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Special Communication | Clinician's Corner

Messenger Molecules and Cell Death:  Therapeutic Implications

Thomas W. Sedlak, MD, PhD; Solomon H. Snyder, MD
JAMA. 2006;295(1):81-89. doi:10.1001/jama.295.1.81.
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Published online

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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Figures

Figure 1. Pathway of Bilirubin Production and Recycling by Biliverdin Reductase and Production of Carbon Monoxide
Graphic Jump Location

Bilirubin is generated by the sequential action of 2 enzymes, heme oxygenase and biliverdin reductase. In the first reaction, the heme ring is broken open and leads to the production of biliverdin, iron, and the gaseous messenger molecule, carbon monoxide (CO). Cytochrome P450 reductase provides reducing equivalents for the reaction. In the second reaction, biliverdin is reduced to the yellow pigment bilirubin, which itself may serve as an antioxidant and revert back to biliverdin. The recycling function of biliverdin reductase explains the ability of bilirubin to detoxify a 10 000-fold excess of oxidants. Inhibition of bilirubin conjugation may be a useful target to mildly increase bilirubin levels for clinical benefit. NADP indicates nicotinamide adenine dinucleotide phosphate; NADPH, reduced NADP.

Figure 2. Cell Death Pathway of Nitric Oxide (NO), Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH), and Siah1
Graphic Jump Location

Nitric oxide, a gaseous messenger released in response to cell death stimuli, is produced by the action of nitric oxide synthase (NOS), which uses the amino acid arginine as a substrate. Nitric oxide nitrosylates GAPDH at sulfur residues, and the S-nitrosylated GAPDH binds to and stabilizes the cell death protein Siah1, after which the GAPDH-Siah1 complex enters the nucleus and promotes cell death. Molecules that disrupt the GAPDH-Siah1 interaction, such as deprenyl and TCH346, may prove useful in blocking cell death. NADP indicates nicotinamide adenine dinucleotide phosphate; NADPH, reduced NADP.

Figure 3. Cytochrome c, Inositol-1,4,5-Triphosphate (IP3) Receptors, and Calcium Release During Cell Death
Graphic Jump Location

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