Stress-responsive sestrins link p53 with redox regulation and mammalian target of rapamycin signaling.
The tumor suppressor p53 protects organisms from most types of cancer through multiple mechanisms. The p53 gene encodes a stress-activated transcriptional factor that transcriptionally regulates a large set of genes with versatile functions. These p53-activated genes mitigate consequences of stress regulating cell viability, growth, proliferation, repair, and metabolism. Recently, we described a novel antioxidant function of p53, which is important for its tumor suppressor activity. Among the many antioxidant genes activated by p53, Sestrins (Sesns) are critical for suppression of reactive oxygen species (ROS) and protection from oxidative stress, transformation, and genomic instability. Sestrins can regulate ROS through their direct effect on antioxidant peroxiredoxin proteins and through the AMP-activated protein kinase-target of rapamycin signaling pathway. The AMP-activated protein kinase-target of rapamycin axis is critical for regulation of metabolism and autophagy, two processes associated with ROS production, and deregulation of this pathway increases vulnerability of the organism to stress, aging, and age-related diseases, including cancer. Recently, we have shown that inactivation of Sestrin in fly causes accumulation of age-associated damage. Hence, Sestrins can link p53 with aging and age-related diseases.
Budanov
Andrei V
AV
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA. abudanov@ucsd.edu
D000375:Aging; D000818:Animals; D001343:Autophagy / Q000502:physiology; D004249:DNA Damage / Q000502:physiology; D005786:Gene Expression Regulation; D006360:Heat-Shock Proteins / Q000378:metabolism / Q000502:physiology; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D020123:Sirolimus / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism* / Q000502:physiology; D000084622:Sestrins
D006360:Heat-Shock Proteins; D009687:Nuclear Proteins; D017382:Reactive Oxygen Species; D020123:Sirolimus; D016159:Tumor Suppressor Protein p53; C117338:SESN1 protein, human; D000084622:Sestrins; C465398:SESN2 protein, human; C485523:SESN3 protein, human