Axin determines cell fate by controlling the p53 activation threshold after DNA damage
| Autor: | Zailian Lu, Ka Ruan, Huiling Guo, Shu-Yong Lin, Jiahuai Han, Guili Lian, Yanhai Wang, Sheng-Cai Lin, Zhiyun Ye, Xuan Wang, Qinxi Li |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
DNA damage
Ubiquitin-Protein Ligases Apoptosis Cell Cycle Proteins Genotoxic Stress Ataxia Telangiectasia Mutated Proteins Biology Cell fate determination Protein Serine-Threonine Kinases Lysine Acetyltransferase 5 law.invention Mice Axin Protein law Cell Line Tumor Animals Humans Cell Lineage Histone Acetyltransferases chemistry.chemical_classification DNA ligase Papilloma Kinase Tumor Suppressor Proteins Wnt signaling pathway Cell Biology Cell biology DNA-Binding Proteins Repressor Proteins chemistry Acetyltransferase Checkpoint Kinase 1 Mutation Suppressor Tumor Suppressor Protein p53 Protein Kinases DNA Damage Protein Binding |
| Zdroj: | Nature cell biology. 11(9) |
| ISSN: | 1476-4679 |
| Popis: | Cells can undergo either cell-cycle arrest or apoptosis after genotoxic stress, based on p53 activity(1-6). Here we show that cellular fate commitment depends on Axin forming distinct complexes with Pirh2, Tip60, HIPK2 and p53. In cells treated with sublethal doses of ultra-violet (UV) radiation or doxorubicin (Dox), Pirh2 abrogates Axin-induced p53 phosphorylation at Ser 46 catalysed by HIPK2, by competing with HIPK2 for binding to Axin. However, on lethal treatment, Tip60 interacts with Axin and abrogates Pirh2-Axin binding, forming an Axin-Tip60-HIPK2-p53 complex that allows maximal p53 activation to trigger apoptosis. We also provide evidence that the ATM/ATR pathway mediates the Axin-Tip60 complex assembly. An axin mutation promotes carcinogenesis in Axin(Fu)/+ (Axin-Fused) mice, consistent with a dominantnegative role for Axin(Fu) in p53 activation. Thus, Axin is a critical determinant in p53-dependent tumour suppression in which Pirh2 and Tip60 have different roles in triggering cell-cycle arrest or apoptosis depending on the severity of genotoxic stress. |
| Databáze: | OpenAIRE |
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