Protein kinase C delta activates topoisomerase IIalpha to induce apoptotic cell death in response to DNA damage.
DNA topoisomerase II is an essential nuclear enzyme that modulates DNA processes by altering the topological state of double-stranded DNA. This enzyme is required for chromosome condensation and segregation; however, the regulatory mechanism of its activation is largely unknown. Here we demonstrate that topoisomerase IIalpha is activated in response to genotoxic stress. Concomitant with the activation, the expression of topoisomerase IIalpha is increased following DNA damage. The results also demonstrate that the proapoptotic kinase protein kinase C delta (PKCdelta) interacts with topoisomerase IIalpha. This association is in an S-phase-specific manner and is required for stabilization and catalytic activation of topoisomerase IIalpha in response to DNA damage. Conversely, inhibition of PKCdelta activity attenuates DNA damage-induced activation of topoisomerase IIalpha. Finally, aberrant activation of topoisomerase IIalpha by PKCdelta is associated with induction of apoptosis upon exposure to genotoxic agents. These findings indicate that PKCdelta regulates topoisomerase IIalpha and thereby cell fate in the genotoxic stress response.
Yoshida
Kiyotsugu
K
Department of Molecular Genetics, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan. yos.mgen@mri.tmd.ac.jp
Yamaguchi
Tomoko
T
Shinagawa
Hirokuni
H
Taira
Naoe
N
Nakayama
Keiichi I
KI
Miki
Yoshio
Y
D000951:Antigens, Neoplasm / Q000378:metabolism*; D017209:Apoptosis; D002384:Catalysis; D002478:Cells, Cultured; D004249:DNA Damage; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation; D004795:Enzyme Stability; D006801:Humans; D025941:Protein Interaction Mapping; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D051745:Protein Kinase C-delta; D004250:DNA Topoisomerases, Type II