Role of AIF in caspase-dependent and caspase-independent cell death.
The major challenge in treating cancer is that many tumor cells carry mutations in key apoptotic genes such as p53, Bcl family proteins or those affecting caspase signaling. Such defects render treatment with traditional chemotherapeutic agents ineffective. Many studies have demonstrated the importance of caspase-independent cell death pathways in injury, degenerative diseases and tumor tissue. It is now recognized that in addition to their critical role in the production of cellular energy, mitochondria are also the source of key proapoptotic molecules involved in caspase activation. More recently, it has been discovered that in response to apoptotic stimuli, mitochondria can also release caspase-independent cell death effectors such as AIF and Endonuclease G. In this review, we examine the role of Bcl family proteins and poly(ADP-ribose) polymerase-1 signaling in the regulation of these apoptotic pathways and address the ongoing controversies in this field. Continued study of the mechanisms of apoptosis including caspase-independent death processes are likely to reveal novel therapeutic targets for the treatment of diverse human pathologies including cancer, neurodegenerative diseases and acute injuries such as stroke or myocardial infarction.
Cregan
Sean P
SP
Department of Cellular and Molecular Medicine, Ottawa Health Research Institute, University of Ottawa, 451 Smyth Rd., Ottawa, Canada K1H 8M5.
Dawson
Valina L
VL
Slack
Ruth S
RS
D000818:Animals; D017209:Apoptosis; D051033:Apoptosis Inducing Factor; D020169:Caspases / Q000502:physiology*; D005420:Flavoproteins / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology*; D008928:Mitochondria / Q000502:physiology; D011065:Poly(ADP-ribose) Polymerases / Q000502:physiology
C494829:AIFM1 protein, human; D051033:Apoptosis Inducing Factor; D005420:Flavoproteins; D008565:Membrane Proteins; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases