The Molecular Mechanism And Biological Function Of The Regulation Of P53 Activity By Axin Complex

Cells can undergo cell-cycle arrest to repair damaged DNA or apoptosis toeliminate permanently damaged cells that carry inaccurate genetic informationfollowing genotoxic stresses.The two cell fates are determined by signaling cascadesthat seem to converge on p53 signaling.However,how thresholds of p53 activationare intricately controlled by orchestration of increasingly many factors remainsunclear.Here we show that Axin,a central regulator of Wnt signaling,forms distinctcomplexes with Pirh2 and Tip60 as well as HIPK2 and p53 at their endogenous levels,during different cellular commitments.In cells treated with sublethal doses of UVordoxorubicin,Pirh2 abrogates Axin-induced p53 phosphorylation at Ser-46 catalyzedby HIPK2,through competing against HIPK2 binding to Axin.However,in responseto lethal treatments,Tip60 interaction with Axin is increased by ATM/ATR kinasesand pushes off Pirh2,forming Axin-Tip60-HIPK2-p53 complex that allows formaximal p53 activation to trigger apoptosis.p53 transactivation is greatlycompromised upon lethal Dox treatment in the skin fibroblasts derived from Axin^Fu/+mice coinciding with Axin mutation promotes carcinogenesis in Axin^Fu/+ mice and thedominant-negative role of Axin^Fu protein on p53 activation.Thus,Axin is a criticaldeterminant for p53-dependent tumor suppression,in which Pirh2 and Tip60 playswitching roles to trigger cell-cycle arrest or apoptosis upon different severity ofgenotoxic stress.