Knobloch Jürgen, Schmitz Ingo, Götz Katrin, Schulze-Osthoff Klaus, Rüther Ulrich
University of Cologne, Medical Clinic III, Department of Pneumology, Kerpener Strasse 62, D-50924 Cologne, Germany.
Mol Cell Biol. 2008 Jan;28(2):529-38. doi: 10.1128/MCB.00553-07.
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.
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，它也是一种致畸剂，会导致人类出现出生缺陷，如肢体截断和小眼畸形。沙利度胺导致的肢体截断是胚胎肢体发育过程中细胞死亡增加以及随之而来的肢体生长紊乱所致。我们在此证明，在原代人类胚胎细胞和鸡胚中，沙利度胺通过骨形态发生蛋白（Bmp）诱导的信号传导可保护活性PTEN不被蛋白酶体降解，从而导致Akt信号传导受到抑制。结果，半胱天冬酶依赖性细胞死亡通过内在和Fas死亡受体凋亡途径被刺激。最重要的是，鸡胚中沙利度胺诱导的肢体畸形和小眼畸形可以通过药理学PTEN抑制剂以及胰岛素（一种Akt信号传导的刺激剂）得到挽救。因此，我们得出结论，PTEN/Akt信号传导的扰动和半胱天冬酶活性的刺激是沙利度胺致畸作用的核心。
