冬酶依赖性细胞死亡是由内在和Fas死亡受体凋亡途径刺激的。最重要的是，沙利度胺诱导的鸡胚肢体畸形和小眼畸形可以通过药理学的PTEN抑制剂以及胰岛素（Akt信号的刺激剂）来挽救。因此，我们得出结论，干扰PTEN/Akt信号和刺激caspase活性是沙利度胺致畸作用的核心。
ABSTRACT Thalidomide, a drug used for the treatment of multiple myeloma and inflammatory diseases, is also a teratogen that causes birth defects, such as limb truncations and microphthalmia, in humans. Thalidomide-induced limb truncations result from increased cell death during embryonic limb development and consequential disturbance of limb outgrowth. Here we demonstrate in primary human embryonic cells and in the chicken embryo that thalidomide-induced signaling through bone morphogenetic proteins (Bmps) protects active PTEN from proteasomal degradation, resulting in suppression of Akt signaling. As a consequence, caspase-dependent cell death is stimulated by the intrinsic and Fas death receptor apoptotic pathway. Most importantly, thalidomide-induced limb deformities and microphthalmia in chicken embryos could be rescued by a pharmacological PTEN inhibitor as well as by insulin, a stimulant of Akt signaling. We therefore conclude that perturbation of PTEN/Akt signaling and stimulation of caspase activity is central to the teratogenic effects of thalidomide.