News and Publications

Role of Reactive Oxygen Species in Regulating the Fate of Cells

P.A. Maher, Y. Sagara, J.F. Reilly, S. Martinez

We focus on understanding the factors that determine the fate of a cell. Whether a cell lives or dies or proliferates, remains quiescent, or differentiates can have important consequences throughout the life span of an organism. Inappropriate events in an embryo can lead to developmental defects and later in adulthood to a variety of pathophysiologic conditions.

Among the factors that mediate the fate of a cell is fibroblast growth factor 2 (FGF-2), a member of a family of proteins that play critical roles in a wide range of biological processes, including angiogenesis, wound healing, and neoplastic transformation. We recently identified several signaling pathways that mediate cell type--specific outcomes to treatment with FGF-2. One of these pathways is specifically required for FGF-2--mediated cell proliferation. Understanding how treatment of cells with FGF-2 regulates the activity of this pathway could provide a means for controlling inappropriate cell proliferation in diseases such as cancer.

We discovered that the pathway required for FGF-2--mediated cell proliferation is activated by a novel mechanism that involves the generation of reactive oxygen species. Although according to conventional wisdom, reactive oxygen species are generally harmful to cells, recent evidence suggests that these molecules can also mediate specific intracellular signaling pathways. However, relatively little is known about the specific mechanisms through which reactive oxygen species act. One of our current goals is to understand how these simple molecules can regulate the generation of diverse cellular phenotypes.

Although reactive oxygen species can mediate positive outcomes in cells under certain conditions, they can also promote cell death. In nerve cells, oxidative stress, an imbalance in the production and removal of reactive oxygen species, is associated with the nerve cell death that occurs in a number of neurodegenerative diseases and with the cognitive decline associated with normal aging. We are studying pathways involved in protecting nerve cells from oxidative stress. We use a model system that mimics several of the changes seen in the nerve cells that die in Parkinson's disease. In this model, oxidative stress is induced in nerve cells by causing a decrease in glutathione, the major intracellular antioxidant.

Depletion of glutathione leads to an exponential increase in the levels of reactive oxygen species and a subsequent increase in intracellular calcium levels, which is, literally, the "kiss of death." We identified molecules that can act at each of these 3 steps to block cell death, and we are characterizing the specific modes of action. Of particular interest are molecules that increase the intracellular levels of glutathione. These molecules increase glutathione levels by a novel mechanism that involves modulating the activity of translation initiation factor eIF2a. This factor controls the rate of protein synthesis in cells, and its activity can be modulated by certain types of stress. This modulation results in a decrease in overall protein synthesis but an upregulation in the synthesis of a small subset of proteins. Our data suggest that this small subset includes the rate-limiting enzyme for glutathione biosynthesis and that the upregulation of this enzyme allows cells to become more resistant to conditions in which intracellular glutathione is depleted.

These data suggest that low levels of certain types of stress may actually be beneficial to nerve cells, protecting the cells from more severe forms of stress such as the oxidative stress that leads to cell death in both experimental models and in neurodegenerative diseases. Thus, the whole organism appears to recapitulate the individual cell: a little stress can be good, but too much can have catastrophic consequences.

PUBLICATIONS

Maher, P. How protein kinase C activation protects nerve cells from oxidative stress-induced cell death. J. Neurosci. 21:2929, 2001.

Maher, P. The role of calcium in oxidative stress-induced nerve cell death. Recent Res. Dev. Neurochem. 3:275, 2000.

Maher, P., Schubert, D. Signaling by reactive oxygen species in the nervous system. Cell. Mol. Life Sci. 57:1287, 2000.

Maher, P.A. Disruption of cell-substrate adhesion activates the protein tyrosine kinase pp60^c-src. Exp. Cell Res. 260:189, 2000.

Peng, H., Moffett, J., Myers, J., Fang, X., Stachowiak, E.K., Maher, P., Kratz, E., Hines, J., Fluharty, S.J., Mizukoshi, E., Bloom, D.C., Stachowiak, M.K. Novel nuclear signaling pathway mediates activation of the fibroblast growth factor-2 gene by type 1 and type 2 angiotensin II receptors. Mol. Biol. Cell 12:449, 2001.

Piotrowicz, R.S., Ding, L., Maher, P., Levin, E.G. Inhibition of cell migration by 24-kDa fibroblast growth factor-2 is dependent upon the estrogen receptor. J. Biol. Chem. 276:3963, 2001.

Reilly, J.F., Maher, P.A. Importin ß-mediated nuclear import of fibroblast growth factor receptor: Role in cell proliferation. J. Cell Biol. 152:1307, 2001.

Tan, S., Somia, N., Maher, P., Schubert, D. Regulation of antioxidant metabolism by translation initiation factor 2a. J. Cell Biol. 152:997, 2001.