title: Tetraploidization or autophagy: The ultimate fate of senescent human endometrial stem cells under ATM or p53 inhibition.
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(2)O(2)-induced senescence of hMESCs. ATM or p53 down regulation was shown to modulate differently the cellular fate of H(2)O(2)-treated hMESCs. ATM inhibition allowed H(2)O(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(2)O(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.
authors.affiliation: a Department of Intracellular Signaling and Transport , Institute of Cytology, Russian Academy of Sciences , St. Petersburg , Russia.
authors.forename: Aleksandra V
authors.initials: AV
authors.lastname: Borodkina
authors.affiliation: a Department of Intracellular Signaling and Transport , Institute of Cytology, Russian Academy of Sciences , St. Petersburg , Russia.
authors.forename: Alla N
authors.initials: AN
authors.lastname: Shatrova
authors.affiliation: a Department of Intracellular Signaling and Transport , Institute of Cytology, Russian Academy of Sciences , St. Petersburg , Russia.
authors.forename: Pavel I
authors.initials: PI
authors.lastname: Deryabin
authors.affiliation: a Department of Intracellular Signaling and Transport , Institute of Cytology, Russian Academy of Sciences , St. Petersburg , Russia.
authors.forename: Anastasiya A
authors.initials: AA
authors.lastname: Grukova
authors.affiliation: 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.
authors.forename: Nikolay N
authors.initials: NN
authors.lastname: Nikolsky
authors.affiliation: a Department of Intracellular Signaling and Transport , Institute of Cytology, Russian Academy of Sciences , St. Petersburg , Russia.
authors.forename: Elena B
authors.initials: EB
authors.lastname: Burova
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D016922:Cellular Senescence / Q000187:drug effects / Q000502:physiology*; D004717:Endometrium / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D011753:Pyrones / Q000494:pharmacology; D057891:Tetraploidy; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C495818:2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one; D009025:Morpholines; D011753:Pyrones; D016159:Tumor Suppressor Protein p53; D006861:Hydrogen Peroxide; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins
keywords: ATM kinase; autophagy; cellular senescence; oxidative stress; p53; stem cells; tetraploidization