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Interplay between Mdm2 and HIPK2 in the DNA damage response

Xiao-Peng Zhang1, Feng Liu2, Wei Wang3

  • 1National 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.

Journal of the Royal Society, Interface
|May 16, 2014
PubMed

Insights

The interplay between HIPK2 and Mdm2 regulates the p53 pathway during DNA damage. Mdm2-dependent HIPK2 degradation promotes survival after mild damage, while HIPK2 accumulation triggers apoptosis in severe DNA damage scenarios.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Systems Biology

Background:

  • The tumor suppressor p53 is crucial for the DNA damage response (DDR), inducing cell-cycle arrest or apoptosis.
  • Phosphorylation of p53 at Ser46 by HIPK2 is a key event for apoptosis induction.
  • HIPK2 is degraded by Mdm2, a negative regulator of p53, while HIPK2 also downregulates Mdm2.

Purpose of the Study:

  • To model the p53 pathway network, focusing on the Mdm2-HIPK2 interplay in the DDR.
  • To elucidate the role of this interplay in response to ultraviolet radiation-induced DNA damage.
  • To understand how these interactions dictate cell fate decisions (survival vs. apoptosis).

Main Methods:

  • Development of a four-module network model for the p53 pathway.
  • Numerical simulations to analyze pathway dynamics under varying DNA damage levels.
  • Investigating the impact of Mdm2-dependent HIPK2 degradation and its inhibition.

Main Results:

  • Mdm2-mediated degradation of HIPK2 promotes cell survival following mild DNA damage.
  • Inhibition of HIPK2 degradation is sufficient to induce apoptosis, regardless of damage severity.
  • Severe DNA damage leads to HIPK2 accumulation and increased p53 phosphorylation at Ser46, promoting apoptosis.
  • Multiple Mdm2 downregulation mechanisms ensure apoptosis in cells with irreparable DNA damage.

Conclusions:

  • The dynamic interplay between Mdm2 and HIPK2 is critical for regulating p53 activity in the DDR.
  • HIPK2 accumulation, driven by Mdm2 downregulation, is a key switch for apoptosis induction in response to severe DNA damage.
  • Targeting HIPK2 presents a promising strategy for cancer therapy by modulating the p53-mediated DDR.
Keywords:
HIPK2 degradationcell-fate decisiondownregulation of nuclear Mdm2p53 phosphorylation

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