The p75NTR tumor suppressor induces cell cycle arrest facilitating caspase mediated apoptosis in prostate tumor cells
The p75NTR tumor suppressor induces cell cycle arrest facilitating caspase mediated apoptosis in prostate tumor cells
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DOI：
10.1016/j.bbrc.2006.01.073
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发表时间：
2006-03-24
影响因子：
3.1
通讯作者：
Djakiew, DL
中科院分区：
文献类型：
--
作者：
Khwaja, F;Tabassum, A;Djakiew, DL
p75神经营养因子受体（p75（NTR））是一种死亡受体，属于膜蛋白肿瘤坏死因子受体超家族。这项研究表明，p75（NTR）通过诱导细胞在GO/GI中的积累和细胞周期S期的减少来延缓细胞周期进程。通过p75的死亡结构域缺失（ADD）显性负性拮抗剂（NTR）从细胞周期进展中拯救肿瘤细胞，表明死亡结构域以配体非依赖性方式转导抗增殖活性。相反，另外的NGF配体挽救了细胞周期进展的阻滞，细胞周期蛋白/cdk全酶复合物的组分发生了相应的变化。在配体的情况下，p75（NTR）依赖性细胞周期阻滞促进前列腺癌细胞凋亡核碎片的增加。p75（NTR）表达细胞的凋亡发生通过内在的线粒体途径，导致一个连续的半胱天冬酶-9和-7级联。由于p75的死亡结构域缺失的显性负性拮抗剂（NTR）拯救了PC-3细胞中内在的半胱天冬酶相关的凋亡，这表明p75（NTR）对于配体非依赖性凋亡诱导是不可或缺的。此外，配体改善p75（NTR）依赖性内在凋亡级联反应的能力表明，NGF作为表达p75（NTR）的前列腺癌细胞的存活因子发挥作用。(c)2006年爱思唯尔公司All rights reserved.
The p75 neurotrophin receptor (p75(NTR)) is a death receptor which belongs to the tumor necrosis factor receptor super-family of membrane proteins. This study shows that p75(NTR) retarded cell cycle progression by induced accumulation of cells in GO/GI and a reduction in the S phase of the cell cycle. The rescue of tumor cells from cell cycle progression by a death domain deleted (ADD) dominant-negative antagonist of p75(NTR) showed that the death domain transduced anti-proliferative activity in a ligand-independent manner. Conversely, addition of NGF ligand rescued retardation of cell cycle progression with commensurate changes in components of the cyclin/cdk holoenzyme complex. In the absence of ligand, p75(NTR)-dependent cell cycle arrest facilitated an increase in apoptotic nuclear fragmentation of the prostate cancer cells. Apoptosis of p75(NTR) expressing cells occurred via the intrinsic mitochondrial pathway leading to a sequential caspase-9 and -7 cascade. Since the death domain deleted dominant-negative antagonist of p75(NTR) rescued intrinsic caspase associated apoptosis in PC-3 cells, this shows p75(NTR) was integral to ligand independent induction of apoptosis. Moreover, the ability of ligand to ameliorate the p75(NTR)-dependent intrinsic apoptotic cascade indicates that NGF functioned as a survival factor for p75(NTR) expressing prostate cancer cells. (c) 2006 Elsevier Inc. All rights reserved.