TY - JOUR
T1 - Messenger molecules and cell death
T2 - Therapeutic implications
AU - Sedlak, Thomas W.
AU - Snyder, Solomon H.
PY - 2006/4/1
Y1 - 2006/4/1
N2 - 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.
AB - 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.
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U2 - 10.1001/jama.295.1.81
DO - 10.1001/jama.295.1.81
M3 - Review article
C2 - 16391220
AN - SCOPUS:29944439735
VL - 295
SP - 81
EP - 89
JO - JAMA - Journal of the American Medical Association
JF - JAMA - Journal of the American Medical Association
SN - 0098-7484
IS - 1
ER -