Molecules and Cells

  • 제42권11호
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  • Pages.773-782
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  • 2019
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  • 1016-8478(pISSN)
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  • 0219-1032(eISSN)
한국분자세포생물학회 (Korean Society for Molecular and Cellular Biology)
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Dephosphorylation of p53 Ser 392 Enhances Trimethylation of Histone H3 Lys 9 via SUV39h1 Stabilization in CK2 Downregulation-Mediated Senescence

  • Park, Jeong-Woo (School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University) ;
  • Bae, Young-Seuk (School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University)
  • 투고 : 2019.02.07
  • 심사 : 2019.09.07
  • 발행 : 2019.11.30
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초록

Cellular senescence is an irreversible form of cell cycle arrest. Senescent cells have a unique gene expression profile that is frequently accompanied by senescence-associated heterochromatic foci (SAHFs). Protein kinase CK2 (CK2) downregulation can induce trimethylation of histone H3 Lys 9 (H3K9me3) and SAHFs formation by activating SUV39h1. Here, we present evidence that the PI3K-AKT-mTOR-reactive oxygen species-p53 pathway is necessary for CK2 downregulation-mediated H3K9me3 and SAHFs formation. CK2 downregulation promotes SUV39h1 stability by inhibiting its proteasomal degradation in a p53-dependent manner. Moreover, the dephosphorylation status of Ser 392 on p53, a possible CK2 target site, enhances the nuclear import and subsequent stabilization of SUV39h1 by inhibiting the interactions between p53, MDM2, and SUV39h1. Furthermore, $p21^{Cip1/WAF1}$ is required for CK2 downregulation-mediated H3K9me3, and dephosphorylation of Ser 392 on p53 is important for efficient transcription of $p21^{Cip1/WAF}$. Taken together, these results suggest that CK2 downregulation induces dephosphorylation of Ser 392 on p53, which subsequently increases the stability of SUV39h1 and the expression of $p21^{Cip1/WAF1}$, leading to H3K9me3 and SAHFs formation.

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참고문헌

  1. Ait-Si-Ali, S., Guasconi, V., Fritsch, L., Yahi, H., Sekhri, R., Naguibneva, I., Robin, P., Cabon, F., Polesskaya, A., and Harel-Bellan, A. (2004). A Suv39h-dependent mechanism for silencing S-phase genes in differentiating but not in cycling cells. EMBO J. 23, 605-615. https://doi.org/10.1038/sj.emboj.7600074
  2. Bieging, K.T., Mello, S.S., and Attardi, L.D. (2014). Unravelling mechanisms of p53-mediated tumour suppression. Nat. Rev. Cancer 14, 359-370. https://doi.org/10.1038/nrc3711
  3. Bosch-Presegue, L., Raurell-Vila, H., Marazuela-Duque, A., Kane-Goldsmith, N., Valle, A., Oliver, J., Serrano, L., and Vaquero, A. (2011). Stabilization of Suv39H1 by SirT1 is part of oxidative stress response and ensures genome protection. Mol. Cell 42, 210-223. https://doi.org/10.1016/j.molcel.2011.02.034
  4. Campisi, J. (2005). Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell 120, 513-522. https://doi.org/10.1016/j.cell.2005.02.003
  5. Cross, B., Chen, L., Cheng, Q., Li, B., Yuan, Z.M., and Chen, J. (2011). Inhibition of p53 DNA binding function by the MDM2 protein acidic domain. J. Biol. Chem. 286, 16018-16029. https://doi.org/10.1074/jbc.M111.228981
  6. Fritsch, L., Robin, P., Mathieu, J.R., Souidi, M., Hinaux, H., Rougeulle, C., Harel-Bellan, A., Ameyar-Zazoua, M., and Ait-Si-Ali, S. (2010). A subset of the histone H3 lysine 9 methyltransferases Suv39h1, G9a, GLP, and SETDB1 participate in a multimeric complex. Mol. Cell 37, 46-56. https://doi.org/10.1016/j.molcel.2009.12.017
  7. Funayama, R. and Ishikawa, F. (2007). Cellular senescence and chromatin structure. Chromosoma 116, 431-440. https://doi.org/10.1007/s00412-007-0115-7
  8. Harper, J.W., Adami, G.R., Wei, N., Keyomarsi, K., and Elledge, S.J. (1993). The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclindependent kinases. Cell 75, 805-816. https://doi.org/10.1016/0092-8674(93)90499-G
  9. Hublitz, P., Albert, M., and Peters, A.H. (2009). Mechanisms of transcriptional repression by histone lysine methylation. Int. J. Dev. Biol. 53, 335-354. https://doi.org/10.1387/ijdb.082717ph
  10. Jeon, S.M., Lee, S.J., Kwon, T.K., and Bae, Y.S. (2010). NADPH oxidase is involved in protein kinase CKII down-regulation-mediated senescence through elevation of the level of reactive oxygen species in human colon cancer cells. FEBS Lett. 584, 3137-3142. https://doi.org/10.1016/j.febslet.2010.05.054
  11. Kang, J.Y., Kim, J.J., Jang, S.Y., and Bae, Y.S. (2009). The p53-p21(Cip1/WAF1) pathway is necessary for cellular senescence induced by the inhibition of protein kinase CKII in human colon cancer cells. Mol. Cells 28, 489-494. https://doi.org/10.1007/s10059-009-0141-9
  12. Kim, J.A. (2018). Cooperative instruction of signaling and metabolic pathways on the epigenetic landscape. Mol. Cells 41, 264-270. https://doi.org/10.14348/MOLCELLS.2018.0076
  13. Kim, Y.Y., Park, B.J., Kim, D.J., Kim, W.H., Kim, S., Oh, K.S., Lim, J.Y., Kim, J., Park, C., and Park, S.I. (2004). Modification of serine 392 is a critical event in the regulation of p53 nuclear export and stability. FEBS Lett. 572, 92-98. https://doi.org/10.1016/j.febslet.2004.07.014
  14. Kouzarides, T. (2007). Chromatin modifications and their function. Cell 128, 693-705. https://doi.org/10.1016/j.cell.2007.02.005
  15. Kruse, J.P. and Gu, W. (2009). Modes of p53 regulation. Cell 137, 609-622. https://doi.org/10.1016/j.cell.2009.04.050
  16. Maison, C. and Almouzni, G. (2004). HP1 and the dynamics of heterochromatin maintenance. Nat. Rev. Mol. Cell Biol. 5, 296-304. https://doi.org/10.1038/nrm1355
  17. Meek, D.W. (1999). Mechanisms of switching on p53: a role for covalent modification? Oncogene 18, 7666-7675. https://doi.org/10.1038/sj.onc.1202951
  18. Mungamuri, S.K., Benson, E.K., Wang, S., Gu, W., Lee, S.W., and Aaronson, S.A. (2012). p53-Mediated heterochromatin reorganization regulates its cell fate decisions. Nat. Struct. Mol. Biol. 19, 478-484. https://doi.org/10.1038/nsmb.2271
  19. Mungamuri, S.K., Qiao, R.F., Yao, S., Manfredi, J.J., Gu, W., and Aaronson, S.A. (2016). USP7 enforces heterochromatinization of p53 target promoters by protecting SUV39H1 from MDM2-mediated degradation. Cell Rep. 14, 2528-2537. https://doi.org/10.1016/j.celrep.2016.02.049
  20. Narita, M., Nunez, S., Heard, E., Narita, M., Lin, A.W., Hearn, S.A., Spector, D.L., Hannon, G.J., and Lowe, S.W. (2003). Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell 113, 703-716. https://doi.org/10.1016/S0092-8674(03)00401-X
  21. Nielsen, S.J., Schneider, R., Bauer, U.M., Bannister, A.J., Morrison, A., O'Carroll, D., Firestein, R., Cleary, M., Jenuwein, T., Herrera, R.E., et al. (2001). Rb targets histone H3 methylation and HP1 to promoters. Nature 412, 561-565. https://doi.org/10.1038/35087620
  22. Park, J.H., Kim, J.J., and Bae, Y.S. (2013). Involvement of PI3K-AKT-mTOR pathway in protein kinase CKII inhibition-mediated senescence in human colon cancer cells. Biochem. Biophys. Res. Commun. 433, 420-425. https://doi.org/10.1016/j.bbrc.2013.02.108
  23. Park, J.W., Kim, J.J., and Bae, Y.S. (2018). CK2 downregulation induces senescence-associated heterochromatic foci formation through activating SUV39h1 and inactivating G9a. Biochem. Biophys. Res. Commun. 505, 67-73. https://doi.org/10.1016/j.bbrc.2018.09.099
  24. Roninson, I.B. (2003). Tumor cell senescence in cancer treatment. Cancer Res. 63, 2705-2715.
  25. Ryu, S.W., Woo, J.H., Kim, Y.H., Lee, Y.S., Park, J.W., and Bae, Y.S. (2006). Downregulation of protein kinase CKII is associated with cellular senescence. FEBS Lett. 580, 988-994. https://doi.org/10.1016/j.febslet.2006.01.028
  26. Simabuco, F.M., Morale, M.G., Pavan, I.C.B., Morelli, A.P., Silva, F.R., and Tamura, R.E. (2018). p53 and metabolism: from mechanism to therapeutics. Oncotarget 9, 23780-23823. https://doi.org/10.18632/oncotarget.25267
  27. Tachibana, M., Ueda, J., Fukuda, M., Takeda, N., Ohta, T., Iwanari, H., Sakihama, T., Kodama, T., Hamakubo, T., and Shinkai, Y. (2005). Histone methyltransferases G9a and GLP form heteromeric complexes and are both crucial for methylation of euchromatin at H3-K9. Genes Dev. 19, 815-826. https://doi.org/10.1101/gad.1284005
  28. Vaquero, A., Scher, M., Erdjument-Bromage, H., Tempst, P., Serrano, L., and Reinberg, D. (2007). SIRT1 regulates the histone methyl-transferase SUV39H1 during heterochromatin formation. Nature 450, 440-444. https://doi.org/10.1038/nature06268
  29. Wade, M., Li, Y.C., and Wahl, G.M. (2013). MDM2, MDMX and p53 in oncogenesis and cancer therapy. Nat. Rev. Cancer 13, 83-96. https://doi.org/10.1038/nrc3430