Distinct roles of the IκB kinase α and β subunits in liberating nuclear factor κB (NFκB) from IκB and in phosphorylating the p65 subunit of NF-κB
Distinct roles of the IκB kinase α and β subunits in liberating nuclear factor κB (NFκB) from IκB and in phosphorylating the p65 subunit of NF-κB
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DOI：
10.1074/jbc.m110572200
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发表时间：
2002-02-08
影响因子：
4.8
通讯作者：
Stark, GR
中科院分区：
文献类型：
--
作者：
Sizemore, N;Lerner, N;Stark, GR
磷脂酰肌醇3′-激酶（PI3K）和丝氨酸/苏氨酸激酶AKT在响应促炎细胞因子白介素-1 （IL-1）和肿瘤坏死因子（TNF）的核因子kappaB (NF-kappaB) p65亚基的磷酸化和反激活中起关键作用。小鼠胚胎成纤维细胞（mef）缺乏IkappaB激酶（IKK）的α或β亚基，在IL-1或TNF治疗后缺乏nf - kappab依赖性转录。然而，与ikkβ -null MEFs相比，IKKalpha-null MEFs在细胞因子刺激的ikappabeta - α降解或NF-kappaB的核易位中并没有实质性缺陷。IKKalpha-或ikkβ -null MEFs的IKK复合物都缺乏pi3k介导的NF-kappaB p65亚基反活化结构域的磷酸化，以响应IL-1和TNF。PI3K或AKT的组成激活形式不会增强IKKalpha-或ikkβ -无效MEFs中细胞因子刺激的NF-kappaB激活。综上所述，这些数据表明，IKKbeta是NF-kappaB释放和p65磷酸化所必需的，而IKKalpha仅是细胞因子诱导的NF-kappaB p65亚基的磷酸化和激活所必需的，这些磷酸化和激活是由PI3K/AKT通路介导的。
Phosphatidylinositol 3'-kinase (PI3K) and the serine/threonine kinase AKT have critical roles in phosphorylating and transactivating the p65 subunit of nuclear factor kappaB (NF-kappaB) in response to the pro-inflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor (TNF). Mouse embryo fibroblasts (MEFs) lacking either the alpha or beta subunit of IkappaB kinase (IKK) were deficient in NF-kappaB-dependent transcription following treatment with IL-1 or TNF. However, in contrast to IKKbeta-null MEFs, IKKalpha-null MEFs were not substantially defective in the cytokine-stimulated degradation of Ikappabetaalpha or in the nuclear translocation of NF-kappaB The IKK complexes from IKKalpha- or IKKbeta-null MEFs were both deficient in PI3K-mediated phosphorylation of the transactivation domain of the p65 subunit of NF-kappaB in response to IL-1 and TNF, and constitutively activated forms of PI3K or AKT did not potentiate cytokine-stimulated activation of NF-kappaB in either IKKalpha- or IKKbeta-null MEFs. Collectively, these data indicate that, in contrast to IKKbeta, which is required for both NF-kappaB liberation and p65 phosphorylation, IKKalpha is required solely for the cytokine-induced phosphorylation and activation of the p65 subunit of NF-kappaB that are mediated by the PI3K/AKT pathway.