Actin cytoskeletal function is spared, but apoptosis is increased, in WAS patient hematopoietic cells
Actin cytoskeletal function is spared, but apoptosis is increased, in WAS patient hematopoietic cells
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DOI：
10.1182/blood.v95.4.1283.004k44_1283_1292
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发表时间：
2000-02-15
期刊：
影响因子：
20.3
通讯作者：
Omann, GM
中科院分区：
文献类型：
--
作者：
Rengan, R;Ochs, HD;Omann, GM
Wiskott-Aldrich综合征蛋白（WASP）的突变已被假设为导致缺陷的肌动蛋白细胞骨架功能。这种肌动蛋白细胞骨架的功能障碍与Wiskott-Aldrich综合征（WAS）的发病机制有关。相反，它被发现，刺激肌动蛋白聚合是动力学正常的造血谱系中受影响的WAS。还发现WAS血小板中的肌动蛋白细胞骨架能够产生与活化相关的标志性细胞结构特征。进一步分析显示WAS淋巴细胞中的加速细胞死亡，如通过增加的半胱天冬酶-3活性所证明的。这种增加的活性导致这些细胞的加速凋亡。此外，使用细胞松弛素B抑制淋巴细胞中的肌动蛋白聚合并不加速这些细胞中的细胞凋亡。这表明在WAS淋巴细胞中观察到的加速的细胞凋亡并不继发于由WAS基因突变引起的肌动蛋白聚合的潜在缺陷。这些数据表明，WASP并没有发挥普遍的作用，在信号肌动蛋白聚合，但确实发挥作用，在延迟细胞死亡。因此，WAS基因突变的主要后果是加速淋巴细胞凋亡，可能是通过上调FAS介导的细胞死亡途径。这种加速的细胞凋亡可能最终导致在WAS中观察到的临床表现。(C)2000年，美国血液学会。
Mutations in the Wiskott-Aldrich syndrome protein (WASP) have been hypothesized to cause defective actin cytoskeletal function. This resultant dysfunction of the actin cytoskeleton has been implicated in the pathogenesis of Wiskott-Aldrich syndrome (WAS). In contrast, it was found that stimulated actin polymerization is kinetically normal in the hematopoietic lineages affected in WAS. It was also found that the actin cytoskeleton in WAS platelets is capable of producing the hallmark cytoarchitectural features associated with activation, Further analysis revealed accelerated cell death in WAS lymphocytes as evidenced by increased caspase-3 activity. This increased activity resulted in accelerated apoptosis of these cells. CD95 expression was also increased in these cells, suggesting an up-regulation in the FAS pathway in WAS lymphocytes, Additionally, inhibition of actin polymerization in lymphocytes using cytochalasin B did not accelerate apoptosis in these cells, This suggests that the accelerated apoptosis observed in WAS lymphocytes was not secondary to an underlying defect in actin polymerization caused by mutation of the WAS gene. These data indicate that WASP does not play a universal role in signaling actin polymerization, but does play a role in delaying cell death. Therefore, the principal consequence of mutations in the WAS gene is to accelerate lymphocyte apoptosis, potentially through upregulation of the FAS-mediated cell death pathway. This accelerated apoptosis may ultimately give rise to the clinical manifestations observed in WAS. (C) 2000 by The American Society of Hematology.