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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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Phosphorylation of p53 at threonine 155 is required for Jab1-mediated nuclear export of p53

  • Lee, Eun-Woo (Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)) ;
  • Oh, Wonkyung (DNA Repair Research Center, Chosun University School of Medicine) ;
  • Song, Hosung Paul (Korea International School) ;
  • Kim, Won Kon (Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB))
  • Received : 2017.05.11
  • Accepted : 2017.05.25
  • Published : 2017.07.31
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Abstract

The Jun activation-domain binding protein 1 (Jab1) induces p53 nuclear export and cytoplasmic degradation, but the underlying mechanism is poorly understood. Here, we show that phosphorylation at the threonine 155 residue is essential for Jab1-mediated p53 nuclear export. Jab1 stimulated phosphorylation of p53 at T155 was inhibited by curcumin, an inhibitor of COP9 signalosome (CSN)-associated kinases. The T155E mutant, which mimics phosphorylated p53, exhibited spontaneous cytoplasmic localization in the absence of Jab1. This process was prevented by leptinomycin B (LMB), but not by curcumin. The substitution of threonine 155 for valine (T155V) abrogated Jab1-mediated p53 nuclear export, indicating that phosphorylation at this site is essential for Jab1-mediated regulation of p53. Although T155E can be localized in the cytoplasm in the absence of Mdm2, the translocation of T155E was significantly enhanced by ectopic Hdm2 expression. Our data suggests that Jab1-mediated phosphorylation of p53 at Thr155 residue mediates nuclear export of p53.

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References

  1. 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
  2. Lane DP (1992) Cancer. p53, guardian of the genome. Nature 358, 15-16 https://doi.org/10.1038/358015a0
  3. Levine AJ (1997) p53, the cellular gatekeeper for growth and division. Cell 88, 323-331 https://doi.org/10.1016/S0092-8674(00)81871-1
  4. Vousden KH and Lu X (2002) Live or let die: the cell's response to p53. Nat Rev Cancer 2, 594-604 https://doi.org/10.1038/nrc864
  5. Haupt Y, Maya R, Kazaz A and Oren M (1997) Mdm2 promotes the rapid degradation of p53. Nature 387, 296-299 https://doi.org/10.1038/387296a0
  6. Kubbutat MH, Jones SN and Vousden KH (1997) Regulation of p53 stability by Mdm2. Nature 387, 299-303 https://doi.org/10.1038/387299a0
  7. Charni M, Aloni-Grinstein R, Molchadsky A and Rotter V (2017) p53 on the crossroad between regeneration and cancer. Cell Death Differ 24, 8-14 https://doi.org/10.1038/cdd.2016.117
  8. Roth J, Dobbelstein M, Freedman DA, Shenk T and Levine AJ (1998) Nucleo-cytoplasmic shuttling of the hdm2 oncoprotein regulates the levels of the p53 protein via a pathway used by the human immunodeficiency virus rev protein. EMBO J 17, 554-564 https://doi.org/10.1093/emboj/17.2.554
  9. Wei N and Deng XW (1999) Making sense of the COP9 signalosome. A regulatory protein complex conserved from Arabidopsis to human. Trends Genet 15, 98-103 https://doi.org/10.1016/S0168-9525(98)01670-9
  10. Tomoda K, Kubota Y, Arata Y et al (2002) The cytoplasmic shuttling and subsequent degradation of p27Kip1 mediated by Jab1/CSN5 and the COP9 signalosome complex. J Biol Chem 277, 2302-2310 https://doi.org/10.1074/jbc.M104431200
  11. Doronkin S, Djagaeva I and Beckendorf SK (2003) The COP9 signalosome promotes degradation of Cyclin E during early Drosophila oogenesis. Dev Cell 4, 699-710 https://doi.org/10.1016/S1534-5807(03)00121-7
  12. Kim BC, Lee HJ, Park SH et al (2004) Jab1/CSN5, a component of the COP9 signalosome, regulates transforming growth factor beta signaling by binding to Smad7 and promoting its degradation. Mol Cell Biol 24, 2251-2262 https://doi.org/10.1128/MCB.24.6.2251-2262.2004
  13. Callige M, Kieffer I and Richard-Foy H (2005) CSN5/Jab1 is involved in ligand-dependent degradation of estrogen receptor {alpha} by the proteasome. Mol Cell Biol 25, 4349-4358 https://doi.org/10.1128/MCB.25.11.4349-4358.2005
  14. Lee EW, Oh W and Song J (2006) Jab1 as a mediator of nuclear export and cytoplasmic degradation of p53. Mol Cells 22, 133-140
  15. Oh W, Lee EW, Sung YH et al (2006) Jab1 induces the cytoplasmic localization and degradation of p53 in coordination with Hdm2. J Biol Chem 281, 17457-17465 https://doi.org/10.1074/jbc.M601857200
  16. Oh W, Yang MR, Lee EW et al (2006) Jab1 mediates cytoplasmic localization and degradation of West Nile virus capsid protein. J Biol Chem 281, 30166-30174 https://doi.org/10.1074/jbc.M602651200
  17. Kim JH, Choi JK, Cinghu S et al (2009) Jab1/CSN5 induces the cytoplasmic localization and degradation of RUNX3. J Cell Biochem 107, 557-565 https://doi.org/10.1002/jcb.22157
  18. Guo H, Jing L, Cheng Y et al (2016) Down-regulation of the cyclin-dependent kinase inhibitor p57 is mediated by Jab1/Csn5 in hepatocarcinogenesis. Hepatology 63, 898-913 https://doi.org/10.1002/hep.28372
  19. Lu R, Hu X, Zhou J et al (2016) COPS5 amplification and overexpression confers tamoxifen-resistance in ERalphapositive breast cancer by degradation of NCoR. Nat Commun 7, 12044 https://doi.org/10.1038/ncomms12044
  20. Tomoda K, Yoneda-Kato N, Fukumoto A, Yamanaka S and Kato JY (2004) Multiple functions of Jab1 are required for early embryonic development and growth potential in mice. J Biol Chem 279, 43013-43018 https://doi.org/10.1074/jbc.M406559200
  21. Bech-Otschir D, Kraft R, Huang X et al (2001) COP9 signalosome-specific phosphorylation targets p53 to degradation by the ubiquitin system. EMBO J 20, 1630-1639 https://doi.org/10.1093/emboj/20.7.1630
  22. Yang WH, Kim JE, Nam HW et al (2006) Modification of p53 with O-linked N-acetylglucosamine regulates p53 activity and stability. Nat Cell Biol 8, 1074-1083 https://doi.org/10.1038/ncb1470
  23. Stommel JM, Marchenko ND, Jimenez GS, Moll UM, Hope TJ and Wahl GM (1999) A leucine-rich nuclear export signal in the p53 tetramerization domain: regulation of subcellular localization and p53 activity by NES masking. EMBO J 18, 1660-1672 https://doi.org/10.1093/emboj/18.6.1660
  24. Carter S, Bischof O, Dejean A and Vousden KH (2007) C-terminal modifications regulate MDM2 dissociation and nuclear export of p53. Nat Cell Biol 9, 428-435 https://doi.org/10.1038/ncb1562
  25. Lohrum MA, Woods DB, Ludwig RL, Balint E and Vousden KH (2001) C-terminal ubiquitination of p53 contributes to nuclear export. Mol Cell Biol 21, 8521-8532 https://doi.org/10.1128/MCB.21.24.8521-8532.2001
  26. Li M, Brooks CL, Wu-Baer F, Chen D, Baer R and Gu W (2003) Mono-versus polyubiquitination: differential control of p53 fate by Mdm2. Science 302, 1972-1975 https://doi.org/10.1126/science.1091362
  27. Coutts AS, Adams CJ and La Thangue NB (2009) p53 ubiquitination by Mdm2: a never ending tail? DNA Repair (Amst) 8, 483-490 https://doi.org/10.1016/j.dnarep.2009.01.008
  28. Boyd SD, Tsai KY and Jacks T (2000) An intact HDM2 RING-finger domain is required for nuclear exclusion of p53. Nat Cell Biol 2, 563-568 https://doi.org/10.1038/35023500
  29. Geyer RK, Yu ZK and Maki CG (2000) The MDM2 RING-finger domain is required to promote p53 nuclear export. Nat Cell Biol 2, 569-573 https://doi.org/10.1038/35023507
  30. Dai C and Gu W (2010) p53 post-translational modification: deregulated in tumorigenesis. Trends Mol Med 16, 528-536 https://doi.org/10.1016/j.molmed.2010.09.002
  31. Cai X and Liu X (2008) Inhibition of Thr-55 phosphorylation restores p53 nuclear localization and sensitizes cancer cells to DNA damage. Proc Natl Acad Sci U S A 105, 16958-16963 https://doi.org/10.1073/pnas.0804608105
  32. Brooks CL and Gu W (2006) p53 ubiquitination: Mdm2 and beyond. Mol Cell 21, 307-315 https://doi.org/10.1016/j.molcel.2006.01.020
  33. Lee EW, Lee MS, Camus S et al (2009) Differential regulation of p53 and p21 by MKRN1 E3 ligase controls cell cycle arrest and apoptosis. EMBO J 28, 2100-2113 https://doi.org/10.1038/emboj.2009.164
  34. Seo J, Lee EW, Sung H et al (2016) CHIP controls necroptosis through ubiquitylation- and lysosomedependent degradation of RIPK3. Nat Cell Biol 18, 291-302 https://doi.org/10.1038/ncb3314
  35. Lee EW, Kim JH, Ahn YH et al (2012) Ubiquitination and degradation of the FADD adaptor protein regulate death receptor-mediated apoptosis and necroptosis. Nat Commun 3, 978 https://doi.org/10.1038/ncomms1981