Axin determines cell fate by controlling the p53 activation threshold after DNA damage.
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.
Li
Qinxi
Q
Xiamen University, Fujian, China.
Lin
Shuyong
S
Wang
Xuan
X
Lian
Guili
G
Lu
Zailian
Z
Guo
Huiling
H
Ruan
Ka
K
Wang
Yanhai
Y
Ye
Zhiyun
Z
Han
Jiahuai
J
Lin
Sheng-Cai
SC
D000818:Animals; D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins; D060466:Axin Protein; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D019070:Cell Lineage; D000071877:Checkpoint Kinase 1; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism; D051548:Histone Acetyltransferases / Q000378:metabolism; D006801:Humans; D000074443:Lysine Acetyltransferase 5; D051379:Mice; D009154:Mutation / Q000235:genetics; D010212:Papilloma / Q000473:pathology; D011485:Protein Binding; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D060466:Axin Protein; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5; C485369:RCHY1 protein, human; D044767:Ubiquitin-Protein Ligases; D011494:Protein Kinases; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D000071877:Checkpoint Kinase 1; D017346:Protein Serine-Threonine Kinases