The neuronal apoptosis inhibitory protein suppresses neuronal differentiation and apoptosis in PC12 cells
The neuronal apoptosis inhibitory protein suppresses neuronal differentiation and apoptosis in PC12 cells
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DOI：
10.1093/hmg/9.17.2479
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发表时间：
2000-10-12
影响因子：
3.5
通讯作者：
Sendtner, M
中科院分区：
文献类型：
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作者：
Götz, R;Karch, C;Sendtner, M
人神经元凋亡抑制蛋白（NAIP）基因已被发现为脊髓性肌萎缩症的候选基因，脊髓性肌萎缩症是一种以脊髓运动神经元缺失为特征的遗传性疾病。人5号染色体上的端粒NAIP基因在许多最严重形式的疾病NAIP，c-IAP 1的情况下与存活运动神经元（SMN）一起缺失。（骨化抑制剂-1），c-IAP 2，X-IAP，存活素和Apollon包含细胞凋亡家族的哺乳动物抑制剂，并含有N-末端结构域，3个不完全重复的类似于65个氨基酸的结构域，命名为杆状病毒IAP重复（BIR）基序。我们在小鼠基因组中鉴定了6个NAIP基因，发现它们在广泛的组织中表达。我们研究了NAIP在大鼠嗜铬细胞瘤PC 12细胞系中的作用，这些细胞在神经生长因子（NGF）存在下分化成类似交感神经元的细胞，我们观察到NAIP过表达损害了NGF诱导的神经突生长，NAIP的BIR基序（残基1-345）对于该效应不是必需的。然而，NAIP的BIR结构域对于在NGF剥夺或TNF-α受体刺激后防止PC 12细胞中的凋亡是必需的。全长NAIP的表达而非BIR缺失的NAIP的表达防止细胞死亡。这与NAIP-PC 12细胞裂解物中细胞死亡效应蛋白酶半胱天冬酶-3的活性降低相关，如通过荧光四肽底物Asp-Glu-Val-Asp的切割所测量的。因此，细胞分化的失调和/或半胱天冬酶抑制可能导致NAIP突变的脊髓性肌萎缩中的运动神经元功能障碍和细胞死亡。
The human neuronal apoptosis inhibitory protein (NAIP) gene has been discovered as a candidate gene for spinal muscular atrophy, a genetic disorder characterized by motor neuron loss in the spinal cord. The telomeric NAIP gene on human chromosome 5 is deleted together with survival motor neurons (SMN) in many cases of the most severe forms of the disorder, NAIP, c-IAP1 (inhibitor of apoptosis-l), c-IAP2, X-IAP, survivin and Apollon comprise the mammalian inhibitors of the apoptosis family and contain an N-terminal domain with 1-3 imperfect repeats of an similar to 65 amino acids domain named the baculovirus IAP repeat (BIR) motif, We identified six NAIP genes in the mouse genome which were found to be expressed in a broad range of tissues, Furthermore, we have investigated the effects of NAIP in the rat pheochromocytoma PC12 cell line, These cells differentiate in the presence of nerve growth factor (NGF) into cells that resemble sympathetic neurons, We observed that NAIP overexpression impaired NGF-induced neurite outgrowth, The BIR motifs of NAIP (residues 1-345) were not required for this effect. However, the BIR domains of NAIP were essential to prevent apoptosis in PC12 cells after NGF deprivation or TNF-alpha receptor stimulation, Expression of full-length but not BIR-deleted-NAIP protects against cell death. This correlates with reduced activity of the cell death effector protease, caspase-3, in lysates of NAIP-PC12 cells, as measured by cleavage of the fluorogenic tetrapeptide substrate Asp-Glu-Val-Asp, Thus, unregulation of cellular differentiation and/or caspase suppression may contribute to motoneuron dysfunction and cell death in spinal muscular atrophy where NAIP is mutated.