TY - JOUR
T1 - Inositol Pyrophosphates Mediate the DNA-PK/ATM-p53 Cell Death Pathway by Regulating CK2 Phosphorylation of Tti1/Tel2
AU - Rao, Feng
AU - Cha, Jiyoung
AU - Xu, Jing
AU - Xu, Risheng
AU - Vandiver, M. Scott
AU - Tyagi, Richa
AU - Tokhunts, Robert
AU - Koldobskiy, Michael A.
AU - Fu, Chenglai
AU - Barrow, Roxanne
AU - Wu, Mingxuan
AU - Fiedler, Dorothea
AU - Barrow, James C.
AU - Snyder, Solomon H.
N1 - Funding Information:
We thank Drs. S.J. Boulton, F. Basserman, and S.J. Elledge for kindly providing the phospho-Tel2 (S487/491) antibody, phospho-Tti1 (S828) antibody, and shTti1 construct, respectively. We also acknowledge Drs. J. Barbi, F. Pan, Y. Dang, and J. Liu for kindly providing experimental tools, and members of the Snyder laboratory for reagents and discussions. This work was supported by U.S. Public Health Service Grant DA-000266 (to S.H.S.).
PY - 2014/4/10
Y1 - 2014/4/10
N2 - 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.
AB - 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.
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U2 - 10.1016/j.molcel.2014.02.020
DO - 10.1016/j.molcel.2014.02.020
M3 - Article
C2 - 24657168
AN - SCOPUS:84898022580
SN - 1097-2765
VL - 54
SP - 119
EP - 132
JO - Molecular cell
JF - Molecular cell
IS - 1
ER -