The p53-cathepsin axis cooperates with ROS to activate programmed necrotic death upon DNA damage
Proceedings of the National Academy of Sciences, 2009•National Acad Sciences
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 …
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 …
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.”
National Acad Sciences