E1A enhances cellular sensitivity to DNA-damage-induced apoptosis through PIDD-dependent caspase-2 activation.
Expression of the adenoviral protein, E1A, sensitizes mammalian cells to a wide variety of apoptosis-inducing agents through multiple cellular pathways. For example, E1A sensitizes cells to apoptosis induced by TNF-superfamily members by inhibiting NF-kappa B (NF-κB)-dependent gene expression. In contrast, E1A sensitization to nitric oxide, an inducer of the intrinsic apoptotic pathway, is not dependent upon repression of NF-κB-dependent transcription but rather is dependent upon caspase-2 activation. The latter observation suggested that E1A-induced enhancement of caspase-2 activation might be a critical factor in cellular sensitization to other intrinsic apoptosis pathway-inducing agents. Etoposide and gemcitabine are two DNA damaging agents that induce intrinsic apoptosis. Here we report that E1A-induced sensitization to both of these agents, like NO, is independent of NF-κB activation but dependent on caspase-2 activation. The results show that caspase-2 is a key mitochondrial-injuring caspase during etoposide and gemcitabine-induced apoptosis of E1A-positive cells, and that caspase-2 is required for induction of caspase-3 activity by both chemotherapeutic agents. Expression of PIDD was required for caspase-2 activation, mitochondrial injury and enhanced apoptotic cell death. Furthermore, E1A-enhanced sensitivity to injury-induced apoptosis required PIDD cleavage to PIDD-CC. These results define the PIDD/caspase-2 pathway as a key apical, mitochondrial-injuring mechanism in E1A-induced sensitivity of mammalian cells to chemotherapeutic agents.
Research Section, Edward Hines, Jr. VA Hospital, 5000 S 5th Ave., Hines, IL 60141, USA; Division of Infectious Diseases, Loyola University Medical Center; Infectious Diseases and Immunology Research Institute, Loyola University Chicago-Stritch School of Medicine, Maywood, IL, USA; Department of Microbiology and Immunology, Loyola University Chicago-Stritch School of Medicine, Maywood, IL, USA.
Jay R
JR
Radke
Department of Medicine, Section of Infectious Diseases, University of Illinois at Chicago , Chicago, IL, USA.
Zeba K
ZK
Siddiqui
Department of Microbiology and Immunology, Loyola University Chicago-Stritch School of Medicine , Maywood, IL, USA.
Iris
I
Figueroa
Research Section, Edward Hines, Jr. VA Hospital, 5000 S 5th Ave., Hines, IL 60141, USA; Division of Infectious Diseases, Loyola University Medical Center; Infectious Diseases and Immunology Research Institute, Loyola University Chicago-Stritch School of Medicine, Maywood, IL, USA; Department of Microbiology and Immunology, Loyola University Chicago-Stritch School of Medicine, Maywood, IL, USA.
James L
JL
Cook