Messenger molecules and cell death: therapeutic implications.
Programmed cell death, also called apoptosis, participates not only in normal physiologic processes such as development of the immune system, but also in many diseases. A loss of normal cell death may occur in cancer, and excessive cell death is found in a variety of neurodegenerative conditions. We describe 3 distinct pathways that regulate cell death. First, bilirubin, often thought to be a toxic end product of heme metabolism, serves as a physiologic cytoprotectant that may attenuate multiple forms of morbidity. In a second pathway, the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mediates a novel cell death cascade. Cytotoxic stimuli, via nitric oxide generation, lead to the binding of GAPDH to the protein Siah1, translocation of GAPDH-Siah1 to the nucleus, and ultimately cell death. Third, cytochrome c, released from mitochondria early in apoptosis, synergizes with inositol-1,4,5-triphosphate (IP3) to elicit massive cellular calcium release, resulting in cell death. These pathways may regulate cell survival in a variety of pathologic states and represent fertile targets for novel therapies.
Sedlak
Thomas W
TW
Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, Md 21205, USA.
Snyder
Solomon H
SH
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001663:Bilirubin / Q000502:physiology*; D015220:Calcium Channels / Q000502:physiology; D045304:Cytochromes c / Q000502:physiology*; D016503:Drug Delivery Systems; D024601:Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+) / Q000502:physiology*; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors; D009336:Necrosis / Q000503:physiopathology; D052247:Nitric Oxide Synthase Type II / Q000502:physiology; D009687:Nuclear Proteins / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000502:physiology; D000098563:Seven in Absentia Proteins
D015220:Calcium Channels; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D009687:Nuclear Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D045304:Cytochromes c; D052247:Nitric Oxide Synthase Type II; D024601:Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+); D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins; D001663:Bilirubin