Discovery of "Programmed Cell Life" Genes

Jeffrey A. Johnson, Ph.D.
University of Wisconsin, Madison
R01ES08089, R01ES10042, and P30ES09090

Background: Oxidative stress is associated with neuronal cell death following acute insults such as epilepsy, ischemia, hypoxia, and hypoglycemia. It is also believed to be involved in a number of chronic neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis. The mechanism by which the cells die is apoptosis or programmed cell death. The central nervous system (CNS) is particularly susceptible to oxidative stress because of its high metabolic rate which results in high rates of oxidant formation which overwhelms anti-oxidant mechanisms such as glutathione (GSH) formation.

Other researchers have shown that treating cells in culture with tert-butylhydroquinone (tBHQ), which induces detoxification enzymes via the antioxidant responsive element (ARE), can protect cells from oxidative stress. In these experiments GSH was depleted, leading to increased oxidative stress followed by apoptosis suggesting that the protective effect of tBHQ may be due to the coordinated up-regulation of several genes. The current study investigated whether the tBHQ-mediated activation of ARE is a principal component generating this protective effect.

Advance: Using a neural cell line, these investigators determined that pretreatment with tBHQ reduced hydrogen peroxide-induced cell death. Introduction of a selective inhibitor of a particular enzyme in this pathway completely reversed the protective effect of tBHQ. Microarray analysis of gene expression profiles associated with tBHQ were performed in the presence and absence of the inhibitor. Expression increased for a total of 63 genes following tBHQ treatment. The inhibitor blocked the enhanced expression in 49 of the 63 genes.

Implication: These experiments are the first to demonstrate a set of "programmed cell life" genes involved in providing protection against oxidative stress-induced programmed cell death. Disturbance in the equilibrium of this system in such a way that increase programmed cell death must be counterbalanced by increases in the expression of this set of genes.

Citation: Li J, Lee JM, Johnson JA. Microarray analysis reveals an antioxidant responsive element-driven gene set involved in conferring protection from an oxidative stress-induced apoptosis in IMR-32 cells. J Biol Chem. 2002 Jan 4;277(1):388-94.