News and Publications

Role of Reactive Oxygen Species in Regulating the Fate of Cells

P.A. Maher, Y. Sagara, E. Mizukoshi

Reactive oxygen species (ROS) (superoxide, hydrogen peroxide, hydroxyl radical) are produced as the products or byproducts of a number of chemical reactions in the human body. In addition, cellular exposure to a variety of chemical and physical sources can cause increases in ROS. In the traditional view, ROS are harmful molecules that can indiscriminately kill cells. Indeed, ROS are implicated in the pathophysiology of eye diseases such as age-related macular degeneration, neurodegenerative diseases such as Alzheimer's and Parkinson's diseases, and even in the decline of neuronal function during normal aging.

However, ROS also are produced in cells in response to treatment with growth factors and can play important roles in growth factor-stimulated proliferation and differentiation. For example, we study fibroblast growth factor 2, a member of a family of proteins that play critical roles in a wide range of biological processes. We found that proliferation induced by this growth factor in both fibroblasts and endothelial cells depends on the production of ROS.

Thus, although high levels of ROS may be detrimental to the cell, low levels may be essential for normal cellular function. We are examining both the "good" and the "bad" sides of ROS signaling in an effort to understand how cells respond to these simple molecules and how those responses can be modulated by other agents.

Recently, we focused on identifying and characterizing agents that can block the accumulation of ROS. In nerve cells, the ability of these agents to reduce oxidative stress, which can be defined as an imbalance between the production and removal of ROS, can promote cell survival. For other cell types, such as fibroblasts and endothelial cells, these same agents could prevent inappropriate cell proliferation. In the course of these studies, we identified several mechanisms whereby agents can block the accumulation of ROS.

First, some agents are antioxidants; they interact directly with ROS and thereby remove the ROS from the cell. Second, other agents induce one or more of the defense systems used by cells to protect the cells from various types of stress. Although cells contain specific antioxidant defense systems, we found that the activation of defense systems designed to protect cells from other types of stress can also help protect cells from oxidative stress. Indeed, some of the agents that are most effective in reducing oxidative stress appear to do so by activating multiple defense systems.

Finally, a third group of agents blocks the production of ROS by mitochondria. Mitochondria normally reduce oxygen in the course of generating ATP. However, 1%-2% of this oxygen is constitutively converted to ROS, and this percentage becomes particularly important in nerve cells, which use relatively large amounts of oxygen. Furthermore, trauma and a variety of toxic agents can enhance the generation of ROS by mitochondria. Thus, agents that can block ROS production by mitochondria could be particularly effective in reducing oxidative stress, especially in diseases that have a mitochondrial component, such as Parkinson's disease.

We identified agents in each of the 3 groups and are characterizing their effects on both the good and the bad sides of ROS signaling. Among the most effective agents are the flavonoids, polyphenolic compounds ubiquitously distributed in fruits and vegetables. Several flavonoids can not only protect nerve cells from oxidative stress but also stimulate neuronal differentiation, suggesting that the compounds might be useful in the treatment of diseases that lead to the death of nerve cells.

PUBLICATIONS

Chen, Q., Yoshida, H., Schubert, D., Maher, P., Mallory, M., Masliah, E. Presenilin binding protein is associated with neurofibrillary alterations in Alzheimer's disease and stimulates tau phosphorylation. Am. J. Pathol. 159:1597, 2001.

Maher, P. Phorbol esters inhibit fibroblast growth factor-2-stimulated fibroblast proliferation by a p38 MAP kinase dependent pathway. Oncogene 21:1978, 2002.

Peng, H., Myers, J., Fang, X., Stachowiak, E.K., Maher, P.A, Martins, G.G., Popescu, G., Berezney, R., Stachowiak, M.K. Integrative nuclear FGFR1 signaling (INFS) pathway mediates activation of the tyrosine hydroxylase gene by angiotensin II, depolarization and protein kinase C. J. Neurochem. 81:506, 2002.

Reilly, J.F., Martinez, S.D., Mickey, G., Maher, P.A. A novel role for farnesyl pyrophosphate synthase in fibroblast growth factor-mediated signal transduction. Biochem. J. 366:501, 2002.

Sagara, Y., Ishige, K., Tsai, C., Maher, P. Tyrphostins protect neuronal cells from oxidative stress. J. Biol. Chem. 277:36204, 2002.

Tan, S., Schubert, D., Maher, P. Oxytosis: a novel form of programmed cell death. Curr. Top. Med. Chem. 1:497, 2001.