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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Phosphorylation of p53 by IκB kinase 2 promotes its degradation by β-TrCP
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Phosphorylation of p53 by IκB kinase 2 promotes its degradation by β-TrCP

机译：IκB激酶2使p53磷酸化，促进其被β-TrCP降解

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摘要

Functional inactivation of p53 and constitutive activation of the NF-Κb pathway has been associated with several human cancers. In this study, we show that IκB kinase 2 (IKK2/IKKβ), which is critical for NF-Κb activation, also phosphorylates p53. Phosphorylation of p53 at serines 362 and 366 by IKK2 leads to its recruitment to and ubiquiti-nation by β-TrCP1. Degradation of ubiquitinated p53 is independent of Mdm2, because it occurs in both wild-type and Mdm2~(-/-) cells. SiRNA-mediated reduction in the levels of β-TrCP1 and other members of the SCF~(β-TrCP1)E3 ubiquitin ligase complex or overexpression of a dominant negative form of β-TrCP1 enhances p53 stability. Substitutions at Ser-362 and 366 of p53 by alanines (p53 AA) result in reduced phosphorylation of p53 by IKK2, decreased association with β-TrCP1, and thus increased stability of p53 and expression of p53 target genes such as p21, altering the G1 phase of the cell cycle. Our results identify IKK2 and β-TrCP1 as novel regulators of the p53 pathway and suggest that blocking of IKK2 and β-TrCP1 could be a means of regulating p53 stability and thereby modulating its biological activity.
机译：p53的功能失活和NF-κb途径的组成性活化与几种人类癌症有关。在这项研究中，我们显示了对NF-κb激活至关重要的IκB激酶2（IKK2 /IKKβ）也使p53磷酸化。 IKK2将p53丝氨酸362和366磷酸化，导致其被β-TrCP1募集并被泛素化。泛素化的p53的降解与Mdm2无关，因为它发生在野生型和Mdm2〜（-/-）细胞中。 SiRNA介导的β-TrCP1和SCF〜（β-TrCP1）E3泛素连接酶复合物其他成员水平的降低或β-TrCP1显性负性形式的过表达增强了p53的稳定性。丙氨酸（p53 AA）取代p53的Ser-362和366导致IKK2减少p53的磷酸化，降低与β-TrCP1的结合，从而增加p53的稳定性和p53靶基因如p21的表达，从而改变G1细胞周期的阶段。我们的结果确定了IKK2和β-TrCP1是p53途径的新型调节剂，并表明阻断IKK2和β-TrCP1可能是调节p53稳定性从而调节其生物学活性的手段。

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  • 作者

    Yifeng Xia; Roanna C. Padre; Tatiana Hurtado De Mendoza; Virginie Bottero; Vinay B. Tergaonkar; Inder M. Verma;

  • 作者单位

    Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA 92037;

    Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA 92037 J & J Pharmaceutical Services, Horsham, PA 19044;

    Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA 92037;

    Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA 92037 Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064;

    Institute of Molecular and Cell Biology, Singapore 138673;

    Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA 92037;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    β-TrCPI; DNA damage; IKK2; p53 stability;

    机译：β-TrCPI;DNA损伤;IKK2;p53稳定性;

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