The p53–p66shc–Manganese Superoxide Dismutase (MnSOD) network: A mitochondrial intrigue to generate reactive oxygen species

Pani, Giovambattista; Koch, Osvaldo R.; Galeotti, T.

doi:10.1016/j.biocel.2008.10.011

Cited by 90 publications

(65 citation statements)

References 18 publications

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“…While mitochondrial ROS generally operate in the context of stress cascades eventually linked to cell death [64], lines of evidence exist for a deliberate and finely regulated formation of oxidants in the organelle [65][66][67].…”

Section: A Tale Of 3ms: Motility and Metabolism In Metastasismentioning

confidence: 99%

Metastasis: cancer cell’s escape from oxidative stress

Pani¹,

Galeotti

Chiarugi

2010

Cancer Metastasis Rev

Self Cite

280

218

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According to a "canonical" view, reactive oxygen species (ROS) positively contribute, in different ways, to carcinogenesis and to malignant progression of tumor cells: they drive genomic damage and genetic instability, transduce, as signaling intermediates, mitogenic and survival inputs by growth factor receptors and adhesion molecules, promote cell motility and shape the tumor microenvironment by inducing inflammation/repair and angiogenesis. Chemopreventive and tumor-inhibitory effects of endogenous, diet-derived or supplemented antioxidants largely support this notion. However, emerging lines of evidence indicates that tumor cells also need to defend themselves from oxidative damage in order to survive and successfully spread at distance. This "heresy" has recently received important impulse from studies on the role of antioxidant capacity in cancer stem cells self-renewal and resistance to therapy; additionally, the transforming activity of some oncogenes has been unexpectedly linked to their capacity to maintain elevated intracellular levels of reduced glutathione (GSH), the principal redox buffer. These studies underline the importance of cellular antioxidant capacity in metastasis, as the result of a complex cell program involving enhanced motility and a profound change in energy metabolism. The glycolytic switch (Warburg effect) observed in malignant tissues is triggered by mitochondrial oxidative damage and/or activation of redox-sensitive transcription factors, and results in an increase of cell resistance to oxidants. On the other hand, cytoskeleton rearrangement underlying cell motile and tumor-aggressive behavior use ROS as intermediates and are therefore facilitated by oxidative stress. Along this line of speculation, we suggest that metastasis represents an integrated strategy for cancer cells to avoid oxidative damage and escape excess ROS in the primary tumor site, explaning why redox signaling pathways are often up-regulated in malignancy and metastasis.

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Section: A Tale Of 3ms: Motility and Metabolism In Metastasismentioning

confidence: 99%

Metastasis: cancer cell’s escape from oxidative stress

Pani¹,

Galeotti

Chiarugi

2010

Cancer Metastasis Rev

Self Cite

280

218

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“…However, how ATM senses ROS levels is not clear. p53 has been shown to have a dual role in the regulation of reactive oxygen species, a major source of cellular stress (8,27,35). On one hand, very high levels of p53 (such as in overexpression studies) or high levels of stress will induce p53-dependent prooxidant genes (36), which can facilitate apoptosis.…”

mentioning

confidence: 99%

Requirement of the ATM/p53 Tumor Suppressor Pathway for Glucose Homeostasis

Armata

Golebiowski²,

Jung

et al. 2010

Molecular and Cellular Biology

111

126

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Ataxia telangiectasia (A-T) patients can develop multiple clinical pathologies, including neuronal degeneration, an elevated risk of cancer, telangiectasias, and growth retardation. Patients with A-T can also exhibit an increased risk of insulin resistance and type 2 diabetes. The ATM protein kinase, the product of the gene mutated in A-T patients (Atm), has been implicated in metabolic disease, which is characterized by insulin resistance and increased cholesterol and lipid levels, blood pressure, and atherosclerosis. ATM phosphorylates the p53 tumor suppressor on a site (Ser15) that regulates transcription activity. To test whether the ATM pathway that regulates insulin resistance is mediated by p53 phosphorylation, we examined insulin sensitivity in mice with a germ line mutation that replaces the p53 phosphorylation site with alanine. The loss of p53 Ser18 (murine Ser15) led to increased metabolic stress, including severe defects in glucose homeostasis. The mice developed glucose intolerance and insulin resistance. The insulin resistance correlated with the loss of antioxidant gene expression and decreased insulin signaling. N-Acetyl cysteine (NAC) treatment restored insulin signaling in late-passage primary fibroblasts. The addition of an antioxidant in the diet rendered the p53 Ser18-deficient mice glucose tolerant. This analysis demonstrates that p53 phosphorylation on an ATM site is an important mechanism in the physiological regulation of glucose homeostasis.

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“…6 Further, the p53 gene is responsive to a large number of environmental stressors [1][2][3][4] implicated in the maintenance of mtDNA CN 5,6,28,53 and mitochondrial respiration. 1,6 To this end, p53 gene CNs were evaluated by qPCR in the trios.…”

Section: Higher Incidence Of Altered P53 Gene Copy Ratio In Children mentioning

confidence: 99%

“…The p53 gene is responsive to a large number of environmental stressors by regulating maintenance of genomic stability, 1 changes in oxidative stress, [2][3][4] mitochondrial DNA (mtDNA) copy number (CN), 5,6 and mitochondrial respiration 1,6 as well as the neurotoxic response to flame retardants 7,8 and pesticide exposures. [9][10][11][12] Studies have linked p53 to developmental abnormalities 13 (see also Supplemental Table 5), and regions adjacent to 17p13.1 encoding for proteins with important roles in brain function and neurodevelopment (eg, axonal dynein heavy chain 2 and Na + /K + ATPase subunit β-2) and others have been found to be associated with autism (AU) (eg, ephrin-B3 14 ).…”

mentioning

confidence: 99%

Role ofp53, Mitochondrial DNA Deletions, and Paternal Age in Autism: A Case-Control Study

Wong¹,

Napoli²,

Krakowiak³

et al. 2016

Pediatrics

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The tumor suppressor p53 responds to a variety of environmental stressors by regulating cell cycle arrest, apoptosis, senescence, DNA repair, bioenergetics and mitochondrial DNA (mtDNA) copy number maintenance. Developmental abnormalities have been reported in p53-deficient mice, and altered p53 and p53-associated pathways in autism (AU). Furthermore, via the Pten-p53 crosstalk, Pten haploinsufficient-mice have autisticlike behavior accompanied by brain mitochondrial dysfunction with accumulation of mtDNA deletions.

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The p53–p66shc–Manganese Superoxide Dismutase (MnSOD) network: A mitochondrial intrigue to generate reactive oxygen species

Cited by 90 publications

References 18 publications

Metastasis: cancer cell’s escape from oxidative stress

Metastasis: cancer cell’s escape from oxidative stress

Requirement of the ATM/p53 Tumor Suppressor Pathway for Glucose Homeostasis

Role ofp53, Mitochondrial DNA Deletions, and Paternal Age in Autism: A Case-Control Study

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