The p53-cathepsin axis cooperates with ROS to activate programmed necrotic death upon DNA damage

Ho Chou Tu, Decheng Ren, Gary X. Wang, David Y. Chen, Todd D. Westergard, Hyungjin Kim, Satoru Sasagawa, James J.D. Hsieh, Emily H.Y. Cheng

Research output: Contribution to journalArticlepeer-review

92 Scopus citations


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."

Original languageEnglish
Pages (from-to)1093-1098
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number4
StatePublished - Jan 27 2009


  • Apoptosis
  • BAK
  • BAX
  • Caspase-independent cell death
  • Necrosis


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