Interplay between Mdm2 and HIPK2 in the DNA damage response.
The tumour suppressor p53 is activated to induce cell-cycle arrest or apoptosis in the DNA damage response (DDR). p53 phosphorylation at Ser46 by HIPK2 (homeodomain-interacting protein kinase 2) is a critical event in apoptosis induction. Interestingly, HIPK2 is degraded by Mdm2 (a negative regulator of p53), whereas Mdm2 is downregulated by HIPK2 through several mechanisms. Here, we develop a four-module network model for the p53 pathway to clarify the role of interplay between Mdm2 and HIPK2 in the DDR evoked by ultraviolet radiation. By numerical simulations, we reveal that Mdm2-dependent HIPK2 degradation promotes cell survival after mild DNA damage and that inhibition of HIPK2 degradation is sufficient to trigger apoptosis. In response to severe damage, p53 phosphorylation at Ser46 is promoted by the accumulation of HIPK2 due to downregulation of nuclear Mdm2 in the later phase of the response. Meanwhile, the concentration of p53 switches from moderate to high levels, contributing to apoptosis induction. We show that the presence of three mechanisms for Mdm2 downregulation, i.e. repression of mdm2 expression, inhibition of its nuclear entry and HIPK2-induced degradation, guarantees the apoptosis of irreparably damaged cells. Our results agree well with multiple experimental observations, and testable predictions are also made. This work advances our understanding of the regulation of p53 activity in the DDR and suggests that HIPK2 should be a significant target for cancer therapy.
National Laboratory of Solid State Microstructures and Department of Physics, Nanjing University, Nanjing 210093, People's Republic of China Kuang Yaming Honors School, Nanjing University, Nanjing 210093, People's Republic of China.
Xiao-Peng
XP
Zhang
National Laboratory of Solid State Microstructures and Department of Physics, Nanjing University, Nanjing 210093, People's Republic of China fliu@nju.edu.cn.
Feng
F
Liu
National Laboratory of Solid State Microstructures and Department of Physics, Nanjing University, Nanjing 210093, People's Republic of China wangwei@nju.edu.cn.
Wei
W
Wang
D017209:Apoptosis; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D059447:Cell Cycle Checkpoints; D004249:DNA Damage; D004260:DNA Repair; D005786:Gene Expression Regulation; D006801:Humans; D008954:Models, Biological; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D059748:Proteolysis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014466:Ultraviolet Rays
D002352:Carrier Proteins; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C115114:HIPK2 protein, human; D017346:Protein Serine-Threonine Kinases
HIPK2 degradation; cell-fate decision; downregulation of nuclear Mdm2; p53 phosphorylation