Identification of a unique core domain of par-4 sufficient for selective apoptosis induction in cancer cells
Identification of a unique core domain of par-4 sufficient for selective apoptosis induction in cancer cells
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DOI：
10.1128/mcb.23.16.5516-5525.2003
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发表时间：
2003-08-01
影响因子：
5.3
通讯作者：
Rangnekar, VM
中科院分区：
文献类型：
--
作者：
El-Guendy, N;Zhao, YM;Rangnekar, VM
最近的研究表明，亮氨酸拉链结构域蛋白PAR-4通过激活Fas死亡前通路和同时抑制NF-kappaB转录活性来诱导某些癌细胞的凋亡。然而，参与细胞凋亡的PAR-4在细胞内的定位或功能域仍不清楚。在本研究中，结构-功能分析表明，抑制NF-kappaB活性和细胞凋亡依赖于PAR-4通过二分核定位序列NLS2转位到细胞核。对PAR-4诱导的细胞凋亡具有抵抗力的癌细胞将PAR-4保留在细胞质中。有趣的是，一个包含NLS2而不是C端亮氨酸拉链结构域的59个氨基酸的核心是诱导Fas途径激活、抑制NF-kappaB活性和细胞凋亡的必要条件和充分条件。最重要的是，这个核心区扩大了诱导凋亡的靶点范围，延伸到先前耐药的癌细胞，但不包括正常细胞。这些发现已经确定了一个独特的选择性诱导癌细胞凋亡的死亡诱导结构域(SAC结构域)，它有望识别癌症和正常细胞之间的关键差异，并用于癌症的分子治疗。
Recent studies indicated that the leucine zipper domain protein Par-4 induces apoptosis in certain cancer cells by activation of the Fas prodeath pathway and coparallel inhibition of NF-kappaB transcriptional activity. However, the intracellular localization or functional domains of Par-4 involved in apoptosis remained unknown. In the present study, structure-function analysis indicated that inhibition of NF-kappaB activity and apoptosis is dependent on Par-4 translocation to the nucleus via a bipartite nuclear localization sequence, NLS2. Cancer cells that were resistant to Par-4-induced apoptosis retained Par-4 in the cytoplasm. Interestingly, a 59-amino-acid core that included NLS2 but not the C-terminal leucine zipper domain was necessary and sufficient to induce Fas pathway activation, inhibition of NF-kappaB activity, and apoptosis. Most important, this core domain had an expanded target range for induction of apoptosis, extending to previously resistant cancer cells but not to normal cells. These findings have identified a unique death-inducing domain selective for apoptosis induction in cancer cells (SAC domain) which holds promise for identifying key differences between cancer and normal cells and for molecular therapy of cancer.