Prolyl hydroxylase-1 negatively regulates IκB kinase-β, giving insight into hypoxia-induced NFκB activity
Prolyl hydroxylase-1 negatively regulates IκB kinase-β, giving insight into hypoxia-induced NFκB activity
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DOI：
10.1073/pnas.0602235103
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发表时间：
2006-11-28
影响因子：
11.1
通讯作者：
Taylor, Cormac T.
中科院分区：
文献类型：
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作者：
Cummins, Eoin P.;Berra, Edurne;Taylor, Cormac T.
缺氧是肿瘤生长微环境的一个特征。转录因子NF κ B B在缺氧中被激活，这一事件对肿瘤进展具有重要意义。在这里，我们证明了缺氧通过一个途径激活NF κ B，该途径涉及I κ B激酶-β（IKK β）的激活，导致I κ B α的磷酸化依赖性降解和NF κ B的释放。此外，通过增加IKK β的库和/或激活潜力，缺氧放大了细胞对TNF α刺激的敏感性。在其激活环内，IKK β包含进化上保守的LxxK共有基序，用于通过脯氨酰羟化酶（PHD）进行羟基化。通过用针对PHD-1或PHD-2的siRNA或泛脯氨酰羟化酶抑制剂DMOG处理细胞来模拟缺氧导致NF κ B活化。相反地，PHD-1的过表达降低了奎宁刺激的NF κ B B报告活性，进一步表明PHD-1在控制NF κ B B活性中的抑制作用。缺氧增加IKK β的表达和活性，并且推定的IKK β羟基化位点的脯氨酸残基（P191 A）的定点突变导致缺氧诱导的丧失。因此，我们假设缺氧通过降低IKK β的PH依赖性羟基化释放NF κ B B活性抑制，这一事件可能通过致瘤信号通路的扩增促进肿瘤的发生和进展。
Hypoxia is a feature of the microenvironment of a growing tumor. The transcription factor NF kappa B is activated in hypoxia, an event that has significant implications for tumor progression. Here, we demonstrate that hypoxia activates NFKB through a pathway involving activation of I kappa B kinase-beta (IKK beta) leading to phosphorylation-dependent degradation of I kappa B alpha and liberation of NF kappa B. Furthermore, through increasing the pool and/or activation potential of IKK beta, hypoxia amplifies cellular sensitivity to stimulation with TNF alpha. Within its activation loop, IKK beta contains an evolutionarily conserved LxxLAP consensus motif for hydroxylation by prolyl hydroxylases (PHDs). Mimicking hypoxia by treatment of cells with siRNA against PHD-1 or PHD-2 or the pan-prolyl hydroxylase inhibitor DMOG results in NF kappa B activation. Conversely, overexpression of PHD-1 decreases cytokine-stimulated NF kappa B reporter activity, further suggesting a repressive role for PHD-1 in controlling the activity of NF kappa B. Hypoxia increases both the expression and activity of IKK beta, and site-directed mutagenesis of the proline residue (P191A) of the putative IKK beta hydroxylation site results in a loss of hypoxic inducibility. Thus, we hypothesize that hypoxia releases repression of NF kappa B activity through decreased PHD-dependent hydroxylation of IKK beta, an event that may contribute to tumor development and progression through amplification of tumorigenic signaling pathways.