Special Communication
Clinician's Corner
January 4, 2006

Messenger Molecules and Cell DeathTherapeutic Implications

Author Affiliations

Author Affiliations: Departments of Neuroscience and Psychiatry and Behavioral Sciences (Drs Sedlak and Snyder) and Pharmacology and Molecular Sciences (Dr Snyder), Johns Hopkins School of Medicine, Baltimore, Md.

JAMA. 2006;295(1):81-89. doi:10.1001/jama.295.1.81

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.