Sindbis viral vector induced apoptosis requires translational inhibition and signaling through Mcl-1 and Bak.
Sindbis viral vector induced apoptosis requires translational inhibition and signaling through Mcl-1 and Bak.
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Sindbis 病毒载体诱导的细胞凋亡需要通过 Mcl-1 和 Bak 进行翻译抑制和信号传导。
DOI：
10.1186/1476-4598-9-37
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发表时间：
2010-02-12
期刊：
影响因子：
37.3
通讯作者：
Meruelo D
中科院分区：
文献类型：
--
作者：
Venticinque L;Meruelo D
辛德毕斯病毒载体能够在体内有效地靶向和杀死肿瘤细胞，如使用胰腺癌和卵巢癌模型所示。感染导致细胞凋亡在体外和体内。辛德毕斯载体摄取由LAMR介导，LAMR在许多不同的肿瘤类型上上调，因此赋予载体对广泛癌症的特异性。在这项研究中，我们阐明了两种肿瘤细胞系，MOSEC，来自卵巢上皮和Pan 02，来自胰腺癌细胞凋亡的机制。对细胞凋亡机制的全面了解将有助于设计更有效的肿瘤治疗载体。在MOSEC和Pan 02模型中，辛德毕斯载体诱导的细胞凋亡的初始阶段再次证实，由于与基因组复制相关的双链RNA中间体，病毒感染被PKR感知。PKR激活通过eIF 2 α磷酸化和应激反应的启动导致翻译抑制。我们的研究表明，两个蛋白质，Mcl-1和JNK的作用，密切联系辛德毕斯诱导的翻译停滞和细胞应激。翻译停滞抑制抗凋亡Bcl-2蛋白Mcl-1的合成。JNK激活触发Bad从14-3-3释放，最终导致细胞凋亡。这些来自翻译停滞和细胞应激的信号传播到线粒体，其中Bad和Bik分别与Bcl-xl和Mcl-1结合。这些异二聚体的形成取代了巴克，从而导致半胱天冬酶9切割并通过线粒体细胞凋亡途径进行信号传导。宿主细胞对辛德毕斯的反应是通过PKR激活触发的。我们的研究表明，PKR激活和随后的翻译停滞与细胞应激和细胞凋亡有关。我们还发现翻译停滞和细胞凋亡之间的连接点是Mcl-1，一种蛋白质，其恒定的翻译是抑制细胞凋亡所必需的。利用这些信息，可以设计表达或抑制本研究中涉及的蛋白质的载体，以增强其治疗潜力。
Sindbis viral vectors are able to efficiently target and kill tumor cells in vivo, as shown using pancreatic and ovarian cancer models. Infection results in apoptosis both in vitro and in vivo. Sindbis vector uptake is mediated by the LAMR, which is upregulated on a number of different tumor types, thus conferring specificity of the vector to a wide range of cancers. In this study we elucidate the mechanism of apoptosis in two tumor cell lines, MOSEC, derived from the ovarian epithelium and Pan02, derived from a pancreatic adenocarcinoma. A comprehensive understanding of the mechanism of apoptosis would facilitate the design of more effective vectors for cancer therapy. The initial phase of Sindbis vector induced apoptosis in MOSEC and Pan02 models reconfirms that viral infection is sensed by PKR due to double-stranded RNA intermediates associated with genomic replication. PKR activation results in translation inhibition through eIF2α phosphorylation and initiation of the stress response. Our studies indicate that the roles of two proteins, Mcl-1 and JNK, intimately link Sindbis induced translational arrest and cellular stress. Translational arrest inhibits the synthesis of anti-apoptotic Bcl-2 protein, Mcl-1. JNK activation triggers the release of Bad from 14-3-3, which ultimately results in apoptosis. These signals from translational arrest and cellular stress are propagated to the mitochondria where Bad and Bik bind to Bcl-xl and Mcl-1 respectively. Formation of these heterodimers displaces Bak, which results in caspase 9 cleavage and signaling through the mitochondrial pathway of apoptosis. The host cell response to Sindbis is triggered through PKR activation. Our studies demonstrate that PKR activation and subsequent translational arrest is linked to both cellular stress and apoptosis. We have also found the linkage point between translational arrest and apoptosis to be Mcl-1, a protein whose constant translation is required for inhibition of apoptosis. With this information vectors can be designed, which express or repress proteins implicated in this study, to enhance their therapeutic potential.
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DOI：
10.1038/nrc2644
发表时间：
2009-06
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
影响因子：
11.4
作者：
Grandgirard, D;Studer, E;Michel, MR
通讯作者：
Michel, MR
影响因子：
3.3
作者：
McInerney, GM;Kedersha, NL;Liljeström, P
通讯作者：
Liljeström, P
影响因子：
3.7
作者：
Glomb-Reinmund, S;Kielian, M
通讯作者：
Kielian, M
DOI：
10.1083/jcb.153.5.1011
发表时间：
2001-05-28
期刊：
The Journal of cell biology
影响因子：
--
作者：
Novoa I;Zeng H;Harding HP;Ron D
通讯作者：
Ron D