Aggregates of oxidized proteins (lipofuscin) induce apoptosis through proteasome inhibition and dysregulation of proapoptotic proteins
Aggregates of oxidized proteins (lipofuscin) induce apoptosis through proteasome inhibition and dysregulation of proapoptotic proteins
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DOI：
10.1016/j.freeradbiomed.2005.01.003
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发表时间：
2005-04-15
影响因子：
7.4
通讯作者：
Katzeff, H
中科院分区：
文献类型：
--
作者：
Powell, SR;Wang, P;Katzeff, H
细胞衰老可能伴随着氧化蛋白（也称为脂褐素）的大量聚集。脂褐素样物质（LIP）的细胞积累导致细胞死亡的假设是蛋白酶体抑制的结果。用合成的LIP孵育大鼠新生心肌细胞长达48小时。这伴随着细胞自身荧光的增加（48小时增加207%，p < 0.05）和LIP颗粒内化的电镜证据。LIP孵育导致细胞凋亡，48 h后细胞活力下降46% （p < 0.05）。虽然20S-蛋白酶体活性在6 h后提高了74%，但20S-和26s -蛋白酶体活性在48 h后均下降（分别为-54% （p < 0.05）和-50%），并伴有泛素化蛋白的大量增加。几个蛋白酶体调节的促凋亡蛋白，包括c-Jun（2.9倍，p < 0.05）、Bax（1.8倍，p < 0.05）和p27(kip1)(3.2倍，p < 0.05)，在48 h后增加。对Bax和p27（kip1）泛素化同源物的观察表明，增加的部分原因是蛋白酶体对这些蛋白的降解减少。本研究的结果与以下结论一致：LIP的积累导致蛋白酶体的抑制，蛋白酶体由于几种促凋亡蛋白的失调而引发凋亡级联反应。(c) 2005爱思唯尔公司版权所有。
Cellular senescence may be accompanied by accumulation of large aggregates of oxidized proteins, also known as lipofuscin. The hypothesis that cellular accumulation of lipofuscin-like materials (LIP) results in cell death as a result of proteasome inhibition was examined. Rat neonatal cardiomyocytes were incubated with synthetic LIP for up to 48 h. This was accompanied by increases in cellular autofluorescence (207% by 48 h; p < 0.05) and electron microscopic evidence of internalization of LIP particles. LIP incubation resulted in loss of viability (-46% by 48 h; p < 0.05) through apoptotic cell death. Although 20S-proteasome activity was increased by 74% after 6 h, both 20S- and 26S-proteasome activities were decreased after 48 h of incubation (-54% (p < 0.05) and -50%, respectively), accompanied by large increases in ubiquitinated proteins. Several proteasome-regulated proapoptotic proteins, including c-Jun (2.9-fold; p < 0.05), Bax (1.8-fold; p < 0.05), and p27(kip1) (3.2-fold;p < 0.05), were observed to be increased by 48 h. Observation of ubiquitinated homologues of Bax and p27(kip1) suggested that part of the increase was due to decreased proteasomal degradation of these proteins. The results of this study are consistent with the conclusion that accumulation of LIP results in inhibition of the proteasome, which initiates an apoptotic cascade as a result of dysregulation of several proapoptotic proteins. (c) 2005 Elsevier Inc. All rights reserved.