Skip to main content
SpringerLink
Log in

The Role of P53-Dependent Autophagy in the Regulation of Pluripotent Cell Bevavior

  • Published:
Cell and Tissue Biology Aims and scope Submit manuscript

Abstract

Embryonic stem cells (ESCs), and their artificial counterparts, induced pluripotent stem cells (iPSCs) give rise to all differentiated cell types in adult organism.Therefore, pluripotent cells are an inexhaustible cell source for regenerative medicine. However, the successful clinical application of ESCs and iPSCs is associated with the risk of teratoma formation after transplantation of their differentiated products. Oncogenic potential is believed to be associated with the preservation of pluripotent cells resistant to differentiation. For unknown reason under mitogenic stimuli these defective cells did not activate the mechanisms of exit from pluripotency and remained undifferentiated. During embryogenesis, there are special mechanisms for eliminating the abnormal cells unsuitable for embryo development, which are massively triggered before gastrulation, the initial stage of cell differentiation into germ layers. It is known that, prior to implantation, autophagy plays a critical role in embryo formation and can be considered as one of the main cellular strategies aimed at large-scale restructuring of intracellular material after fertilization. It can be proposed that unless massive intracellular reorganization of embryonic cells occur effective, such cells will have defective proteostasis, affecting their differentiation potential. Therefore, the high level of apoptosis observed before gastrulation in embryogenesis is associated with the elimination of mutant cells that are not suitable for differentiation. Damaged cells are marked with the activated p53 protein indicating the p53-dependent elimination mechanisms. And, apparently, the mechanism of the p53 activation is associated with damaged cellular proteostasis, regulated by autophagy. Thus, the p53-dependent autophagy can play a key role in determining the fate of pluripotent cells: induction of cell death and/or resistance to differentiation. We have shown that the p53 protein is tightly integrated with autophagy and, under defective proteostasis, p53 effectively induces autophagy-mediated cell death in pluripotent cells.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.
Fig. 2.

Similar content being viewed by others

REFERENCES

  1. Amir, H., Touboul, T., Sabatini, K., Chhabra, D., Garitaonandia, I., Loring, J.F., Morey, R., and Laurent, L.C., Spontaneous single-copy loss of TP53 in human embryonic stem cells markedly increases cell proliferation and survival, Stem Cells, 2017, vol. 35, p. 872.

    Article  CAS  Google Scholar 

  2. Baker, D.E.C., Harrison, N.J., Maltby, E., Smith, K., Moore, H.D., Shaw, P.J., Heath, P.R., Holden, H., and Andrews, P.W., Adaptation to culture of human embryonic stem cells and oncogenesis in vivo, Nat. Biotechnol., 2007, vol. 25, p. 207.

    Article  CAS  Google Scholar 

  3. Bowling, S., Di, Gregorio, A., Sancho, M., Pozzi, S., Aarts, M., Signore, M., Schneider, M.D., Martinez-Barbera, J.P., Gil, J., and Rodríguez, T.A., P53 and mTOR signalling determine fitness selection through cell competition during early mouse embryonic development, Nat. Commun., 2018, vol. 9, p. 1763.

    Article  Google Scholar 

  4. Budanov, A.V., and Karin, M., The p53-regulated sestrin gene products inhibit mTOR signaling, Cell, 2008, vol. 134, p. 451.

    Article  CAS  Google Scholar 

  5. Cho, S.J., Kim, K.T., Jeong, H.C., Park, J.C., Kwon, O.S., Song, Y.H., Shin, J.G., Kang, S., Kim, W., Shin, H.D., Lee, M.O., Moon, S.H., and Cha, H.J., Selective elimination of culture-adapted human embryonic stem cells with BH3 mimetics, Stem Cell Rep., 2018, vol. 11, p. 1244.

    Article  CAS  Google Scholar 

  6. Crighton, D., Wilkinson, S., O’Prey, J., Syed, N., Smith, P., Harrison, P.R., Gasco, M., Garrone, O., Crook, T., and Ryan, K.M., DRAM, a p53-induced modulator of autophagy, is critical for apoptosis, Cell, 2006, vol. 126, p. 121.

    Article  CAS  Google Scholar 

  7. Draper, J.S., Smith, K., Gokhale, P., Moore, H.D., Maltby, E., Johnson, J., Meisner, L., Zwaka, T.P., Thomson, J.A., and Andrews, P.W., Recurrent gain of chromosomes 17q and 12 in cultured human embryonic stem cells, Nat. Biotechnol., 2004, vol. 22, p. 53.

    Article  CAS  Google Scholar 

  8. Eby, K.G., Rosenbluth, J.M., Mays, D.J., Marshall, C.B., Barton, C.E., Sinha, S., Johnson, K.N., Tang, L., and Pietenpol, J.A., ISG20L1 is a p53 family target gene that modulates genotoxic stress-induced autophagy, Mol. Cancer, 2010, vol. 9, p. 95.

    Article  Google Scholar 

  9. Feng, Z., Hu, W., de, Stanchina, E., Teresky, A.K., Jin, S., Lowe, S., and Levine, A.J., The regulation of AMФK beta1, TSC2, and PTEN expression by p53: stress, cell and tissue specificity, and the role of these gene products in modulating the IGF-1-AKT-mTOR pathways, Cancer Res., 2007, vol. 67, p. 3043.

    Article  CAS  Google Scholar 

  10. Gangloff, Y.-G., Mueller, M., Dann, S.G., Svoboda, P., Sticker, M., Spetz, J.-F., Um, S.H., Brown, E.J., Cereghini, S., Thomas, G., and Kozma, S.C., Disruption of the mouse mTOR gene leads to early postimplantation lethality and prohibits embryonic stem cell development, Mol. Cell. Biol., 2004, vol. 24, p. 9508.

    Article  CAS  Google Scholar 

  11. Gao, W., Shen, Z., Shang, L., and Wang, X., Upregulation of human autophagy-initiation kinase ULK1 by tumor suppressor p53 contributes to DNA-damage-induced cell death, Cell Death Differ., 2011, vol. 18, p. 1598.

    Article  CAS  Google Scholar 

  12. García, C.P., Videla, Richardson, G.A., Dimopoulos, N.A., Fernandez, Espinosa, D.D., Miriuka, S.G., Sevlever, G.E., Romorini, L., and Scassa, M.E., Human pluripotent stem cells and derived neuroprogenitors display differential degrees of susceptibility to BH3 mimetics ABT-263, WEHI-539 and ABT-199, PLoS One, 2016, vol. 11. e0152607.

    Article  Google Scholar 

  13. Gong, J., Gu, H., Zhao, L., Wang, L., Liu, P., Wang, F., Xu, H., and Zhao, T., Phosphorylation of ULK1 by AMФK is essential for mouse embryonic stem cell self-renewal and pluripotency. Cell Death Dis., 2018, vol. 9, p. 38.

    Article  Google Scholar 

  14. Grigorash, B.B., Suvorova, I.I., and Pospelov. V.A., AICAR-dependent activation of AMФK kinase is not accompanied by G1/S block in mouse embryonic stem cells, Mol. Biol., 2018, vol. 52, p. 499.

    Article  Google Scholar 

  15. Hardie, D.G., Schaffer, B.E., and Brunet, A., AMФK: an energy-sensing pathway with multiple inputs and outputs, Trends Cell Biol., 2016, vol. 26, p. 190.

    Article  CAS  Google Scholar 

  16. Heyer, B.S., MacAuley, A., Behrendtsen, O., and Werb, Z., Hypersensitivity to DNA damage leads to increased apoptosis during early mouse development, Genes Dev., 2000, vol. 14, p. 2072.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Jones, R.G., Plas, D.R., Kubek, S., Buzzai, M., Mu, J., Xu, Y., Birnbaum, M.J., and Thompson, C.B., AMP-activated protein kinase induces a p53-dependent metabolic checkpoint, Mol. Cell, 2005, vol. 18, p. 283.

    Article  CAS  Google Scholar 

  18. Kenzelmann, Broz, D., Spano, Mello, S., Bieging, K.T., Jiang, D., Dusek, R.L., Brady, C.A., Sidow, A., and Attardi, L.D., Global genomic profiling reveals an extensive p53-regulated autophagy program contributing to key p53 responses, Genes Dev., 2013, vol. 27, p. 1016.

    Article  Google Scholar 

  19. Kim, J., Yang, G., Kim, Y., Kim, J., and Ha, J., AMФK activators: mechanisms of action and physiological activities, Exp. Mol. Med., 2016, vol. 48. e224. https://doi.org/10.1038/emm.2016.16

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Levayer, R., and Moreno, E., Mechanisms of cell competition: themes and variations, J. Cell Biol., 2013, vol. 200, p. 689.

    Article  CAS  Google Scholar 

  21. Li, M., He, Y., Dubois, W., Wu, X., Shi, J., and Huang, J., Distinct regulatory mechanisms and functions for p53-activated and p53-repressed DNA damage response genes in embryonic stem cells, Mol. Cell, 2012, vol. 46, p. 30.

    Article  CAS  Google Scholar 

  22. Lin, T., and Lin, Y., p53 switches off pluripotency on differentiation, Stem Cell Res. Ther., 2017, vol. 8, p. 44.

    Article  Google Scholar 

  23. Malik, S.A., Orhon, I., Morselli, E., Criollo, A., Shen, S., Mariño, G., BenYounes, A., Bénit, P., Rustin, P., Maiuri, M.C., and Kroemer, G., BH3 mimetics activate multiple pro-autophagic pathways, Oncogene, 2011, vol. 30, p. 3918.

    Article  CAS  Google Scholar 

  24. Manova, K., Tomihara-Newberger, C., Wang, S., Godelman, A., Kalantry, S., Witty-Blease, K., De, Leon, V., Chen, W.S., Lacy, E., and Bachvarova, R.F., Apoptosis in mouse embryos: elevated levels in pregastrulae and in the distal anterior region of gastrulae of normal and mutant mice. Dev. Dynam., 1998, vol. 213, p. 293.

    Article  CAS  Google Scholar 

  25. Mathieu, J., Detraux, D., Kuppers, D., Wang, Y., Cavanaugh, C., Sidhu, S., Levy, S., Robitaille, A.M., Fer-reccio, A., Bottorff, T., McAlister, A., Somasundaram, L., Artoni, F., Battle, S., D.Hawkins, R., Moon, R.T., Ware, C.B., Paddison, P.J., and Ruohola-Baker, H., Folliculin regulates mTORC1/2 and WNT pathways in early human pluripotency, Nat. Commun., 2019, vol. 10, p. 632.

    Article  CAS  Google Scholar 

  26. Moreno, E., Basler, K., and Morata, G., Cells compete for decapentaplegic survival factor to prevent apoptosis in Drosophila wing development, Nature, 2002, vol. 416, p. 755.

    Article  CAS  Google Scholar 

  27. Morselli, E., Tasdemir, E., Maiuri, M.C., Galluzzi, L., Kepp, O., Criollo, A., Vicencio, J.M., Soussi, T., and Kroemer, G., Mutant p53 protein localized in the cytoplasm inhibits autophagy, Cell Cycle (Georgetown, Tex.), 2008, vol. 7, p. 3056.

    Article  CAS  Google Scholar 

  28. Murakami, M., Ichisaka, T., Maeda, M., Oshiro, N., Hara, K., Edenhofer, F., Kiyama, H., Yonezawa, K., and Yamanaka, S., mTOR is essential for growth and proliferation in early mouse embryos and embryonic stem cells, Mol. Cell. Biol., 2004, vol. 24, p. 6710.

    Article  CAS  Google Scholar 

  29. Parzych, K.R., and Klionsky, D.J., An overview of autophagy: morphology, mechanism, and regulation, Antioxid. Redox Signal., 2014, vol. 20, p. 460.

    Article  CAS  Google Scholar 

  30. Possik, E., Jalali, Z., Nouët, Y., Yan, M., Gingras, M.-C., Schmeisser, K., Panaite, L., Dupuy, F., Kharitidi, D., Chotard, L., Jones, R.G., Hall, D.H., and Pause, A., Folliculin regulates AMФK-dependent autophagy and metabolic stress survival, PLoS Genetics, 2014, vol. 10. e1004273. https://doi.org/10.1371/journal.pgen.1004273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Sancho, M., Di-Gregorio, A., George, N., Pozzi, S., Sánchez, J.M., Pernaute, B., and Rodríguez, T.A., Competitive interactions eliminate unfit embryonic stem cells at the onset of differentiation, Dev. Cell, 2013, vol. 26, p. 19.

    Article  CAS  Google Scholar 

  32. Schier, A.F., The maternal-zygotic transition: death and birth of RNAs, Science, 2007, vol. 316, p. 406.

    Article  CAS  Google Scholar 

  33. Speidel, D., The role of DNA damage responses in p53 biology, Arch. Toxicol., 2015, vol. 89, p. 501.

    Article  CAS  Google Scholar 

  34. Spits, C., Mateizel, I., Geens, M., Mertzanidou, A., Staessen, C., Vandeskelde, Y., Van der Elst, J., Liebaers, I., and Sermon, K., Recurrent chromosomal abnormalities in human embryonic stem cells, Nat. Biotechnol., 2008, vol. 26, p. 1361.

    Article  CAS  Google Scholar 

  35. Spruce, T., Pernaute, B., Di-Gregorio, A., Cobb, B.S., Merkenschlager, M., Manzanares, M., and Rodriguez, T.A., An early developmental role for miRNAs in the maintenance of extraembryonic stem cells in the mouse embryo, Dev. Cell, 2010, vol. 19, p. 207.

    Article  CAS  Google Scholar 

  36. Suvorova, I.I., Knyazeva, A.R., and Pospelov, V.A., Resveratrol-induced p53 activation is associated with autophagy in mouse embryonic stem cells, Biochem. Biophys. Res. Commun., 2018, vol. 503, p. 2180.

    Article  CAS  Google Scholar 

  37. Suvorova, I.I., Knyazeva, A.R., Petukhov, A.V., Aksenov, N.D., and Pospelov, V.A., Resveratrol enhances pluripotency of mouse embryonic stem cells by activating AMФK/Ulk1 pathway, Cell Death Dis., 2019, vol. 5, p. 61.

    Article  Google Scholar 

  38. Tasdemir, E., Maiuri, M.C., Galluzzi, L., Vitale, I., Djavaheri-Mergny, M., D’Amelio, M., Criollo, A., Morselli, E., Zhu, C., Harper, F., Nannmark, U., Samara, C., Pinton, P., Vicencio, J.M., Carnuccio, R., Moll, U.M., Madeo, F., Paterlini-Brechot, P., Rizzuto, R., Sza-badkai, G., Pierron, G., Blomgren, K., Tavernarakis, N., Codogno, P., Cecconi, F., and Kroemer, G., Regulation of autophagy by cytoplasmic p53, Nat. Cell Biol., 2008, vol. 10, p. 676.

    Article  CAS  Google Scholar 

  39. Tsukamoto, S., Kuma, A., Murakami, M., Kishi, C., Yamamoto, A., and Mizushima, N., Autophagy is essential for preimplantation development of mouse embryos, Science, 2008, vol. 321, p. 117.

    Article  CAS  Google Scholar 

  40. Wang, S., Xia, P., Ye, B., Huang, G., Liu, J., and Fan, Z., Transient activation of autophagy via Sox2-mediated suppression of mTOR is an important early step in reprogramming to pluripotency, Cell Stem Cell, 2013, vol. 13, p. 617.

    Article  CAS  Google Scholar 

Download references

Funding

This work was financially supported by the Russian Foundation for Basic Research, project no. 18-015-00230A.

Author information

Authors and Affiliations

  1. Institute of Cytology, Russian Academy of Sciences, 194064, St. Petersburg, Russia

    G. I. Sutula, M. L. Vorobev & I. I. Suvorova

Authors
  1. G. I. Sutula
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. L. Vorobev
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. I. I. Suvorova
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to I. I. Suvorova.

Ethics declarations

The authors declare that they have no conflict of interest.

The authors did not perform experiments with animals or human beings as subjects.

Additional information

Abbreviations: IPSC—induced pluripotent stem cell; ESC—embryonic stem cells, ADP and AMP—adenosindi and adenosine monophosphate, respectively; AMPK—AMP-activated protein kinase; mTOR—mammalian rapamycin target (mammalian target of rapamycin).

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sutula, G.I., Vorobev, M.L. & Suvorova, I.I. The Role of P53-Dependent Autophagy in the Regulation of Pluripotent Cell Bevavior. Cell Tiss. Biol. 14, 332–340 (2020). https://doi.org/10.1134/S1990519X20050089

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S1990519X20050089

Keywords:

Search

Navigation