The Tumor Suppressor Gene ARF as a Sensor of Oxidative Stress

M.      Liontos; I.      S. Pateras; K.      Evangelou; V.      G. Gorgoulis

Abstract

Oxidative stress as a result of either exogenous stimuli or cellular metabolism affects several cellular processes such as proliferation, apoptosis, cell death and senescence. Consequently, it is implicated in the pathogenesis of various human diseases like cancer, diabetes mellitus, atherosclerosis, neurodegenerative diseases and aging. Oxidative stress is implicated in carcinogenesis either by directly provoking DNA damage or through the regulation of intracellular signaling cascades. In both cases the cellular response to oxidative stress is determined by the cellular context. ARF, the alternative protein product of the CDKN2A locus has been recently recognized as a novel sensor of oxidative stress, in a β-catenin and Hsp70-mediated manner. Since, improved understanding of cellular responses to oxidative stress may facilitate the design of novel antineoplastic regimens, we herein review the mechanisms by which oxidative stress promotes carcinogenesis, focusing on the role of ARF as a sensor of oxidative stress.

Keywords: ARF, DNA damage, free radicals, oxidative stress, ROS/RNS, signaling, radiation, nitric oxide, peroxynitrite anion, nitrosative stress, macromolecules, oxidation, UV light, cosmic rays, chemotherapeutics