The p53-cathepsin axis cooperates with ROS to activate programmed necrotic death upon DNA damage.
Three forms of cell death have been described: apoptosis, autophagic cell death, and necrosis. Although genetic and biochemical studies have formulated a detailed blueprint concerning the apoptotic network, necrosis is generally perceived as a passive cellular demise resulted from unmanageable physical damages. Here, we conclude an active de novo genetic program underlying DNA damage-induced necrosis, thus assigning necrotic cell death as a form of "programmed cell death." Cells deficient of the essential mitochondrial apoptotic effectors, BAX and BAK, ultimately succumbed to DNA damage, exhibiting signature necrotic characteristics. Importantly, this genotoxic stress-triggered necrosis was abrogated when either transcription or translation was inhibited. We pinpointed the p53-cathepsin axis as the quintessential framework underlying necrotic cell death. p53 induces cathepsin Q that cooperates with reactive oxygen species (ROS) to execute necrosis. Moreover, we presented the in vivo evidence of p53-activated necrosis in tumor allografts. Current study lays the foundation for future experimental and therapeutic discoveries aimed at "programmed necrotic death."
Tu
Ho-Chou
HC
Department of Medicine, Molecular Oncology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Ren
Decheng
D
Wang
Gary X
GX
Chen
David Y
DY
Westergard
Todd D
TD
Kim
Hyungjin
H
Sasagawa
Satoru
S
Hsieh
James J-D
JJ
Cheng
Emily H-Y
EH
D000818:Animals; D002403:Cathepsins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D005347:Fibroblasts / Q000473:pathology / Q000648:ultrastructure; D006801:Humans; D051379:Mice; D009336:Necrosis / Q000473:pathology*; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000473:pathology / Q000648:ultrastructure; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015533:Transcriptional Activation / Q000235:genetics; D014184:Transplantation, Homologous; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000172:deficiency / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000172:deficiency / Q000378:metabolism
C494773:Bak1 protein, mouse; C494827:Bax protein, mouse; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D002403:Cathepsins; D003546:Cysteine Endopeptidases; C404746:cathepsin Q