Cell cycle-dependent regulation of FLIP levels and susceptibility to Fas-mediated apoptosis.
Cell cycle-dependent regulation of FLIP levels and susceptibility to Fas-mediated apoptosis.
复制标题
FLIP 水平的细胞周期依赖性调节和对 Fas 介导的细胞凋亡的易感性。
作者：
A. Algeciras;Thomas S. Griffith;D. H. Lynch;Carlos V. Paya
活化诱导的外周血T细胞死亡是Fas与Fas配体相互作用的结果。静息的外周T细胞对Fas诱导的细胞凋亡具有抗性，并且仅在其激活后才变得敏感。我们研究了TCR刺激后静息外周T细胞对Fas介导的凋亡的敏感性的分子机制。TCR活化降低FLIP（FLICE样抑制蛋白）的稳态蛋白水平，FLIP是Fas信号传导途径的抑制剂。通过加入可溶性HIV反式激活蛋白-FLIP嵌合体重建细胞内FLIP水平完全恢复TCR原代T细胞对Fas介导的凋亡的抗性。通过环孢菌素A抑制IL-2产生，或通过雷帕霉素或抗IL-2中和Ab抑制IL-2信号传导，可防止FLIP水平降低，并赋予T细胞活化后对Fas介导的细胞凋亡的抗性。使用细胞周期阻断剂，我们证明，活化的T细胞在G1期逮捕含有高水平的FLIP蛋白，而活化的T细胞在S期逮捕FLIP蛋白水平降低。这些发现将FLIP蛋白水平的调节与细胞周期进展联系起来，并为在细胞周期的S期观察到的TCR诱导的凋亡增加提供了解释。
Activation-induced cell death of peripheral T cells results from the interaction between Fas and Fas ligand. Resting peripheral T cells are resistant to Fas-induced apoptosis and become susceptible only after their activation. We have investigated the molecular mechanism mediating the sensitization of resting peripheral T cells to Fas-mediated apoptosis following TCR stimulation. TCR activation decreases the steady state protein levels of FLIP (FLICE-like inhibitory protein), an inhibitor of the Fas signaling pathway. Reconstitution of intracellular FLIP levels by the addition of a soluble HIV transactivator protein-FLIP chimera completely restores resistance to Fas-mediated apoptosis in TCR primary T cells. Inhibition of IL-2 production by cyclosporin A, or inhibition of IL-2 signaling by rapamycin or anti-IL-2 neutralizing Abs prevents the decrease in FLIP levels and confers resistance to Fas-mediated apoptosis following T cell activation. Using cell cycle-blocking agents, we demonstrate that activated T cells arrested in G1 phase contain high levels of FLIP protein, whereas activated T cells arrested in S phase have decreased FLIP protein levels. These findings link regulation of FLIP protein levels with cell cycle progression and provide an explanation for the increase in TCR-induced apoptosis observed during the S phase of the cell cycle.
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影响因子：
7.8
作者：
A. Chinnaiyan;Vishva M. Dixit
通讯作者：
A. Chinnaiyan;Vishva M. Dixit
影响因子：
32.4
作者：
SINGER, GG;ABBAS, AK
通讯作者：
ABBAS, AK
影响因子：
32.4
作者：
WILLERFORD, DM;CHEN, JZ;ALT, FW
通讯作者：
ALT, FW
DOI：
10.1073/pnas.94.20.10699
发表时间：
1997-09-30
影响因子：
11.1
作者：
Ezhevsky, SA;Nagahara, H;Dowdy, SF
通讯作者：
Dowdy, SF
自身免疫 lpr 和 gld 小鼠脾淋巴细胞凋亡异常。
DOI：
--
发表时间：
1995
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Reap,EA;Leslie,D;Abrahams,M;Eisenberg,RA;Cohen,PL
通讯作者：
Cohen,PL