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

Abstract

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."

• Authors: 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
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 106 Issue 4 Pg. 1093-8 (Jan 27 2009) ISSN: 1091-6490 [Electronic] United States
• PMID: 19144918 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Bak1 protein, mouse
• Bax protein, mouse
• Reactive Oxygen Species
• Tumor Suppressor Protein p53
• bcl-2 Homologous Antagonist-Killer Protein
• bcl-2-Associated X Protein
• Cathepsins
• Cysteine Endopeptidases
• cathepsin Q

Topics

• Animals
• Cathepsins (genetics, metabolism)
• Cell Line, Tumor
• Cysteine Endopeptidases (genetics, metabolism)
• DNA Damage
• Fibroblasts (pathology, ultrastructure)
• Humans
• Mice
• Necrosis (pathology)
• Neoplasm Transplantation
• Neoplasms (pathology, ultrastructure)
• Reactive Oxygen Species (metabolism)
• Transcriptional Activation (genetics)
• Transplantation, Homologous
• Tumor Suppressor Protein p53 (metabolism)
• bcl-2 Homologous Antagonist-Killer Protein (deficiency, metabolism)
• bcl-2-Associated X Protein (deficiency, metabolism)