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

Overview

MeSH Major

  • Cathepsins
  • Cysteine Endopeptidases
  • DNA Damage
  • Necrosis
  • Reactive Oxygen Species
  • Tumor Suppressor Protein p53

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."

publication date

  • January 27, 2009

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC2633558

Digital Object Identifier (DOI)

  • 10.1073/pnas.0808173106

PubMed ID

  • 19144918

Additional Document Info

start page

  • 1093

end page

  • 8

volume

  • 106

number

  • 4