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      Mitochondrial dysfunction and oxidative stress in aging and cancer

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          Abstract

          Aging and cancer are the most important issues to research. The population in the world is growing older, and the incidence of cancer increases with age. There is no doubt about the linkage between aging and cancer. However, the molecular mechanisms underlying this association are still unknown. Several lines of evidence suggest that the oxidative stress as a cause and/or consequence of the mitochondrial dysfunction is one of the main drivers of these processes. Increasing ROS levels and products of the oxidative stress, which occur in aging and age-related disorders, were also found in cancer. This review focuses on the similarities between ageing-associated and cancer-associated oxidative stress and mitochondrial dysfunction as their common phenotype.

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          A genetic model for colorectal tumorigenesis.

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            Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a.

            Oncogenic ras can transform most immortal rodent cells to a tumorigenic state. However, transformation of primary cells by ras requires either a cooperating oncogene or the inactivation of tumor suppressors such as p53 or p16. Here we show that expression of oncogenic ras in primary human or rodent cells results in a permanent G1 arrest. The arrest induced by ras is accompanied by accumulation of p53 and p16, and is phenotypically indistinguishable from cellular senescence. Inactivation of either p53 or p16 prevents ras-induced arrest in rodent cells, and E1A achieves a similar effect in human cells. These observations suggest that the onset of cellular senescence does not simply reflect the accumulation of cell divisions, but can be prematurely activated in response to an oncogenic stimulus. Negation of ras-induced senescence may be relevant during multistep tumorigenesis.
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              Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions.

              DNA damage checkpoint genes, such as p53, are frequently mutated in human cancer, but the selective pressure for their inactivation remains elusive. We analysed a panel of human lung hyperplasias, all of which retained wild-type p53 genes and had no signs of gross chromosomal instability, and found signs of a DNA damage response, including histone H2AX and Chk2 phosphorylation, p53 accumulation, focal staining of p53 binding protein 1 (53BP1) and apoptosis. Progression to carcinoma was associated with p53 or 53BP1 inactivation and decreased apoptosis. A DNA damage response was also observed in dysplastic nevi and in human skin xenografts, in which hyperplasia was induced by overexpression of growth factors. Both lung and experimentally-induced skin hyperplasias showed allelic imbalance at loci that are prone to DNA double-strand break formation when DNA replication is compromised (common fragile sites). We propose that, from its earliest stages, cancer development is associated with DNA replication stress, which leads to DNA double-strand breaks, genomic instability and selective pressure for p53 mutations.
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                Author and article information

                Journal
                Oncotarget
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                19 July 2016
                5 June 2016
                : 7
                : 29
                : 44879-44905
                Affiliations
                1 Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia
                2 National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Moscow, Russia
                3 A.V. Vishnevsky Institute of Surgery, Moscow, Russia
                4 Moscow Institute of Physics and Technology, Dolgoprudny, Russia
                Author notes
                Correspondence to: Anna V. Kudryavtseva, rhizamoeba@ 123456mail.ru
                Article
                9821
                10.18632/oncotarget.9821
                5216692
                27270647
                52bac34c-8a6f-4da2-98a0-79a01bacec6e
                Copyright: © 2016 Kudryavtseva et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 23 November 2015
                : 28 May 2016
                Categories
                Research Paper: Gerotarget (Focus on Aging)

                Oncology & Radiotherapy
                oxidative stress,mitochondrial dysfunction,ros,aging,cancer,gerotarget
                Oncology & Radiotherapy
                oxidative stress, mitochondrial dysfunction, ros, aging, cancer, gerotarget

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