Tumor suppressor genes and ROS: complex networks of interactions
Vuruşaner, Beyza and Poli, Giuseppe and Başağa, Hüveyda (2012) Tumor suppressor genes and ROS: complex networks of interactions. Free Radical Biology and Medicine, 52 (1). pp. 7-18. ISSN 0891-5849 (print) ; 1873-4596 (online)
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Official URL: http://dx.doi.org/10.1016/j.freeradbiomed.2011.09.035
Tumor suppressor genes regulate diverse cellular activities including DNA damage repair, cell cycle arrest, mitogenic signaling, cell differentiation, migration, and programmed cell death. In this review the tumor suppressor genes p53, FoxO, retinoblastoma (RB), p21, p16, and breast cancer susceptibility genes 1 and 2 (BRCA1 and BRCA2) and their roles in oxidative stress are summarized with a focus on the links and interplay between their pathways and reactive oxygen species (ROS). The results of a number of studies have demonstrated an antioxidant role for tumor suppressor proteins, activating the expression of some well-known antioxidant genes in response to oxidative stress. On the other hand, recent studies have revealed a pro-oxidant role for p53 by which cellular ROS are increased by enhanced transcription of proapoptotic genes. A tightly regulated feedback loop between ROS and FoxO proteins, with ROS regulating FoxO activity through posttranslational modifications and protein interactions and FoxO controlling intracellular ROS levels, has been demonstrated. Furthermore, these studies have shown that FoxO transcription factors and p38 mitogen-activated protein kinases may interact with the RB pathway under stress conditions. In addition, cellular senescence studies established an unexpected role for ROS in inducing and maintaining senescence-induced tumor suppression that blocks cytokinesis to ensure senescent cells never divide again. p21 and p16 have been shown to act as tumor suppressor proteins and this function extends beyond cell cycle control and includes important roles in regulating oxidative stress. Consequently, these important interactions indicate a critical potential role for tumor suppressor genes in the cellular response against oxidative stress and emphasize links between ROS and tumor suppressor genes that might be therapeutic targets in oxidative damage-associated diseases.
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