Research Article: The Role of p66shc in Oxidative Stress and Apoptosis

Date Published: , 2010

Publisher: A.I. Gordeyev

Author(s): E.R. Galimov.



p66shcis a gene that regulates the level of reactive oxygen species (ROS), apoptosis induction, and lifespan in mammals. Miceknocked out forp66shchave a lifespan~30% longeranddemonstrate an enhanced resistance to oxidative stress and age-related pathologies such as hypercholesterolemia, ischemia, and hyperglycemia. In this respect, p66shc is a promising pharmacological target for the treatment of age-related diseases. In this review, an attempt has been made to survey and put to a critical analysis data concerning the involvement of p66shс in the different signaling pathways that regulate oxidative stress and apoptosis.

Partial Text

The identification of the mutations that lead to the prolongation of the lifespan of various model organisms shows that aging can be considered as a genetic program [1]. One of these genes is p66shc , the deletion of which results in a 30% increase in the lifespan. It is important to note that miceknocked out for p66shc , in comparison with other mouse models with a prolonged lifespan (e.g., mice with the deleted gene of a growth hormone receptor), are fertile and exhibit a normal phenotype [2]. These mice are resistant to oxidative stress and age-related pathologies such as atherosclerosis [3], endothelial disorders [4], AGE (advanced glycation end products)-dependent glomerulopathy related to diabetes mellitus [5, 6], and ethanol-induced liver affection [7].

Studies on mice with a knocked out p66shc gene revealed decreased levels of intracellular ROS, as determined by means of ROS-sensitive probes, as well as reduced levels of oxidative damages to DNA and proteins, estimated by measuring 8-oxo-deoxiguanosine and nitrotyrosines [3,4,14-16]. The mutant mice exhibited higher resistance to paraquat-induced oxidative stress [2]. Studies on various p66shc -deficient cell lines (ones with a deleted p66shc -gene, or cells with a dominant-negative phenotype caused by a Ser36Ala substitution in the target gene) derived from mice, rats, and a human showed that p66shc plays an important role in apoptosis induced by various agents (Table 1). P66shc-mediated oxidative stress is assumed to be the key factor in these experimental models of apoptosis. In particular, certain published data indicate the importance of p66shc-induced oxidative stress in the p53-dependent apoptotic pathway [14]. Data derived from physiological experiments have led to similar conclusions (Table 2).

By now, we know the mechanisms p66shc exploits to increase intracellular ROS levels: activation of membrane-bound NADPH-oxidases, down-regulation of antioxidant enzymes synthesis, and generation of ROS in mitochondria.

According to current views, p66shc is a pro-apoptotic protein which regulates oxidative stress and induces the mitochondrial apoptosis pathway by means of redox activity. Although the physiological role of p66shc has been extensively studied, little is known about the precise mechanism of action underlying its redox functions and participation in apoptosis induction. Further studies will endeavor to elucidate the precise mechanism of p66shc translocation into mitochondria and the localization of p66shc-dependent ROS production in the cell. Although p66shc phosphorylation at Ser36 is one of the indispensible steps of apoptosis, it was shown that the mitochondrial pool of p66 is not phosphorylated. This indicates that p66shc phosphorylated at Ser36 probably participates in pro-apoptotic events outside mitochondria.