Cells can undergo either cell-cycle arrest or apoptosis after genotoxic stress, based on p53 activity1,2,3,4,5,6. 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 AxinFu/+ (Axin-Fused) mice, consistent with a dominant-negative role for AxinFu 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.
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This work was supported by grants from the 973 Program and 863 Program (2007CB914602, 2006CB503900 and 2006AA02A303), the National Natural Science Foundation of China (30730025, 30871280 and 30770454), the Ministry of Education of China (705030 and B06016), the National Basic Research Program of the Ministry of Science and Technology and the National Science Foundation of Fujian Province (2009J06021). We thank H. You for commenting on the manuscript.
The authors declare no competing financial interests.
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Li, Q., Lin, S., Wang, X. et al. Axin determines cell fate by controlling the p53 activation threshold after DNA damage. Nat Cell Biol 11, 1128–1134 (2009). https://doi.org/10.1038/ncb1927
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