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由干扰素诱导的蛋白激酶PKR触发的细胞凋亡途径需要第三个碱性结构域,在Bcl-2的上游启动,并涉及ICE样蛋白酶。

The apoptosis pathway triggered by the interferon-induced protein kinase PKR requires the third basic domain, initiates upstream of Bcl-2, and involves ICE-like proteases.

作者信息

Lee S B, Rodríguez D, Rodríguez J R, Esteban M

机构信息

Centro Nacional de Biotecnología, CSIC Cantoblanco, Madrid, Spain.

出版信息

Virology. 1997 Apr 28;231(1):81-8. doi: 10.1006/viro.1997.8494.

Abstract

The interferon-induced double-stranded RNA-dependent protein kinase (PKR) is a serine/threonine kinase which exerts antiviral and anticellular functions. The antiviral effect of PKR is mediated by the phosphorylation of the alpha subunit of the translational initiation factor elF-2 alpha, while it is not known whether the anticellular effect is due to phosphorylation of elF-2 alpha, l kappa B, or other unknown substrates. We have previously shown that activation of PKR during infection of cells with a vaccinia virus recombinant expressing the wild-type kinase resulted in a complete inhibition of viral and cellular protein synthesis and in the induction of apoptosis. Here, we report that expression of the human proto-oncogene bcl-2 blocks PKR-induced apoptosis but not PKR-induced inhibition of translation. In addition, PKR-induced apoptosis resulted in a cleavage of the death substrate poly(ADP-ribose) polymerase (PARP). Moreover, induction of apoptosis by PKR was not observed with a mutant lacking the third basic region (aa 234-272). Taken together, these results suggest that the third basic region of PKR is required for PKR-induced apoptosis, the process is initiated upstream of bcl-2 and involves activation of a cellular protease, CPP32, or its family members that cleave PARP.

摘要

干扰素诱导的双链RNA依赖性蛋白激酶(PKR)是一种丝氨酸/苏氨酸激酶,具有抗病毒和抗细胞功能。PKR的抗病毒作用是通过翻译起始因子elF-2α的α亚基磷酸化介导的,而其抗细胞作用是否归因于elF-2α、IκB或其他未知底物的磷酸化尚不清楚。我们先前已表明,在用表达野生型激酶的痘苗病毒重组体感染细胞期间PKR的激活导致病毒和细胞蛋白质合成的完全抑制以及凋亡的诱导。在此,我们报道人原癌基因bcl-2的表达可阻断PKR诱导的凋亡,但不能阻断PKR诱导的翻译抑制。此外,PKR诱导的凋亡导致死亡底物聚(ADP-核糖)聚合酶(PARP)的裂解。而且,用缺乏第三个碱性区域(氨基酸234 - 272)的突变体未观察到PKR诱导的凋亡。综上所述,这些结果表明PKR诱导的凋亡需要PKR的第三个碱性区域,该过程在bcl-2的上游启动,并且涉及细胞蛋白酶CPP32或其切割PARP的家族成员的激活。

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