title: The Role of Deoxycytidine Kinase (dCK) in Radiation-Induced Cell Death.
abstract: Deoxycytidine kinase (dCK) is a key enzyme in deoxyribonucleoside salvage and the anti-tumor activity for many nucleoside analogs. dCK is activated in response to ionizing radiation (IR)-induced DNA damage and it is phosphorylated on Serine 74 by the Ataxia-Telangiectasia Mutated (ATM) kinase in order to activate the cell cycle G2/M checkpoint. However, whether dCK plays a role in radiation-induced cell death is less clear. In this study, we genetically modified dCK expression by knocking down or expressing a WT (wild-type), S74A (abrogates phosphorylation) and S74E (mimics phosphorylation) of dCK. We found that dCK could decrease IR-induced total cell death and apoptosis. Moreover, dCK increased IR-induced autophagy and dCK-S74 is required for it. Western blotting showed that the ratio of phospho-Akt/Akt, phospho-mTOR/mTOR, phospho-P70S6K/P70S6K significantly decreased in dCK-WT and dCK-S74E cells than that in dCK-S74A cells following IR treatment. Reciprocal experiment by co-immunoprecipitation showed that mTOR can interact with wild-type dCK. IR increased polyploidy and decreased G2/M arrest in dCK knock-down cells as compared with control cells. Taken together, phosphorylated and activated dCK can inhibit IR-induced cell death including apoptosis and mitotic catastrophe, and promote IR-induced autophagy through PI3K/Akt/mTOR pathway.
authors.affiliation: Key Laboratory of Radiobiology (Ministry of Health), School of Public Health, Jilin University, Changchun 130021, China. rui.zhong1702@gmail.com.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhong
authors.affiliation: Key Laboratory of Radiobiology (Ministry of Health), School of Public Health, Jilin University, Changchun 130021, China. xin-1017@163.com.|Department Radiology, the 2st Hospitals Affiliated to Jilin University, Changchun 130021, China. xin-1017@163.com.
authors.forename: Rui
authors.initials: R
authors.lastname: Xin
authors.affiliation: Key Laboratory of Radiobiology (Ministry of Health), School of Public Health, Jilin University, Changchun 130021, China. czy081206@163.com.|Department Diagnostic Imaging, Weihai Chest Hospital, Weihai 264220, China. czy081206@163.com.
authors.forename: Zongyan
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Key Laboratory of Radiobiology (Ministry of Health), School of Public Health, Jilin University, Changchun 130021, China. zrcc111@126.com.
authors.forename: Nan
authors.initials: N
authors.lastname: Liang
authors.affiliation: Key Laboratory of Radiobiology (Ministry of Health), School of Public Health, Jilin University, Changchun 130021, China. lyy2405@126.com.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Key Laboratory of Radiobiology (Ministry of Health), School of Public Health, Jilin University, Changchun 130021, China. shmm2001@126.com.
authors.forename: Shumei
authors.initials: S
authors.lastname: Ma
authors.affiliation: Key Laboratory of Radiobiology (Ministry of Health), School of Public Health, Jilin University, Changchun 130021, China. liuxiaod@jlu.edu.cn.|Department Radiation Oncology, the 2nd Hospitals Affiliated to Jilin University, Changchun 130021, China. liuxiaod@jlu.edu.cn.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Liu
mesh_terms: D019943:Amino Acid Substitution; D017209:Apoptosis / Q000235:genetics / Q000528:radiation effects*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D001343:Autophagy / Q000235:genetics / Q000528:radiation effects; D003842:Deoxycytidine Kinase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D059565:G2 Phase Cell Cycle Checkpoints / Q000235:genetics / Q000528:radiation effects; D005720:Gamma Rays; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D018716:Molecular Mimicry; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation / Q000528:radiation effects; D011485:Protein Binding / Q000528:radiation effects; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D064007:Ataxia Telangiectasia Mutated Proteins; D003842:Deoxycytidine Kinase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C576324:ATM protein, human
keywords: apoptosis; autophagy; deoxycytidine kinase (dCK); mitotic catastrophe; radiation