activation of jnk triggers release of brd4 from mitotic chromosomes and mediates protection from drug-induced mitotic stress激活物触发释放brd4从药物引起的有丝分裂染色体有丝分裂和调节保护压力.pdfVIP

Activation of JNK Triggers Release of Brd4 from Mitotic Chromosomes and Mediates Protection from Drug- Induced Mitotic Stress 1,2,3 1 2 3 1 Akira Nishiyama , Anup Dey , Tomohiko Tamura , Minoru Ko , Keiko Ozato * 1 Program in Genomics of Differentiation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, United States of America, 2 Department of Immunology, Yokohama City University Graduate School of Medicine, Kanazawa-ku, Yokohama, Kanagawa, Japan, 3 Section on Developmental Genomics and Aging, Laboratory of Genetics, National Institute of Aging, National Institutes of Health, Baltimore, Maryland, United States of America Abstract Some anti-cancer drugs, including those that alter microtubule dynamics target mitotic cells and induce apoptosis in some cell types. However, such drugs elicit protective responses in other cell types allowing cells to escape from drug-induced mitotic inhibition. Cells with a faulty protective mechanism undergo defective mitosis, leading to genome instability. Brd4 is a double bromodomain protein that remains on chromosomes during mitosis. However, Brd4 is released from mitotic chromosomes when cells are exposed to anti-mitotic drugs including nocodazole. Neither the mechanisms, nor the biological significance of drug-induced Brd4 release has been fully understood. We found that deletion of the internal C- terminal region abolished nocodazole induced Brd4 release from mouse P19 cells. Furthermore, cells expressing truncated Brd4, unable to dissociate from chromosomes were blocked from mitotic progression and failed to complete cell division. We also found that pharmacological and peptide inhibitors of the c-jun-N-terminal kinases (JNK