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Inhibition of dna-dependent protein kinase catalytic subunit by Small Molecule Inhibitor NU7026 Sensitizes Human Leukemic K562 Cells to Benzene Metabolite-induced Apoptosis

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2013年第1期33卷 43-50页

作者：游浩孔萌萌王立萍肖潇廖汉林毕卓悦燕虹王红汪春红马强刘燕群毕勇毅 School of Public Health Wuhan University School of Medicine Jianghan University School of Pharmaceutical Science Wuhan University Receptor Biology Laboratory Toxicology and Molecular Biology BranchHealth Effects Laboratory DivisionNational Institute for Occupational Safety and Health

Benzene is an established leukotoxin and leukemogen in humans. We have previously re- ported that exposure of workers to benzene and to benzene metabolite hydroquinone in cultured cells induced dna-dependent protein kinase catalytic subunit （dna-PKcs） to mediate the cellular response to dna double strand break （DSB） caused by dna-damaging metabolites. In this study, we used a new, small molecule, a selective inhibitor of dna-PKcs, 2-（morpholin-4-yl）-benzo[h]chomen-4-one （NU7026）, as a probe to analyze the molecular events and pathways in hydroquinone-induced dna DSB repair and apoptosis. Inhibition of dna-PKcs by NU7026 markedly potentiated the apoptotic and growth inhibitory effects of hydroquinone in proerythroid leukemic K562 cells in a dose-dependent manner. Treatment with NU7026 did not alter the production of reactive oxygen species and oxidative stress by hydroquinone but repressed the protein level of dna-PKcs and blocked the induction of the kinase mRNA and protein expression by hydroquinone. Moreover, hydroquinone increased the phos- phorylation of Akt to activate Akt, whereas co-treatment with NU7026 prevented the activation of Akt by hydroquinone. Lastly, hydroquinone and NU7026 exhibited synergistic effects on promoting apop- tosis by increasing the protein levels of pro-apoptotic proteins Bax and caspase-3 but decreasing the protein expression of anti-apoptotic protein Bcl-2. Taken together, the findings reveal a central role of dna-PKcs in hydroquinone-induced hematotoxicity in which it coordinates dna DSB repair, cell cycle progression, and apoptosis to regulate the response to hydroquinone-induced dna damage.

关键词： benzene dna-dependent protein kinase catalytic subunit 2-(morpholin-4-yl)- benzo[h]chomen-4-one Akt dna double strand break

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PI3K-like kinases Restrain Pim Gene Expression in Endothelial Cells

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2012年第1期32卷 17-23页

作者：闵新文唐杰汪引芳余明华赵黎丙杨汉东张鹏马业新 Department of Cardiology Tongji HospitalTongji Medical CollegeHuazhong University of Science and Technology Institute of Cardiovascular Science Dongfeng HospitalHubei University of Medicine Department of Anatomy Hubei University of Medicine Department of Physiology Hubei University of Medicine

Pim kinases contribute to tumor formation and development of lymphoma,which shows enhanced dna replication,dna recombination and *** cells (ECs) express all the three members of Pim kinase gene *** hypothesized that dna repair gene would regulate Pim ex-pression in *** umbilical vein endothelial cells (HUVECs) were isolated and maintained in M199 culture *** cellular distribution of Pim-3 in ECs was determined by immunofluorescent *** siRNA fragments were synthesized and transfected by using Lipofectamine *** total cellular RNA was extracted from the cells by using Trizol *** were quantified by semi-quantity *** effects of LY294002 and wortmannin on RNA stability in ECs were also *** data showed that LY294002 and wortmannin,phosphatidylinositol 3-kinase (PI3K) and PI3K-like kinase inhibitors,increased Pim mRNA expression in ECs without altering the mRNA *** interference (RNAi) targeting dna-dependent protein kinase catalytic subunit (dna-PKcs) and ataxia telangiectasia mutated (ATM) increased mRNA expression of Pim-3 and Pim-1,*** of Akt decreased Pim-1 instead of Pm-2 and Pim-3 gene expression in *** etoposide,a nucleoside analogue,which could activate dna-PKcs and ATM,increased Pim expression in *** study indicates that the expression of Pim kinases is physiologically related to dna-PKcs and ATM in ECs.

关键词： endothelial cell Pim-3 phosphatidylinositol 3-kinase dna-dependent protein kinase catalytic subunit ataxia telangiectasia mutated

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