Characterization of transgenic mice with targeted disruption of the catalytic domain of the double-stranded RNA-dependent protein kinase, PKR
Characterization of transgenic mice with targeted disruption of the catalytic domain of the double-stranded RNA-dependent protein kinase, PKR
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DOI：
10.1074/jbc.274.9.5953
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发表时间：
1999-02-26
影响因子：
4.8
通讯作者：
Bell, JC
中科院分区：
文献类型：
--
作者：
Abraham, N;Stojdl, DF;Bell, JC
干扰素诱导的双链RNA依赖的蛋白激酶PKR参与了抗病毒、抗肿瘤和凋亡反应，其他人试图通过靶向破坏PhR基因的氨基末端编码区来研究PKR在这些作用中的需求。通过使用一种旨在破坏PHR催化结构域的策略，我们产生了与另一种PKR中断的小鼠模型类似的基因消融的功能性PKR的小鼠，我们没有观察到PKR丢失对肿瘤抑制的后果。小鼠对流感和牛痘的抗病毒反应似乎也是正常的，在缺乏PKR细胞因子信号的细胞中，I型干扰素途径是正常的，但可能在红系骨髓前体细胞的促红细胞生成素途径中受到损害。与氨基末端靶向Phr小鼠相反，在催化结构域靶向的PKR缺失细胞中，肿瘤坏死因子α诱导的细胞凋亡和抗病毒凋亡反应不受影响。在这些PKR缺失的细胞中观察到完整的真核起始因子-2α磷酸化，为另一种真核起始因子-2α激酶(S)的拯救提供了证据。
The interferon-inducible, double-stranded RNA dependent protein kinase PKR has been implicated in anti-viral, anti-tumor, and apoptotic responses, Others have attempted to examine the requirement of PKR in these roles by targeted disruption at the amino terminal-encoding region of the Phr gene. By using a strategy that aims at disruption of the catalytic domain of PHR, we have generated mice that are genetically ablated for functional PKR Similar to the other mouse model of Pkr disruption, we have observed no consequences of loss of PKR on tumor suppression. Anti-viral response to influenza and vaccinia also appeared to be normal in mice and in cells lacking PKR Cytokine signaling in the type I interferon pathway is normal but may be compromised in the erythropoietin pathway in erythroid bone marrow precursors. Contrary to the aminoterminal targeted Phr mouse, tumor necrosis factor alpha-induced apoptosis and the anti-viral apoptosis response to influenza is not impaired in catalytic domain-targeted Pkr-null cells. The observation of intact eukaryotic initiation factor-2 alpha phosphorylation in these Pkr-null cells provides proof of rescue by another eukaryotic initiation factor-2 alpha kinase(s).