Involvement of hTERT in apoptosis induced by interference with Bcl-2 expression and function
Involvement of hTERT in apoptosis induced by interference with Bcl-2 expression and function
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DOI：
10.1038/sj.cdd.4401670
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发表时间：
2005-11-01
影响因子：
12.4
通讯作者：
Biroccio, A
中科院分区：
文献类型：
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作者：
Del Bufalo, D;Rizzo, A;Biroccio, A
在这里，我们研究了端粒酶对Bcl-2依赖性细胞凋亡的作用。为此，使用了4625 Bcl-2/Bcl-x（L）双特异性反义寡核苷酸和HA 14 -1 Bcl-2抑制剂。我们发现4625寡核苷酸诱导的细胞凋亡与Bcl-2蛋白表达和端粒酶活性降低有关，而HA 14 -1在不影响Bcl-2和端粒酶水平的情况下触发细胞凋亡。有趣的是，HA 14 -1处理导致hTERT从主要核定位到主要细胞质定位的深刻变化。通过RNA干扰下调内源性hTERT蛋白显著增加4625和HA 14 -1诱导的细胞凋亡，而野生型hTERT过表达以p53非依赖性方式阻断Bcl-2依赖性细胞凋亡。无催化活性和生物活性的hTERT突变体表现出与野生型形式相似的行为，表明hTERT抑制4625和HA 14 -1诱导的细胞凋亡，而不管端粒酶活性及其延长端粒的能力如何。最后，hTERT过表达消除了4625和HA 14 -1诱导的线粒体功能障碍和hTERT核转位。总之，我们的结果表明hTERT参与了靶向抑制Bcl-2诱导的线粒体凋亡。
Here, we investigated the role of telomerase on Bcl-2-dependent apoptosis. To this end, the 4625 Bcl-2/Bcl-x(L) bispecific antisense oligonucleotide and the HA14-1 Bcl-2 inhibitor were used. We found that apoptosis induced by 4625 oligonucleotide was associated with decreased Bcl-2 protein expression and telomerase activity, while HA14-1 triggered apoptosis without affecting both Bcl-2 and telomerase levels. Interestingly, HA14-1 treatment resulted in a profound change from predominantly nuclear to a predominantly cytoplasmic localization of hTERT. Downregulation of endogenous hTERT protein by RNA interference markedly increased apoptosis induced by both 4625 and HA14-1, while overexpression of wild-type hTERT blocked Bcl-2-dependent apoptosis in a p53-independent manner. Catalytically and biologically inactive hTERT mutants showed a similar behavior as the wild-type form, indicating that hTERT inhibited the 4625 and HA14-1-induced apoptosis regardless of telomerase activity and its ability to lengthening telomeres. Finally, hTERT overexpression abrogated 4625 and HA14-1-induced mitochondrial dysfunction and nuclear translocation of hTERT. In conclusion, our results demonstrate that hTERT is involved in mitochondrial apoptosis induced by targeted inhibition of Bcl-2.