CUEDC2通过抑制IKK复合体磷酸化下调NF-κB通路
发布时间：2018-08-14 17:05
【摘要】： CUEDC2目前是一个功能未知的蛋白质，通过生物信息学分析发现，CUEDC2包含一个CUE结构域。CUE是一个非常小的中度保守的结构域，大约包含40个氨基酸，预测它能和泛素结合，既能识别单泛素化又能识别多泛素化，目前发现它存在各种真核蛋白质中。最近，我们实验室发现CUEDC2能够和孕激素受体结合，促进孕激素诱导的受体的泛素化和降解(张佩景等，EMBO J．)，，并抑制乳腺癌细胞的生长，这就为CUEDC2在乳腺癌增殖过程中的作用提供了重要的线索。本文为进一步揭示CUEDC2的功能，在应用酵母双杂交技术筛选与CUEDC2相互作用蛋白质的基础上，对其功能尤其是在NF-κB通路中的作用进行了更为深入的研究。 我们通过研究发现一个未知功能的蛋白CUEDC2(CUE Domain Containing 2)能够结合IKKα和IKKβ，并且能够通过使IKKα和IKKβ去磷酸化而抑制NF-κ信号通路。在细胞因子诱导的NF-κB通路激活中，IκB激酶IKKα和IKKβ的激活是关键的步骤。因此，对IKK复合体磷酸化的精确调控是NF-κB通路信号传导的重要组成部分。利用siRNA抑制内源CUEDC2表达导致TNF诱导的NF-κB转录活性增加，过表达CUEDC2增加了细胞对凋亡信号如TNF诱导的凋亡。我们还发现CUEDC2与蛋白磷酸酶1(PP1)的调节亚基生长抑制和DNA损伤蛋白34(GADD34)存在相互作用。此外，我们发现CUEDC2对NF-κB信号通路的抑制是由IKK-CUEDC2-GADD34相互作用介导的。siRNA抑制内源CUEDC2的实验证明CUEDC2对于IKK-CUEDC2-GADD34复合体的形成是必须的，并且作为招募蛋白使IKK去磷酸化。因此，我们发现了NF-κB信号通路一个新的抑制蛋白，对CUEDC2在NF-κB信号通路中的作用提供了线索。
[Abstract]:CUEDC2 is a protein with unknown function. Bioinformatics analysis shows that CUEDC2 contains a CUE domain. Cue is a very small, moderately conserved domain containing about 40 amino acids, which is predicted to bind to ubiquitin. It can recognize both monoubiquitization and polyubiquitin. At present, it is found to exist in various eukaryotic proteins. Recently, our lab found that CUEDC2 binds to progesterone receptors, promoting the ubiquification and degradation of progesterone-induced receptors (Zhang Peijing, et al., Embo J.), and inhibits the growth of breast cancer cells. This provides important clues for the role of CUEDC2 in breast cancer proliferation. In order to further reveal the function of CUEDC2, especially in the NF- 魏 B pathway, was studied based on the screening of proteins interacting with CUEDC2 by yeast two-hybrid technique. We found that an unknown functional protein CUEDC2 (CUE Domain Containing 2) could bind IKK 伪 and IKK 尾, and inhibit NF- 魏 signaling pathway by dephosphorylation of IKK 伪 and IKK 尾. Activation of I 魏 B kinase IKK 伪 and IKK 尾 is a key step in cytokine induced activation of NF- 魏 B pathway. Therefore, the precise regulation of phosphorylation of IKK complex is an important part of NF- 魏 B pathway signal transduction. Inhibition of endogenous CUEDC2 expression by siRNA resulted in an increase in NF- 魏 B transcription activity induced by TNF, while overexpression of CUEDC2 increased apoptosis induced by TNF. We also found that CUEDC2 interacts with regulatory subunit growth inhibition of protein phosphatase 1 (PP1) and DNA damage protein 34 (GADD34). In addition, we found that the inhibition of NF- 魏 B signaling pathway by CUEDC2 is mediated by IKK-CUEDC2-GADD34 interaction. SiRNA inhibits endogenous CUEDC2. It is proved that CUEDC2 is necessary for the formation of IKK-CUEDC2-GADD34 complex, and IKK is dephosphorylated as a recruitment protein. Therefore, we have discovered a new inhibitory protein of NF- 魏 B signaling pathway, which provides clues to the role of CUEDC2 in NF- 魏 B signaling pathway.
【学位授予单位】：中国人民解放军军事医学科学院
【学位级别】：博士
【学位授予年份】：2007
【分类号】：R341
本文编号：2183530
[Abstract]:CUEDC2 is a protein with unknown function. Bioinformatics analysis shows that CUEDC2 contains a CUE domain. Cue is a very small, moderately conserved domain containing about 40 amino acids, which is predicted to bind to ubiquitin. It can recognize both monoubiquitization and polyubiquitin. At present, it is found to exist in various eukaryotic proteins. Recently, our lab found that CUEDC2 binds to progesterone receptors, promoting the ubiquification and degradation of progesterone-induced receptors (Zhang Peijing, et al., Embo J.), and inhibits the growth of breast cancer cells. This provides important clues for the role of CUEDC2 in breast cancer proliferation. In order to further reveal the function of CUEDC2, especially in the NF- 魏 B pathway, was studied based on the screening of proteins interacting with CUEDC2 by yeast two-hybrid technique. We found that an unknown functional protein CUEDC2 (CUE Domain Containing 2) could bind IKK 伪 and IKK 尾, and inhibit NF- 魏 signaling pathway by dephosphorylation of IKK 伪 and IKK 尾. Activation of I 魏 B kinase IKK 伪 and IKK 尾 is a key step in cytokine induced activation of NF- 魏 B pathway. Therefore, the precise regulation of phosphorylation of IKK complex is an important part of NF- 魏 B pathway signal transduction. Inhibition of endogenous CUEDC2 expression by siRNA resulted in an increase in NF- 魏 B transcription activity induced by TNF, while overexpression of CUEDC2 increased apoptosis induced by TNF. We also found that CUEDC2 interacts with regulatory subunit growth inhibition of protein phosphatase 1 (PP1) and DNA damage protein 34 (GADD34). In addition, we found that the inhibition of NF- 魏 B signaling pathway by CUEDC2 is mediated by IKK-CUEDC2-GADD34 interaction. SiRNA inhibits endogenous CUEDC2. It is proved that CUEDC2 is necessary for the formation of IKK-CUEDC2-GADD34 complex, and IKK is dephosphorylated as a recruitment protein. Therefore, we have discovered a new inhibitory protein of NF- 魏 B signaling pathway, which provides clues to the role of CUEDC2 in NF- 魏 B signaling pathway.
【学位授予单位】：中国人民解放军军事医学科学院
【学位级别】：博士
【学位授予年份】：2007
【分类号】：R341
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1 李慧艳;CUEDC2通过抑制IKK复合体磷酸化下调NF-κB通路[D];中国人民解放军军事医学科学院;2007年
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