Interaction between ROS dependent DNA damage, mitochondria and p38 MAPK underlies senescence of human adult stem cells

Borodkina, Aleksandra; Shatrova, A. N.; Абушик, П. А.; Nikolsky, Nikolay; Burova, Elena

doi:10.18632/aging.100673

Cited by 169 publications

(146 citation statements)

References 53 publications

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“…In cellular arrest, DDR induced the activation of p53 and upregulated p21 to inactivate pRb. Moreover, the pharmacological inhibition of the p38 MAPK activation abrogated the hydrogen peroxide-induced cell enlargement and flatten morphology, and it is associated with the regulation of mitochondrial ROS production [15]. Although senescent MSCs remain alive, the loss of MSC function with self-renewal and proliferation capacity leads to undergoing apoptosis or senescence.…”

Section: Ros Oxidative Stress and Cellular Signaling In Mscs Agingmentioning

confidence: 99%

Protective Effects of Ellagic Acid against UVA-induced Oxidative Stress in Human Dermal Papilla

Kim¹,

Han²,

An³

et al. 2016

Asian J Beauty Cosmetol

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MSCs have become an emerging cell source with their immune modulation, high proliferation rate, and differentiation potential; indeed, they have been challenged in clinical trials. Recently, it has shown that ROS play a dual role as both deleterious and beneficial species depending on their concentration in MSCs. Various environmental stresses-induced excessive production of ROS triggers cellular senescence and abnormal differentiation on MSCs. Moreover, MSCs have been suggested to participate in the treatment of ALI/ARDS and COPD as a major cause of high morbidity and mortality. Therapeutic mechanisms of MSCs in the treatment of ARDS/COPD were focused on cell engraftment and paracrine action. However, ROS-mediated therapeutic mechanisms of MSCs still remain largely unknown. Here, we review the key factors associated with cell cycle and chromatin remodeling to accelerate or delay the MSC aging process. In addition, the enhanced ROS production and its associated pathophysiological pathways will be discussed along with the MSC senescence process. Furthermore, the present review highlights how the excessive amount of ROS-mediated oxidative stress might interfere with homeostasis of lungs and residual lung cells in the pathogenesis of ALI/ARDS and COPD.

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Section: Ros Oxidative Stress and Cellular Signaling In Mscs Agingmentioning

confidence: 99%

Protective Effects of Ellagic Acid against UVA-induced Oxidative Stress in Human Dermal Papilla

Kim¹,

Han²,

An³

et al. 2016

Asian J Beauty Cosmetol

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“…In human mesenchyme stem cells, the SakA-homologous MAPK p38 mediates increased mitochondrial activity in an MK2-dependent manner, higher ROS levels, a persistent DNA damage response, DNA double-strand breaks (DSBs), and activation of the ATM pathway. This feedback loop seems necessary to stop the cell cycle and drive cells into senescence (75). Mitochondrial ROS are produced by partial O 2 reduction in the respiratory chain or by damage and loss of membrane potential (76,77).…”

Section: Figmentioning

confidence: 99%

The SrkA Kinase Is Part of the SakA Mitogen-Activated Protein Kinase Interactome and Regulates Stress Responses and Development in Aspergillus nidulans

et al. 2015

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cFungi and many other eukaryotes use specialized mitogen-activated protein kinases (MAPK) of the Hog1/p38 family to transduce environmental stress signals. In Aspergillus nidulans, the MAPK SakA and the transcription factor AtfA are components of a central multiple stress-signaling pathway that also regulates development. Here we characterize SrkA, a putative MAPK-activated protein kinase, as a novel component of this pathway. ⌬srkA and ⌬sakA mutants share a derepressed sexual development phenotype. However, ⌬srkA mutants are not sensitive to oxidative stress, and in fact, srkA inactivation partially suppresses the sensitivity of ⌬sakA mutant conidia to H 2 O 2 , tert-butyl-hydroperoxide (t-BOOH), and menadione. In the absence of stress, SrkA shows physical interaction with nonphosphorylated SakA in the cytosol. We show that H 2 O 2 induces a drastic change in mitochondrial morphology consistent with a fission process and the relocalization of SrkA to nuclei and mitochondria, depending on the presence of SakA. SakA-SrkA nuclear interaction is also observed during normal asexual development in dormant spores. Using SakA and SrkA S-tag pulldown and purification studies coupled to mass spectrometry, we found that SakA interacts with SrkA, the stress MAPK MpkC, the PPT1-type phosphatase AN6892, and other proteins involved in cell cycle regulation, DNA damage response, mRNA stability and protein synthesis, mitochondrial function, and other stress-related responses. We propose that oxidative stress induces DNA damage and mitochondrial fission and that SakA and SrkA mediate cell cycle arrest and regulate mitochondrial function during stress. Our results provide new insights into the mechanisms by which SakA and SrkA regulate the remodelling of cell physiology during oxidative stress and development. W e have proposed that when life was confronted with oxidative stress, cells evolved mechanisms not only to defend against reactive oxygen species (ROS) but also to use this ancestral form of stress to regulate their own growth and differentiation (1, 2). Indeed, the regulated production of ROS by enzymes of the NADPH oxidase family (NOX) is essential for sexual differentiation in Aspergillus nidulans (3) and Neurospora crassa and for polar growth and cell fusion in N. crassa (4), and NOX enzymes play multiple signaling functions in other fungal (5-10), animal, and plant species (11). However, little is known about ROS perception and the mechanisms by which ROS exert their signaling functions.The use of phosphorelay systems to perceive oxidative stress and other types of environmental stress is conserved in bacteria, plants (12), and fungi (13). The fission yeast Schizosaccharomyces pombe uses a multistep phosphorelay composed of the Mak2/3 sensor histidine kinases, Mpr1 HPt protein, and Mcs4 response regulator to transmit H 2 O 2 stress signals to the Spc1 (also known as StyI) mitogen-activated protein kinase (MAPK) cascade (14,15). Spc1 is homologous to Saccharomyces cerevisiae Hog1 and mammalian p38 MAPKs, which are also...

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“…Therefore, our results and data from other researchers indicate that the initiation of markedly adverse effects in astrocytes requires a dose rang of TCDD that is much higher than that triggering AhR activation. Mounting evidences have indicated that ROS were key players in stress-induced premature senescence (Borodkina et al, 2014;Lee and Bae, 2014;Liu et al, 2014). The generation of ROS leads to significant accumulation of cell cycle inhibitors, including Rb, p21 and p27 proteins, and oxidative DNA damage, all of which are important features of cell senescence (Stockl et al, 2006;Liu et al, 2014;Wan et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

2, 3, 7, 8‐Tetrachlorodibenzo‐p‐dioxin induces premature senescence of astrocytes via WNT/β‐catenin signaling and ROS production

Nie

Liang

et al. 2014

J of Applied Toxicology

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2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) is a ubiquitous environmental contaminant that could exert significant neurotoxicity in the human nervous system. Nevertheless, the molecular mechanism underlying TCDD-mediated neurotoxicity has not been clarified clearly. Herein, we investigated the potential role of TCDD in facilitating premature senescence in astrocytes and the underlying molecular mechanisms. Using the senescence-associated β-galactosidase (SA-β-Gal) assay, we demonstrated that TCDD exposure triggered significant premature senescence of astrocyte cells, which was accompanied by a marked activation of the Wingless and int (WNT)/β-catenin signaling pathway. In addition, TCDD altered the expression of senescence marker proteins, such as p16, p21 and GFAP, which together have been reported to be upregulated in aging astrocytes, in both dose- and time-dependent manners. Further, TCDD led to cell-cycle arrest, F-actin reorganization and the accumulation of cellular reactive oxygen species (ROS). Moreover, the ROS scavenger N-acetylcysteine (NAC) markedly attenuated TCDD-induced ROS production, cellular oxidative damage and astrocyte senescence. Notably, the application of XAV939, an inhibitor of WNT/β-catenin signaling pathway, ameliorated the effect of TCDD on cellular β-catenin level, ROS production, cellular oxidative damage and premature senescence in astrocytes. In summary, our findings indicated that TCDD might induce astrocyte senescence via WNT/β-catenin and ROS-dependent mechanisms.

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Interaction between ROS dependent DNA damage, mitochondria and p38 MAPK underlies senescence of human adult stem cells

Cited by 169 publications

References 53 publications

Protective Effects of Ellagic Acid against UVA-induced Oxidative Stress in Human Dermal Papilla

Protective Effects of Ellagic Acid against UVA-induced Oxidative Stress in Human Dermal Papilla

The SrkA Kinase Is Part of the SakA Mitogen-Activated Protein Kinase Interactome and Regulates Stress Responses and Development in Aspergillus nidulans

2, 3, 7, 8‐Tetrachlorodibenzo‐p‐dioxin induces premature senescence of astrocytes via WNT/β‐catenin signaling and ROS production

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