Cooperative Phosphorylation of FADD by Aur-A and Plk1 in Response to Taxol Triggers Both Apoptotic and Necrotic Cell Death

被引:40
作者
Jang, Moon-Sun [1 ]
Lee, Su-Jin [1 ]
Kang, Nam Sook [2 ]
Kim, Eunhee [1 ,2 ,3 ]
机构
[1] Chungnam Natl Univ, Coll Biol Sci & Biotechnol, Taejon, South Korea
[2] Chungnam Natl Univ, Grad Sch New Drug Discovery & Dev, Taejon, South Korea
[3] Chungnam Natl Univ, Daedeok R&D Innopolis Bio Brain Ctr BK21, Taejon, South Korea
基金
新加坡国家研究基金会;
关键词
POLO-LIKE KINASE; CANCER-CELLS; DOMAIN; PACLITAXEL; PROTEIN; FAS; OVEREXPRESSION; LOCALIZATION; CONTRIBUTES; SENSITIVITY;
D O I
10.1158/0008-5472.CAN-11-0760
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Administration of the antimitotic chemotherapeutic taxol is known to cause accumulation of the mitotic kinase Aurora-A (Aur-A). Here, we report that Aur-A phosphorylates S203 of the Fas associated with death domain protein (FADD) in response to taxol treatment. In addition, polo-like kinase 1 (Plk1) failed to phosphorylate the Aur-A-unphosphorylatable FADD substitution mutant S203A, indicating that phosphorylation of S203 by Aur-A serves to prime FADD for Plk1-mediated phosphorylation at S194. The double-phosphorylation- mimicking mutant form of FADD, FADD-S194D/S203D (FADD-DD), recruited caspase-8, activating the caspase-dependent cell death pathway. FADD-DD also dissociated the cell death protein RIP1 from FADD, resulting in activation of RIP1 and triggering of caspase-independent cell death. Consistent with its death-promoting potential, FADD-DD showed robust tumor suppressor activity. However, single-phosphorylation-mimicking mutant forms of FADD, FADD-S194D/S203A (FADD-DA) and FADD-S194A/S203D (FADD-AD), were incapable of carrying out such functions, indicating that double phosphorylation of FADD is critical for the execution of cell death and tumor suppression. Collectively, our data show the existence of cooperative actions between Aur-A and Plk1 mitotic kinases in response to taxol, providing a molecular explanation for the action mechanism of taxol. Cancer Res; 71(23); 7207-15. (C) 2011 AACR.
引用
收藏
页码:7207 / 7215
页数:9
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