| Autor: |
Yifeng Xia, Padre, Roanna C., De Mendoza, Tatiana Hurtado, Bottero, Virginie, Tergaonkard, Vinay B., Verm, Inder M. |
| Předmět: |
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| Zdroj: |
Proceedings of the National Academy of Sciences of the United States of America; 2/24/2009, Vol. 106 Issue 8, p2629-2634, 6p |
| Abstrakt: |
Functional inactivation of p53 and constitutive activation of the N F-κB pathway has been associated with several human cancers. In this study, we show that 1κB kinase 2 (IKK2/IKKβ), which is critical for N F-κB activation, also phosphorylates p53. Phosphorylation of p53 at serines 362 and 366 by IKK2 leads to its recruitment to and ubiquitination by β-TrCP1. Degradation of ubiquitinated p53 is independent of Mdm2, because it occurs in both wild-type and Mdm2-1- cells. SiRNA-mediated reduction in the levels of β-TrCP1 and other members of the SCFβ-TcCP1E3 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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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