Inositol pyrophosphates mediate the DNA-PK/ATM-p53 cell death pathway by regulating CK2 phosphorylation of Tti1/Tel2

Mol Cell. 2014 Apr 10;54(1):119-132. doi: 10.1016/j.molcel.2014.02.020. Epub 2014 Mar 20.

Abstract

The apoptotic actions of p53 require its phosphorylation by a family of phosphoinositide-3-kinase-related-kinases (PIKKs), which include DNA-PKcs and ATM. These kinases are stabilized by the TTT (Tel2, Tti1, Tti2) cochaperone family, whose actions are mediated by CK2 phosphorylation. The inositol pyrophosphates, such as 5-diphosphoinositol pentakisphosphate (IP7), are generated by a family of inositol hexakisphosphate kinases (IP6Ks), of which IP6K2 has been implicated in p53-associated cell death. In the present study we report an apoptotic signaling cascade linking CK2, TTT, the PIKKs, and p53. We demonstrate that IP7, formed by IP6K2, binds CK2 to enhance its phosphorylation of the TTT complex, thereby stabilizing DNA-PKcs and ATM. This process stimulates p53 phosphorylation at serine 15 to activate the cell death program in human cancer cells and in murine B cells.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Apoptosis*
  • Ataxia Telangiectasia Mutated Proteins / genetics
  • Ataxia Telangiectasia Mutated Proteins / metabolism*
  • B-Lymphocytes / enzymology
  • B-Lymphocytes / pathology
  • Binding Sites
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Casein Kinase II / genetics
  • Casein Kinase II / metabolism*
  • DNA-Activated Protein Kinase / genetics
  • DNA-Activated Protein Kinase / metabolism*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Enzyme Stability
  • HCT116 Cells
  • HEK293 Cells
  • Humans
  • Inositol Phosphates / metabolism*
  • Intracellular Signaling Peptides and Proteins
  • Mice, Knockout
  • Neoplasms / enzymology
  • Neoplasms / genetics
  • Neoplasms / pathology
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Phosphorylation
  • Phosphotransferases (Phosphate Group Acceptor) / deficiency
  • Phosphotransferases (Phosphate Group Acceptor) / genetics
  • Proto-Oncogene Proteins c-ets / genetics
  • Proto-Oncogene Proteins c-ets / metabolism*
  • RNA Interference
  • Serine
  • Signal Transduction
  • Telomere-Binding Proteins / genetics
  • Telomere-Binding Proteins / metabolism*
  • Transfection
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Carrier Proteins
  • DNA-Binding Proteins
  • ETV7 protein, human
  • Inositol Phosphates
  • Intracellular Signaling Peptides and Proteins
  • Nuclear Proteins
  • Proto-Oncogene Proteins c-ets
  • TP53 protein, human
  • Tel2 protein, mouse
  • Telomere-Binding Proteins
  • Tti1 protein, human
  • Tti1 protein, mouse
  • Tumor Suppressor Protein p53
  • Serine
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • Casein Kinase II
  • DNA-Activated Protein Kinase
  • PRKDC protein, human
  • Prkdc protein, mouse
  • Phosphotransferases (Phosphate Group Acceptor)
  • inositol hexakisphosphate kinase