Arsenite induces apoptosis of murine T lymphocytes through membrane raft-linked signaling for activation of c-Jun amino-terminal kinase
Arsenite induces apoptosis of murine T lymphocytes through membrane raft-linked signaling for activation of c-Jun amino-terminal kinase
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DOI：
10.4049/jimmunol.165.8.4290
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发表时间：
2000-10-15
影响因子：
4.4
通讯作者：
Nakashima, I
中科院分区：
文献类型：
--
作者：
Hossain, K;Akhand, AA;Nakashima, I
由于砷在急性毒性和癌症治疗中的双重作用，砷最近引起了人们的新关注。在这项研究中，我们报告亚砷酸钠诱导的信号级联从细胞表面到细胞核的小鼠胸腺T淋巴细胞，涉及膜筏作为初始信号转导。NaAsO 2通过DNA断裂、caspase激活、Bcl-2/Bax相互调节及膜电位降低诱导细胞凋亡。我们证明，NaAsO 2诱导的caspase激活依赖于姜黄素敏感的c-Jun氨基末端激酶，而几乎不依赖于SB 203580敏感的p38激酶或PD 98059敏感的细胞外信号调节激酶。此外，星形孢菌素严重抑制丝裂原活化蛋白（MAP）家族激酶和c-Jun的激活，部分阻断NaAsO 2介导的聚ADP核糖聚合酶（PARP）降解信号。NaAsO 2可能作为细胞内信号传导的起始细胞、表面事件，诱导GPI锚定蛋白Thy-1的聚集和超氧化物的产生。这种Thy-1聚集和随后的MAP家族激酶和c-Jun的激活以及由NaAsO 2诱导的PARP的降解都被DTT抑制，这表明砷和蛋白质巯基之间的相互作用对这些效应的要求。β-环糊精可以从膜筏上螯合胆固醇，抑制NaAsO 2诱导的蛋白质酪氨酸激酶和MAP家族激酶的激活、PARP的降解和超氧化物的产生。此外，β-环糊精分散了NaAsO 2诱导的Thy-1聚集，这些结果表明，膜筏完整性依赖的细胞表面事件是NaAsO 2诱导的蛋白酪氨酸激酶/c-Jun氨基-酪氨酸激酶的先决条件。末端激酶活化、超氧化物产生和下游半胱天冬酶活化。
Because of its dual roles in acute toxicity and in therapeutic application in cancer treatment, arsenic has recently attracted a renewed attention. In this study, we report NaAsO2-induced signal cascades from the cell surface to the nucleus of murine thymic T lymphocytes that involve membrane rafts as an initial signal transducer. NaAsO2 induced apoptosis through fragmentation of DNA, activation of caspase, and reciprocal regulation of Bcl-2/Bax with the concomitant reduction of membrane potential. We demonstrated that NaAsO2-induced caspase activation is dependent on curcumin-sensitive c-Jun amino-terminal kinase and barely dependent on SB203580-sensitive p38 kinase or PD98059-sensitive extracellular signal-regulated kinase, Additionally, staurosporine, which severely inhibited the activation of mitogen-activated protein (MAP) family kinases and c-Jun, partially blocked the NaAsO2-mediated signal for poly(ADP-ribose) polymerase (PARP) degradation Potentially as the initial cell, surface event for intracellular signaling, NaAsO2 induced aggregation of GPI-anchored protein Thy-1 and superoxide production. This Thy-1 aggregation and subsequent activation of MAP family kinase and c-Jun and the degradation of PARP induced by NaAsO2 were all inhibited by DTT, suggesting the requirement of interaction between arsenic and protein sulfhydryl groups for those effects. beta cyclodextrin, which sequestrates cholesterol from the membrane rafts, inhibited NaAsO2-induced activation of protein tyrosine kinases and MAP family kinases, degradation of PARP, and production of superoxide, In addition, beta cyclodextrin dispersed NaAsO2-induced Thy-1 clustering, These results suggest that a membrane raft integrity-dependent cell surface event is a prerequisite for NaAsO2-induced protein tyrosine kinase/c-Jun amino-terminal kinase activation, superoxide production, and downstream caspase activation.