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Differential regulation of Apak by various DNA damage signals

Shan Wang1, Chunyan Tian, Tingting Xiao

  • 1College of Animal Science and Technology, Shaanxi Key Laboratory of Molecular Biology for Agriculture, Northwest A&F University, 712100, Yangling, Shaanxi, China.

Molecular and Cellular Biochemistry
|July 25, 2009
PubMed

Insights

The ATM and p53-associated KZNF protein (Apak) regulates p53-mediated apoptosis. Different DNA damage signals differentially regulate Apak phosphorylation, impacting its interaction with p53 and subsequent apoptosis.

Area of Science:

  • Molecular Biology
  • Cellular Signaling
  • Cancer Research

Background:

  • The tumor suppressor p53 is central to cellular stress response, mediating cell cycle arrest or apoptosis.
  • ATM and p53-associated KZNF protein (Apak) was identified as a negative regulator of p53-mediated apoptosis.
  • Apak phosphorylation by ATM kinase leads to p53 activation following methyl methanesulfonate (MMS) treatment.

Purpose of the Study:

  • To investigate the regulation of Apak in response to diverse DNA damage signals.
  • To elucidate the differential mechanisms of Apak-p53 interaction modulation by various genotoxic agents.

Main Methods:

  • Cell treatment with various DNA damaging agents (etoposide, doxorubicin, camptothecin, cisplatin, 5-fluorouracil, alpha-lipoic acid).
  • Analysis of Apak phosphorylation status (specifically at Ser68).
  • Assessment of Apak-p53 complex dissociation and p53 transcriptional activity.

Main Results:

  • Four out of seven DNA damage signals induced Apak phosphorylation and dissociation from p53, releasing p53 inhibition.
  • Etoposide, doxorubicin, camptothecin, and cisplatin treatments resulted in Apak phosphorylation and p53 activation.
  • 5-fluorouracil and alpha-lipoic acid treatments did not induce Apak phosphorylation, leading to persistent p53 inhibition.

Conclusions:

  • The Apak-p53 interaction is subject to differential regulation by distinct DNA damage signals.
  • Apak acts as a crucial checkpoint, with its phosphorylation status determining p53's apoptotic or cell cycle arrest function.
  • Understanding these differential regulations could offer new therapeutic strategies targeting p53 pathways in cancer.

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