Inhibition of drug-induced Fas ligand transcription and apoptosis by Bcl-XL
Inhibition of drug-induced Fas ligand transcription and apoptosis by Bcl-XL
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DOI：
10.1023/a:1012203110027
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发表时间：
2001-01-01
影响因子：
4.3
通讯作者：
Srivastava, RK
中科院分区：
文献类型：
--
作者：
Biswas, RS;Cha, HJ;Srivastava, RK
Fas/Fas配体系统触发多种细胞类型的凋亡。Bcl-X-L过表达可拮抗Fas/Fas配体介导的细胞死亡。Bcl-X-L影响fas介导的细胞死亡的机制尚不清楚。我们发现微管损伤药物（如紫杉醇）以Fas/ fasl依赖的方式诱导细胞凋亡。抗FasL抗体、突变Fas或显性阴性FADD抑制Fas/FasL通路可阻断紫杉醇诱导的细胞凋亡。紫杉醇通过激活caspase-8和caspase-3诱导细胞凋亡。Bcl-X-L过表达可抑制紫杉醇诱导的FasL表达和细胞凋亡。Bcl-X-L通过抑制钙调磷酸酶的激活来阻止NFAT（活化T淋巴细胞的核因子）的核易位，钙调磷酸酶是一种钙依赖性磷酸酶，它必须使NFAT去磷酸化才能移动到细胞核。Bcl-X-L中的环域可以抑制Bcl-X-L的抗凋亡功能，可能是调控翻译后修饰的靶点。磷酸化后，Bcl-X-L失去了与钙调磷酸酶结合的能力。没有NFAT核易位，FasL基因不会被转录。因此，紫杉醇和其他干扰微管功能的药物至少在一定程度上通过诱导FasL杀死细胞，而bcl - x - l介导的对这些药物的耐药性与诱导FasL表达失败有关。
Fas/Fas ligand system triggers apoptosis in many cell types. Bcl-X-L overexpresion antagonizes Fas/Fas ligand-mediated cell death. The mechanism by which Bcl-X-L influences Fas-mediated cell death is unclear. We have found that microtubule-damaging drugs (e.g. Paclitaxel) induce apoptosis in a Fas/FasL-dependent manner. Inhibition of Fas/FasL pathway by anti-FasL antibody, mutant Fas or a dominant negative FADD blocks paclitaxel-induced apoptosis. Paclitaxel induced apoptosis through activation of both caspase-8 and caspase-3. Overexpression of Bcl-X-L leads to inhibition of paclitaxel-induced FasL expression and apoptosis. Bcl-X-L prevents the nuclear translocation of NFAT (nuclear factor of activated T lymphocytes) by inhibiting the activation of calcineurin, a calcium-dependent phosphatase that must dephosphorylate NFAT for it to move to the nucleus. The loop domain in Bcl-X-L can suppress the anti-apoptotic function of Bcl-X-L and may be a target for regulatory post-translational modifications. Upon phosphorylation, Bcl-X-L loses its ability to bind with calcineurin. Without NFAT nuclear translocation, the FasL gene is not transcribed. Thus, paclitaxel and other drugs that disturb microtubule function kill cells, at least in part, through the induction of FasL, and Bcl-X-L-mediated resistance to these agents is related to failure to induce FasL expression.