Mikus Peter, Zundel Wayne
Department of Radiation Oncology, Baxter Research Bldg II, Room 204C (Lab 215), 580 S. Preston Street, University of Louisville School of Medicine, Louisville, KY 40202, USA.
Semin Cell Dev Biol. 2005 Aug-Oct;16(4-5):462-73. doi: 10.1016/j.semcdb.2005.03.002.
To understand how cells respond to altered oxygenation, a frequent experimental paradigm is to isolate known components of bona fide oxygen responsive proteins. Recent studies have shown that a protein known as CSN5 or JAB1 interacts with both the HIF-1alpha oxygen-responsive transcription factor and its oxygen-dependent regulator, the Von Hippel-Lindau (pVHL) tumor suppressor. CSN5 is a component of the COP9 Signalosome (CSN) which is a multi-subunit protein that has high homology to the lid of the 19S lid of 26S proteasome. The exact function of the CSN5 interaction with pVHL and HIF-1alpha remains to be fully elucidated, but it is clear that the interaction is both oxygen dependent and that CSN5 may play different roles under oxic and hypoxic responses. Further, evidence has also been published indicating that pVHL can be potentially post-translationally modified by CSN5 (de-neddylation) and that CSN5 transcription is regulated by hypoxia as are many of the key pVHL/HIF-1alpha regulatory genes such as the PHDs and OS-9. This review will give a broad overview of known CSN5 and COP9 Signalosome functions and how these functions impact the pVHL/HIF-1alpha signaling complex and potentially other oxygen-sensitive response networks.
为了解细胞如何对氧合变化作出反应，一种常见的实验范式是分离真正的氧反应蛋白的已知成分。最近的研究表明，一种名为CSN5或JAB1的蛋白质与低氧诱导因子-1α（HIF-1α）氧反应转录因子及其氧依赖性调节因子、冯·希佩尔-林道（pVHL）肿瘤抑制因子相互作用。CSN5是COP9信号小体（CSN）的一个组成部分，CSN是一种多亚基蛋白质，与26S蛋白酶体19S盖子具有高度同源性。CSN5与pVHL和HIF-1α相互作用的确切功能仍有待充分阐明，但很明显这种相互作用是氧依赖性的，并且CSN5可能在有氧和缺氧反应中发挥不同作用。此外，也有证据表明pVHL可能会被CSN5进行翻译后修饰（去泛素化），并且CSN5的转录受缺氧调节，许多关键的pVHL/HIF-1α调节基因如脯氨酰羟化酶（PHDs）和OS-9也是如此。本综述将广泛概述已知的CSN5和COP9信号小体的功能，以及这些功能如何影响pVHL/HIF-1α信号复合体以及潜在的其他氧敏感反应网络。
