INDUCIBLE PHOSPHORYLATION OF I-KAPPA-B-ALPHA IS NOT SUFFICIENT FOR ITS DISSOCIATION FROM NF-KAPPA-B AND IS INHIBITED BY PROTEASE INHIBITORS
INDUCIBLE PHOSPHORYLATION OF I-KAPPA-B-ALPHA IS NOT SUFFICIENT FOR ITS DISSOCIATION FROM NF-KAPPA-B AND IS INHIBITED BY PROTEASE INHIBITORS
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DOI：
10.1073/pnas.91.25.11884
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发表时间：
1994-12-06
影响因子：
11.1
通讯作者：
BALDWIN, AS
中科院分区：
文献类型：
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作者：
FINCO, TS;BEG, AA;BALDWIN, AS
普遍存在的转录因子NF-κ B受其胞质抑制因子I κ B调节。多种细胞刺激导致NF-κ B从I κ B解离，允许NF-κ B易位到细胞核并调节基因表达。虽然NF-κ B在体内的活化与I κ B α的磷酸化和降解有关，但这些事件中的每一个如何促成这一过程仍不清楚。最近，利用蛋白酶抑制剂的研究表明I κ B α的蛋白水解是NF-κ B活化的必要事件。我们在这项研究中证明，这些和一个额外的蛋白酶抑制剂也完全抑制诱导型I κ B α磷酸化。这一令人惊讶的结果表明蛋白酶在NF-κ B活化中的作用更为复杂。此外，本文提供的数据表明，许多这些抑制剂也直接修饰NF-κ B并抑制其DNA结合活性。由于这些蛋白酶抑制剂的多效性作用，很难从它们的使用中得出I κ B α磷酸化和降解如何促进NF-κ B活化的结论。在本研究中，一种更直接的方法证明了I κ B α的磷酸化单独不足以激活NF-κ B。
The ubiquitous transcription factor NF-kappa B is regulated by its cytoplasmic inhibitor I kappa B. A variety of cellular stimuli cause the dissociation of NF-kappa B from I kappa B, allowing NF-kappa B to translocate to the nucleus and regulate gene expression. Although the activation of NF-kappa B in vivo is associated with the phosphorylation and degradation of I kappa B alpha, it has remained unclear how each of these events contributes to this process. Recently, studies utilizing protease inhibitors have suggested that the proteolysis of I kappa B alpha is a necessary event in the activation of NF-kappa B. We demonstrate in this study that these and an additional protease inhibitor also completely repress inducible phosphorylation of I kappa B alpha. This surprising result suggests a more complex role of proteases in NF-kappa B activation. In addition, data presented here indicate that many of these inhibitors also directly modify NF-kappa B and inhibit its DNA binding activity. Due to the pleiotropic effects of these protease inhibitors, it is difficult to conclude from their use how I kappa B alpha phosphorylation and degradation contribute to NF-kappa B activation. In the present study, a more direct approach demonstrates that phosphorylation of I kappa B alpha alone is not sufficient for NF-kappa B activation.