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      Tetraploidization or autophagy: The ultimate fate of senescent human endometrial stem cells under ATM or p53 inhibition

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          ABSTRACT

          Previously we demonstrated that endometrium-derived human mesenchymal stem cells (hMESCs) via activation of the ATM/p53/p21/Rb pathway enter the premature senescence in response to oxidative stress. Down regulation effects of the key components of this signaling pathway, particularly ATM and p53, on a fate of stressed hMESCs have not yet been investigated. In the present study by using the specific inhibitors Ku55933 and Pifithrin-α, we confirmed implication of both ATM and p53 in H 2O 2-induced senescence of hMESCs. ATM or p53 down regulation was shown to modulate differently the cellular fate of H 2O 2-treated hMESCs. ATM inhibition allowed H 2O 2-stimulated hMESCs to escape the permanent cell cycle arrest due to loss of the functional ATM/p53/p21/Rb pathway, and induced bypass of mitosis and re-entry into S phase, resulting in tetraploid cells. On the contrary, suppression of the p53 transcriptional activity caused a pronounced cell death of H 2O 2-treated hMESCs via autophagy induction. The obtained data clearly demonstrate that down regulation of ATM or p53 shifts senescence of human endometrial stem cells toward tetraploidization or autophagy.

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          Most cited references61

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          CDK inhibitors: positive and negative regulators of G1-phase progression.

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            Living on a break: cellular senescence as a DNA-damage response.

            Cellular senescence is associated with ageing and cancer in vivo and has a proven tumour-suppressive function. Common to both ageing and cancer is the generation of DNA damage and the engagement of the DNA-damage response pathways. In this Review, the diverse mechanisms that lead to DNA-damage generation and the activation of DNA-damage-response signalling pathways are discussed, together with the evidence for their contribution to the establishment and maintenance of cellular senescence in the context of organismal ageing and cancer development.
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              Control of apoptosis by p53.

              The p53 tumor suppressor acts to integrate multiple stress signals into a series of diverse antiproliferative responses. One of the most important p53 functions is its ability to activate apoptosis, and disruption of this process can promote tumor progression and chemoresistance. p53 apparently promotes apoptosis through transcription-dependent and -independent mechanisms that act in concert to ensure that the cell death program proceeds efficiently. Moreover, the apoptotic activity of p53 is tightly controlled, and is influenced by a series of quantitative and qualitative events that influence the outcome of p53 activation. Interestingly, other p53 family members can also promote apoptosis, either in parallel or in concert with p53. Although incomplete, our current understanding of p53 illustrates how apoptosis can be integrated into a larger tumor suppressor network controlled by different signals, environmental factors, and cell type. Understanding this network in more detail will provide insights into cancer and other diseases, and will identify strategies to improve their therapeutic treatment.
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                Author and article information

                Journal
                Cell Cycle
                Cell Cycle
                KCCY
                Cell Cycle
                Taylor & Francis
                1538-4101
                1551-4005
                2016
                4 December 2015
                4 December 2015
                : 15
                : 1
                : 117-127
                Affiliations
                [a ]Department of Intracellular Signaling and Transport, Institute of Cytology, Russian Academy of Sciences , St. Petersburg, Russia
                [b ]Department of Medical Physics, St. Petersburg State Polytechnical University , St. Petersburg, Russia
                Author notes
                CONTACT Aleksandra V. Borodkina; borodkina618@ 123456gmail.com

                Supplemental data for this article can be accessed on the publisher's website.

                Article
                1121326
                10.1080/15384101.2015.1121326
                4825783
                26636375
                aefee92e-5066-4193-8226-05a2b5e6c291
                © 2016 The Author(s). Published with license by Taylor & Francis Group, LLC

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-Non-Commercial License http://creativecommons.org/licenses/by-nc/3.0/, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The moral rights of the named author(s) have been asserted.

                History
                : 26 August 2015
                : 19 October 2015
                : 12 November 2015
                Page count
                Figures: 10, Tables: 0, References: 72, Pages: 11
                Categories
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                Cell biology
                cellular senescence,stem cells,oxidative stress,tetraploidization,autophagy,atm kinase,p53
                Cell biology
                cellular senescence, stem cells, oxidative stress, tetraploidization, autophagy, atm kinase, p53

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