Interaction of p53 with Tumor Suppressive and Oncogenic Signaling Pathways to Control Cellular Reactive Oxygen Species Production

Ladelfa, María Fátima; Toledo, María Fernanda; Laiseca, Julieta Eva; Monte, Martín

doi:10.1089/ars.2010.3652

Cited by 54 publications

(40 citation statements)

References 165 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…P53 overexpression is a late event during tumor development and contributes to the progression of lung adenocarcinoma [24,25]. The P53 pathway has been shown to mediate cellular stress responses, inducing cell-cycle arrest, senescence, and apoptosis [26,27]. Induction of p53 by mitotic checkpoint activation is essential for protecting cells from abnormal chromosome ploidization caused by mitotic failure [28].…”

Section: Discussionmentioning

confidence: 99%

Expression and prognostic significance of centromere protein A in human lung adenocarcinoma

et al. 2012

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

Expression and prognostic significance of centromere protein A in human lung adenocarcinoma

et al. 2012

View full text Add to dashboard Cite

“…This regulation is biologically important because the magnitude and duration of p53 activity is a critical determinant of cell fate via regulation of ROS levels, which have a significant impact on cell growth, survival, and tumorigenesis. 33 Another important finding is that the antioxidant function of p53 is derived from the p53R2-catalase pathway, which maintains low ROS levels under physiological conditions. At physiological levels, p53 has a subtle but vital function in maintaining ROS at nontoxic levels through transactivation of a series of genes, including glutathione peroxidase (GPX1), sestrin family members SESN1 and SESN2, 14 aldehyde dehydrogenase (ALDH4A1), 34 TP53-induced glycolysis and apoptosis regulator (TIGAR), 17 TP53-induced nuclear protein 1 (TP53INP1), 20 and mitochondrial SOD2 (MnSOD) expression.…”

Section: Discussionmentioning

confidence: 99%

The critical role of catalase in prooxidant and antioxidant function of p53

et al. 2012

View full text Add to dashboard Cite

The tumor suppressor p53 is an important regulator of intracellular reactive oxygen species (ROS) levels, although downstream mediators of p53 remain to be elucidated. Here, we show that p53 and its downstream targets, p53-inducible ribonucleotide reductase (p53R2) and p53-inducible gene 3 (PIG3), physically and functionally interact with catalase for efficient regulation of intracellular ROS, depending on stress intensity. Under physiological conditions, the antioxidant functions of p53 are mediated by p53R2, which maintains increased catalase activity and thereby protects against endogenous ROS. After genotoxic stress, high levels of p53 and PIG3 cooperate to inhibit catalase activity, leading to a shift in the oxidant/antioxidant balance toward an oxidative status, which could augment apoptotic cell death. These results highlight the essential role of catalase in p53-mediated ROS regulation and suggest that the p53/p53R2-catalase and p53/PIG3-catalase pathways are critically involved in intracellular ROS regulation under physiological conditions and during the response to DNA damage, respectively. Reactive oxygen species (ROS) are generated as products or by-products in cells and function as signaling molecules and cellular toxicants.1,2 Therefore, a series of antioxidant mechanisms maintain and protect intracellular redox homeostasis.2-4 A shift in the balance between oxidants and antioxidants toward oxidation causes DNA mutations, protein oxidation, and lipid peroxidation, which eventually lead to loss of molecular function 1,2,5 and contribute to the pathogenesis of human diseases, including aging and cancer. 3The p53 protein has been proposed as a critical regulator of intracellular ROS levels. Upon activation following DNA damage, p53 can activate several genes that result in increased ROS generation, which contributes to the induction of apoptosis in cells with unrepaired DNA damage.6-10 The induction of apoptosis is central to the tumor-suppressive activity of p53. 11,12 By using the serial analysis of gene expression technique to evaluate the patterns of gene expression following p53 expression, a series of p53-inducible genes (PIG genes) have been identified that are predicted to encode proteins that could generate ROS. 8 Of particular interest is p53-inducible gene 3 (PIG3), which shares sequence similarity with NADPH-quinine oxidoreductase, and is induced by p53 before the onset of apoptosis and contributes to ROS generation.8 Thus, PIG3 is believed to be one of the major factors involved in p53-induced apoptosis through ROS generation. This was the first clear connection between p53 and ROS generation, but the molecular mechanisms of PIG3-induced ROS generation have not yet been elucidated. Under physiological condition, basal levels of p53 can also upregulate antioxidant genes that function to lower ROS levels, and this antioxidant function of p53 is important in preventing oxidative stress-induced DNA damage and tumor development under low-stress conditions.13-21 Thus, p53 has opposing roles in ...

show abstract

“…Because the downregulation of energy pathways and protection against cell death and oxidative stress are hallmarks of anoxia tolerance, it is not surprising to find evidence of p53 activation in the turtle (Zhang et al, 2013). Interestingly, there is also cross-talk between p53 and the phosphoinositide 3-kinase-protein kinase B (PI3K/AKT) pathway (Ladelfa et al, 2011), which is upregulated in the anoxic turtle brain (Milton et al, 2008;Nayak et al, 2011).…”

Section: Neuroprotection At the Molecular Levelmentioning

confidence: 99%

No oxygen? No problem! Intrinsic brain tolerance to hypoxia in vertebrates

Larson

Drew

Folkow

et al. 2014

Journal of Experimental Biology

131

102

View full text Add to dashboard Cite

Many vertebrates are challenged by either chronic or acute episodes of low oxygen availability in their natural environments. Brain function is especially vulnerable to the effects of hypoxia and can be irreversibly impaired by even brief periods of low oxygen supply. This review describes recent research on physiological mechanisms that have evolved in certain vertebrate species to cope with brain hypoxia. Four model systems are considered: freshwater turtles that can survive for months trapped in frozen-over lakes, arctic ground squirrels that respire at extremely low rates during winter hibernation, seals and whales that undertake breath-hold dives lasting minutes to hours, and naked mole-rats that live in crowded burrows completely underground for their entire lives. These species exhibit remarkable specializations of brain physiology that adapt them for acute or chronic episodes of hypoxia. These specializations may be reactive in nature, involving modifications to the catastrophic sequelae of oxygen deprivation that occur in non-tolerant species, or preparatory in nature, preventing the activation of those sequelae altogether. Better understanding of the mechanisms used by these hypoxiatolerant vertebrates will increase appreciation of how nervous systems are adapted for life in specific ecological niches as well as inform advances in therapy for neurological conditions such as stroke and epilepsy.KEY WORDS: Arctic ground squirrel, Cetacean, Hypoxia, Naked mole-rat, Seal, Turtle IntroductionEnvironmental conditions vary enormously for vertebrates, both with respect to the extreme conditions tolerated by a given species at different times and with respect to average living conditions tolerated by different species. Temperature is perhaps the most obvious example: from the poles to the equator, average ambient temperatures vary widely and have been accompanied by physiological adaptations appropriate to resident species; seasonal variations in temperature and resource variability can induce dramatic changes in physiological and/or behavioral patterns including migration and hibernation. Oxygen levels also vary widely, with animals adapted to sea level, high-altitude, underground and aquatic habitats. Oxygen levels can also change dramatically on a shorter-term basis, as can occur in tidal pools or in breath-hold divers. Approximately 20% of the oxygen consumed by the human body is used by the brain. The greater part of this oxygen is used to produce the ATP required to maintain the membrane potentials necessary for electrical signaling with synaptic and action potentials (Harris et al., 2012). In many vertebrates, including adult humans, interruption of the oxygen supply to the brain for more than a few minutes leads to irreversible neurological damage, including neuronal death. Without oxidative phosphorylation, ATP-dependent neuronal processes including ion transport and neurotransmitter reuptake decline sharply. Without pumping, ion gradients fail and neurons depolarize, releasing excessive levels...

show abstract

Interaction of p53 with Tumor Suppressive and Oncogenic Signaling Pathways to Control Cellular Reactive Oxygen Species Production

Cited by 54 publications

References 165 publications

Expression and prognostic significance of centromere protein A in human lung adenocarcinoma

Expression and prognostic significance of centromere protein A in human lung adenocarcinoma

The critical role of catalase in prooxidant and antioxidant function of p53

No oxygen? No problem! Intrinsic brain tolerance to hypoxia in vertebrates

Contact Info

Product

Resources

About