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首页> 外文期刊>Oncogene >Requirement of Hsp90 activity for I|[kappa]|B kinase (IKK) biosynthesis and for constitutive and inducible IKK and NF-|[kappa]|B activation
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Requirement of Hsp90 activity for I|[kappa]|B kinase (IKK) biosynthesis and for constitutive and inducible IKK and NF-|[kappa]|B activation

机译：Hsp90活性为I | [Kappa] | B激酶（IKK）生物合成和组成型和诱导型IKK和NF- | [Kappa] | B活化

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摘要

The molecular chaperone Hsp90 affects the function and fate of a number of signaling molecules. We have investigated the Hsp90 requirement for constitutive and inducible activity of the IB kinase (IKK) complex and of NF-B. Inhibition by the Hsp90 ATPase inhibitors, geldanamycin (GA) and radicicol (RC), revealed that Hsp90 controls IKKs at two levels, inducibility of enzymatic activity and biogenesis, which can be discriminated by short- and long-time GA incubation, respectively. Short-time inhibition of Hsp90 resulted in impaired IKK kinase activation by TNF, IL-1 or phorbolester PMA. Furthermore, GA inhibited constitutive activation of IKK and NF-B in Hodgkin's lymphoma cells. Hsp90 function was also required for trans- and autophosphorylation of transfected IKK. GA exposure for several hours resulted in a downmodulation of IKK complex , and subunits to various extent. Proteasome inhibition interfered with GA mediated IKK depletion and Hsp90 inhibition induced polyubiquitination of IKK and during protein synthesis. In fact, GA blocked biogenesis of IKK and IKK but did not interfere with post-translational turnover. Together, these results define a dual requirement for Hsp90 as a regulator of NF-B signaling by its general involvement in IKK activation and by its role in IKK homeostasis.
机译：分子伴侣Hsp90影响许多信号分子的功能和命运。我们研究了对IB激酶（IKK）复合物和NF-B的组成型和诱导活性的HSP90要求。 HSP90 ATP酶抑制剂，Geldanamycin（Ga）和基胆（Rc）的抑制表明，Hsp90在两个水平下对胰腺活动，酶活性和生物发生的诱导性分别可以通过短期和长时间的GA孵育来区分。 HSP90的短时抑制导致TNF，IL-1或堤防PMA的IKK激酶活化受损。此外，GA在霍奇金淋巴瘤细胞中抑制IKK和NF-B的组成型激活。还需要转染的IKK的杂项和自动磷酸化所需的HSP90功能。 GA暴露几个小时导致IKK复合物的次调，以及各种程度的亚基。蛋白酶体抑制干扰了GA介导的IKK耗尽和HSP90抑制诱导的IKK和蛋白质合成期间的抑制诱导的多覆。事实上，GA阻止了IKK和IKK的生物发生，但没有干扰翻译后的营业额。这些结果在一起定义了HSP90作为NF-B信号调节器的双重要求，通过其在IKK激活和IKK稳态中的作用。

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