XIAP: Apoptotic brake and promising therapeutic target
XIAP: Apoptotic brake and promising therapeutic target
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DOI：
10.1023/a:1011379307472
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发表时间：
2001-01-01
期刊：
影响因子：
7.2
通讯作者：
Korneluk, RG
中科院分区：
文献类型：
--
作者：
Holcik, M;Gibson, H;Korneluk, RG
X 连锁细胞凋亡抑制剂 (XIAP) 是新发现的内在细胞凋亡抑制剂 (IAP) 蛋白家族的关键成员。 IAP 通过抑制不同的半胱天冬酶在体外和体内阻断细胞死亡。尽管已鉴定出其他抑制上游半胱天冬酶的蛋白质，但只有 IAP 已被证明是末端半胱天冬酶级联的内源性阻遏物。反过来，XIAP 的 caspase 抑制活性受到至少两种 XIAP 相互作用蛋白 XAF1 和 Smac/DIABLO 的负调节。除了抑制半胱天冬酶外，几个实验室最近的发现表明，XIAP 还参与许多其他具有生物学意义的细胞活动，包括调节受体介导的信号转导和蛋白质泛素化。 XIAP 还通过一种罕见的帽独立机制进行翻译，该机制由称为 IRES（内部核糖体进入位点）的特定序列介导，该序列存在于 XIAP 5(') UTR 中。因此，XIAP蛋白在各种细胞应激条件下合成，例如血清饥饿和低剂量γ-辐射诱导的细胞凋亡，这些条件导致细胞蛋白合成受到抑制。 XIAP 的多种生物活性、其独特的翻译和翻译后控制以及 caspase 级联的中心地位使得 XIAP 表达的控制成为调节细胞凋亡的非常有前途的分子靶点。治疗益处可以来源于抑制不适当的细胞死亡，例如在神经退行性疾病和缺血性损伤中，或激活潜在的细胞死亡途径，例如在自身免疫性疾病和癌症中，其中细胞凋亡诱导是期望的结果。
The X-linked Inhibitor of Apoptosis, XIAP, is a key member of the newly discovered family of intrinsic inhibitors of apoptosis (IAP) proteins. IAPs block cell death both in vitro and in vivo by virtue of inhibition of distinct caspases. Although other proteins have been identified which inhibit upstream caspases, only the IAPs have been demonstrated to be endogenous repressors of the terminal caspase cascade. In turn, the caspase inhibiting activity of XIAP is negatively regulated by at least two XIAP-interacting proteins, XAF1 and Smac/DIABLO. In addition to the inhibition of caspases, recent discoveries from several laboratories suggest that XIAP is also involved in a number of other biologically significant cellular activities including modulation of receptor-mediated signal transduction and protein ubiquitination. XIAP is also translated by a rare cap-independent mechanism mediated by a specific sequence called IRES (for Internal Ribosome Entry Site) which is found in the XIAP 5(') UTR. XIAP protein is thus synthesized under various conditions of cellular stress such as serum starvation and low dose gamma -irradiation induced apoptosis, conditions that lead to the inhibition of cellular protein synthesis. The multiple biological activities of XIAP, its unique translational and post-translational control and the centrality of the caspase cascade make the control of XIAP expression an exceptionally promising molecular target for modulating apoptosis. Therapeutic benefits can be derived from both the suppression of inappropriate cell death such as in neurodegenerative disorders and ischemic injury or in the activation of latent cell death pathways such as in autoimmune disease and cancer where apoptosis induction is the desired outcome.