Okada Hitoshi, Bakal Chris, Shahinian Arda, Elia Andrew, Wakeham Andrew, Suh Woong-Kyung, Duncan Gordon S, Ciofani Maria, Rottapel Robert, Zúñiga-Pflücker Juan Carlos, Mak Tak W
Advanced Medical Discovery Institute, University of Toronto, 620 University Avenue, Suite 706, Ontario M5G 2C1, Canada.
J Exp Med. 2004 Feb 2;199(3):399-410. doi: 10.1084/jem.20032092.
Because survivin-null embryos die at an early embryonic stage, the role of survivin in thymocyte development is unknown. We have investigated the role by deleting the survivin gene only in the T lineage and show here that loss of survivin blocks the transition from CD4- CD8- double negative (DN) thymocytes to CD4+ CD8+ double positive cells. Although the pre-T cell receptor signaling pathway is intact in survivin-deficient thymocytes, the cells cannot respond to its signals. In response to proliferative stimuli, cycling survivin-deficient DN cells exhibit cell cycle arrest, a spindle formation defect, and increased cell death. Strikingly, loss of survivin activates the tumor suppressor p53. However, the developmental defects caused by survivin deficiency cannot be rescued by p53 inactivation or introduction of Bcl-2. These lines of evidence indicate that developing thymocytes depend on the cytoprotective function of survivin and that this function is tightly coupled to cell proliferation but independent of p53 and Bcl-2. Thus, survivin plays a critical role in early thymocyte development.
由于Survivin基因缺失的胚胎在胚胎早期就会死亡，因此Survivin在胸腺细胞发育中的作用尚不清楚。我们通过仅在T细胞谱系中删除Survivin基因来研究其作用，结果表明Survivin的缺失会阻断从CD4-CD8-双阴性（DN）胸腺细胞到CD4+CD8+双阳性细胞的转变。尽管前T细胞受体信号通路在Survivin缺陷的胸腺细胞中是完整的，但这些细胞无法对其信号作出反应。在增殖刺激下，处于细胞周期的Survivin缺陷型DN细胞表现出细胞周期停滞、纺锤体形成缺陷和细胞死亡增加。引人注目的是，Survivin的缺失会激活肿瘤抑制因子p53。然而，p53失活或引入Bcl-2并不能挽救Survivin缺陷导致的发育缺陷。这些证据表明，发育中的胸腺细胞依赖于Survivin的细胞保护功能，并且该功能与细胞增殖紧密相关，但独立于p53和Bcl-2。因此，Survivin在胸腺细胞早期发育中起着关键作用。
