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Absolute Quantitation of Inositol Pyrophosphates by Capillary Electrophoresis Electrospray Ionization Mass Spectrometry
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Inositol pyrophosphates mediate the DNA-PK/ATM-p53 cell death pathway by regulating CK2 phosphorylation of Tti1/Tel2

Feng Rao1, Jiyoung Cha1, Jing Xu1

  • 1The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Molecular Cell
|March 25, 2014
PubMed

Insights

Inositol pyrophosphate IP7 activates a signaling cascade, enhancing the stability of key kinases like DNA-PKcs and ATM. This leads to p53 phosphorylation and activation of cell death programs in cancer and immune cells.

Area of Science:

  • Molecular Biology
  • Cellular Signaling
  • Cancer Research

Background:

  • The tumor suppressor p53 induces apoptosis upon phosphorylation by phosphoinositide-3-kinase-related kinases (PIKKs), including DNA-PKcs and ATM.
  • The Tel2, Tti1, Tti2 (TTT) cochaperone complex stabilizes PIKKs, with its activity regulated by CK2 phosphorylation.
  • Inositol pyrophosphates, such as 5-diphosphoinositol pentakisphosphate (IP7), are produced by inositol hexakisphosphate kinases (IP6Ks), and IP6K2 is linked to p53-mediated cell death.

Purpose of the Study:

  • To elucidate an apoptotic signaling cascade involving CK2, TTT complex, PIKKs, and p53.
  • To investigate the role of inositol pyrophosphate IP7 in regulating this pathway.

Main Methods:

  • Investigated the interaction between IP7, CK2, and the TTT complex.
  • Assessed the impact of IP7 on CK2-mediated phosphorylation of the TTT complex.
  • Examined the effect on the stability of DNA-PKcs and ATM.
  • Measured p53 phosphorylation at serine 15 and subsequent activation of cell death.

Main Results:

  • IP7, generated by IP6K2, directly binds to CK2.
  • This binding enhances CK2's phosphorylation of the TTT complex, stabilizing DNA-PKcs and ATM.
  • Stabilized PIKKs promote p53 phosphorylation at serine 15, initiating apoptosis.
  • This cascade was confirmed in human cancer cells and murine B cells.

Conclusions:

  • A novel apoptotic signaling pathway is identified, linking IP7 production to p53 activation.
  • IP7 acts as a crucial regulator, stabilizing PIKKs through the CK2-TTT complex.
  • This pathway represents a potential therapeutic target for activating cell death in cancer.

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