Role of oxidative/nitrosative stress-mediated Bcl-2 regulation in apoptosis and malignant transformation.
Azad NG; Iyer A; Vallyathan V; Wang L; Castranova V; Stehlik C; Rojanasakul Y
Ann NY Acad Sci 2010 Aug; 1203:1-6
Bcl-2 is a key apoptosis regulatory protein of the mitochondrial death pathway. The oncogenic potential of Bcl-2 is well established, with its overexpression reported in various cancers. The antiapoptotic function of Bcl-2 is closely associated with its expression levels. Reactive oxygen and nitrogen species (ROS/RNS) are important intracellular signaling molecules that play a key role in various physiological processes including apoptosis. We have recently reported that ROS and RNS can regulate Bcl-2 expression levels, thereby impacting its function. Superoxide anion (·O(2)(-)) plays a proapoptotic role by causing downregulation and degradation of Bcl-2 protein through the ubiquitin-proteasomal pathway. In contrast, nitric oxide (NO)-mediated S-nitrosylation of Bcl-2 prevents its ubiquitination and subsequent proteasomal degradation, leading to inhibition of apoptosis. Interestingly, NO-mediated S-nitrosylation and stabilization of Bcl-2 protein was the primary mechanism involved in the malignant transformation of nontumorigenic lung epithelial cells in response to long-term carcinogen exposure. We describe a novel mechanism of Bcl-2 regulation by ·O(2)(-) and NO, providing a new dimension to reactive species-mediated Bcl-2 stability, apoptotic cell death, and cancer development.
Oncogenic-agents; Proteins; Tumors; Pathology; Oxidative-processes; Malignant-neoplasms; Cancer; Gene-mutation; Nitrogen-oxides; Oxides; Cell-transformation; Cellular-reactions; Physiological-response; Cell-damage; Lung-cells;
Author Keywords: Bcl-2; nitric oxide; superoxide; apoptosis; malignant transformation
Neelam Azad, Ph.D., Kittrell Hall, Queen and Tyler Streets, Department of Pharmaceutical Sciences, School of Pharmacy, Hampton University, Hampton, VA 23668
Annals of the New York Academy of Sciences