Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis
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Ataxia Telangiectasia Mutated Proteins
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Axin Protein
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Cell Cycle Proteins / metabolism
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Cell Line, Tumor
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Cell Lineage*
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Checkpoint Kinase 1
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DNA Damage*
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DNA-Binding Proteins / metabolism
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Histone Acetyltransferases / metabolism
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Humans
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Lysine Acetyltransferase 5
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Mice
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Mutation / genetics
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Papilloma / pathology
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Protein Binding
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Protein Kinases / metabolism
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Protein Serine-Threonine Kinases / metabolism
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Repressor Proteins / metabolism*
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Tumor Suppressor Protein p53 / antagonists & inhibitors
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Tumor Suppressor Protein p53 / metabolism*
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Tumor Suppressor Proteins / metabolism
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Ubiquitin-Protein Ligases / metabolism
Substances
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Axin Protein
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Cell Cycle Proteins
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DNA-Binding Proteins
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Repressor Proteins
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Tumor Suppressor Protein p53
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Tumor Suppressor Proteins
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Histone Acetyltransferases
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KAT5 protein, human
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Lysine Acetyltransferase 5
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RCHY1 protein, human
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Ubiquitin-Protein Ligases
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Protein Kinases
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ATM protein, human
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ATR protein, human
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Ataxia Telangiectasia Mutated Proteins
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Atm protein, mouse
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Checkpoint Kinase 1
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Protein Serine-Threonine Kinases