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DNA damage response involves modulation of Ku70 and Rb functions by cyclin A1 in leukemia cells
Author(s) -
Ji Ping,
Bäumer Nicole,
Yin Taijun,
Diederichs Sven,
Zhang Feng,
Beger Carmela,
Welte Karl,
Fulda Simone,
Berdel Wolfgang E.,
Serve Hubert,
MüllerTidow Carsten
Publication year - 2007
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.22634
Subject(s) - cyclin a , cyclin a2 , cyclin d , cyclin e , cyclin b , cancer research , cyclin , cyclin dependent kinase complex , microbiology and biotechnology , biology , cyclin dependent kinase 2 , chemistry , cell cycle , kinase , biochemistry , apoptosis , protein kinase a
Cyclin A1 plays a critical role in hematopoietic malignancies, notably, acute myeloid leukemia. The molecular mechanisms of cyclin A1 action are incompletely understood. Here, we show that cyclin A1 functions are mediated by the retinoblastoma and the Ku70 pathway. High levels of cyclin A1 and the associated CDK2 kinase activity were associated with increasing levels of phosphorylated retinoblastoma in vivo . UV irradiation induced a switch of the CDK2 towards cyclin A1, with accordance to changes in CDK2 kinase activity. The C‐terminus of cyclin A1 directly interacted with Ku70, and DNA binding activity of Ku70 was modulated by cyclin A1/CDK2 and phosphatase treatment. Cyclin A1‐deficiency induced by shRNA increased apoptosis that is induced by DNA damage and death receptor ligands. Taken together, these analyses demonstrate that cyclin A1 exerts antiapoptotic functions by interacting with retinoblastoma and Ku proteins in leukemia cells. © 2007 Wiley‐Liss, Inc.