The P53-Cathepsin Axis Cooperates with ROS to Activate Programmed Necrotic Death Upon DNA Damage
The p53-cathepsin axis cooperates with ROS to activate programmed necrotic death upon DNA damage Ho-Chou Tua,1, Decheng Rena,1, Gary X. Wanga, David Y. Chena, Todd D. Westergarda, Hyungjin Kima, Satoru Sasagawaa, James J.-D. Hsieha,b, and Emily H.-Y. Chenga,b,c,2 aDepartment of Medicine, Molecular Oncology, bSiteman Cancer Center, and cDepartment of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110 Edited by Stuart A. Kornfeld, Washington University School of Medicine, St. Louis, MO, and approved November 25, 2008 (received for review August 19, 2008) Three forms of cell death have been described: apoptosis, autophagic cells that are deprived of the apoptotic gateway to mediate cyto- cell death, and necrosis. Although genetic and biochemical studies chrome c release for caspase activation (Fig. S1) (9–11, 19, 20). have formulated a detailed blueprint concerning the apoptotic net- Despite the lack of caspase activation (20), DKO cells eventually work, necrosis is generally perceived as a passive cellular demise succumb to various death signals manifesting a much slower death resulted from unmanageable physical damages. Here, we conclude an kinetics compared with wild-type cells (Fig. 1A, Fig. S2, and data active de novo genetic program underlying DNA damage-induced not shown). To investigate the mechanism(s) underlying BAX/ necrosis, thus assigning necrotic cell death as a form of ‘‘programmed BAK-independent cell death, we first examined the morphological cell death.’’ Cells deficient of the essential mitochondrial apoptotic features of the dying DKO cells. Electron microscopy uncovered effectors, BAX and BAK, ultimately succumbed to DNA damage, signature characteristics of necrosis in DKO cells after DNA exhibiting signature necrotic characteristics.
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