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.
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.
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.
Some tools below are only available to our subscribers or users with an online account.
Download citation file:
Web of Science® Times Cited: 29
Customize your page view by dragging & repositioning the boxes below.
More Listings atJAMACareerCenter.com >
Enter your username and email address. We'll send you a link to reset your password.
Enter your username and email address. We'll send instructions on how to reset your password to the email address we have on record.
Athens and Shibboleth are access management services that provide single sign-on to protected resources. They replace the multiple user names and passwords necessary to access subscription-based content with a single user name and password that can be entered once per session. It operates independently of a user's location or IP address. If your institution uses Athens or Shibboleth authentication, please contact your site administrator to receive your user name and password.