Vucic D, Stennicke H R, Pisabarro M T, Salvesen G S, Dixit V M
Department of Molecular Oncology, Genentech Incorporated, 1 DNA Way, San Francisco, California 94080, USA.
Curr Biol. 2000 Nov 2;10(21):1359-66. doi: 10.1016/s0960-9822(00)00781-8.
Inhibitors of apoptosis (IAPs) are a family of cell death inhibitors found in viruses and metazoans. All IAPs have at least one baculovirus IAP repeat (BIR) motif that is essential for their anti-apoptotic activity. IAPs physically interact with a variety of pro-apoptotic proteins and inhibit apoptosis induced by diverse stimuli. This allows them to function as sensors and inhibitors of death signals that emanate from a variety of pathways.
Here we report the characterization of ML-IAP, a novel human IAP that contains a single BIR and RING finger motif. ML-IAP is a powerful inhibitor of apoptosis induced by death receptors and chemotherapeutic agents, probably functioning as a direct inhibitor of downstream effector caspases. Modeling studies of the structure of the BIR domain revealed it to closely resemble the fold determined for the BIR2 domain of X-IAP. Deletion and mutational analysis demonstrated that integrity of the BIR domain was required for anti-apoptotic function. Tissue survey analysis showed expression in a number of embryonic tissues and tumor cell lines. In particular, the majority of melanoma cell lines expressed high levels of ML-IAP in contrast to primary melanocytes, which expressed undetectable levels. These melanoma cells were significantly more resistant to drug-induced apoptosis.
ML-IAP, a novel human IAP, inhibits apoptosis induced by death receptors and chemotherapeutic agents. The BIR of ML-IAP possesses an evolutionarily conserved fold that is necessary for anti-apoptotic activity. Elevated expression of ML-IAP renders melanoma cells resistant to apoptotic stimuli and thereby potentially contributes to the pathogenesis of this malignancy.
凋亡抑制蛋白（IAPs）是在病毒和后生动物中发现的一类细胞死亡抑制因子。所有IAPs都至少有一个杆状病毒IAP重复（BIR）基序，这对它们的抗凋亡活性至关重要。IAPs与多种促凋亡蛋白发生物理相互作用，并抑制由多种刺激诱导的细胞凋亡。这使得它们能够作为源自多种途径的死亡信号的传感器和抑制剂发挥作用。
在此我们报告了ML-IAP的特性，它是一种新型人类IAP，包含一个单一的BIR和环指基序。ML-IAP是死亡受体和化疗药物诱导的细胞凋亡的强力抑制剂，可能作为下游效应半胱天冬酶的直接抑制剂发挥作用。对BIR结构域的建模研究表明，它与X-IAP的BIR2结构域所确定的折叠结构非常相似。缺失和突变分析表明，BIR结构域的完整性是抗凋亡功能所必需的。组织调查分析显示，在许多胚胎组织和肿瘤细胞系中都有表达。特别是，与表达水平检测不到的原代黑素细胞相比，大多数黑色素瘤细胞系都高水平表达ML-IAP。这些黑色素瘤细胞对药物诱导的细胞凋亡具有显著更高的抗性。
ML-IAP是一种新型人类IAP，可抑制死亡受体和化疗药物诱导的细胞凋亡。ML-IAP的BIR具有一种进化上保守的折叠结构，这是抗凋亡活性所必需的。ML-IAP的高表达使黑色素瘤细胞对凋亡刺激产生抗性，从而可能促成这种恶性肿瘤的发病机制。
