p53 pp 117-126 | Cite as

p53 Localization

  • Carl G. Maki
Part of the Molecular Biology Intelligence Unit book series (MBIU, volume 1)


Inactivation of the p53 tumor suppressor pathway is essential for the development of most or all human cancers. Over 50% of cancers harbor missense mutations in p53 that destroy its normal function.1 In cancers that retain wild-type p53, the protein is often inactivated through other means, including being abnormally sequestered in the cytoplasm, over-expression of MDM2 (the key negative regulator of p53), and deletion of p14/Arf (which normally inhibits MDM2 function). P53 undergoes nuclear-cytoplasmic shuttling and, in most unstressed cells, is expressed at low levels localized in both the nucleus and the cytoplasm. In response to DNA damage and other stresses, p53 is subject to various post-translational modifications that result in its stabilization, accumulation in the nucleus, and activation as a transcription factor. While most p53 accumulates in the nucleus following stress, recent studies indicate a significant fraction remains in the cytoplasm, and that both nuclear and cytoplasmic p53 participate in its tumor suppressor program.2 Notably, certain post-translational modifications may direct p53 to specific sub-cellular locales (Table 1), and this appear to be important in unleashing p53’s full growth suppressive capabilities. For example, at least some nuclear p53 that accumulates following certain stresses is directed to sub-nuclear domains (PML bodies) where it is subjected to further activating modifications. Similarly, cytoplasmic p53 is directed to the mitochondria following stress where it interacts with pro- and anti-apoptotic members of the Bcl2 family, resulting in the release of factors from the mitochondria that drive apoptosis. This chapter will review studies of p53 localization control including its nuclear-cytoplasmic shuttling, movement to PML bodies and to the mitochondria.


Nuclear Export Nuclear Import Nuclear Export Signal MDM2 Binding 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Hollstein M, Sidransky D, Vogelstein B et al. p53 mutations in human cancers. Science 1991; 253:49–53.PubMedCrossRefGoogle Scholar
  2. 2.
    Marchenko ND, Wolff S, Erster S et al. Monoubiquitylation promotes mitochondrial p53 translocation. EMBO J 2007; 26:923–934.PubMedCrossRefGoogle Scholar
  3. 3.
    Middeler G, Zerf K, Jenovai S et al. The tumor suppressor p53 is subject to both nuclear import and export, and both are fast, energy-dependent and lectin-inhibited. Oncogene 1997; 14:1407–1417.PubMedCrossRefGoogle Scholar
  4. 4.
    Shaulsky G, Ben-Ze’ev A, Rotter V. Subcellular distribution of the p53 protein during the cell cycle of Balb/c 3T3 cells. Oncogene 1990; 5:1707–1711.PubMedGoogle Scholar
  5. 5.
    Shaulsky G, Goldfinger N, Ben-Ze’ev A et al. Nuclear accumulation of p53 protein is mediated by several nuclear localization signals and plays a role in tumorigenesis. Mol Cell Biol 1990; 10:6565–6577.PubMedGoogle Scholar
  6. 6.
    Dang CV, Lee WM. Nuclear and nucleolar targeting sequences of c-erb-A, c-myb, N-myc, p53, HSP70, and HIV tat proteins. J Biol Chem 1989; 264:18019–18023.PubMedGoogle Scholar
  7. 7.
    Shaulsky G, Goldfinger N, Tosky MS et al. Nuclear localization is essential for the activity of p53 protein. Oncogene 1991; 6:2055–2065.PubMedGoogle Scholar
  8. 8.
    Shaulsky G, Goldfinger N, Peled A et al. Involvement of wild-type p53 protein in the cell cycle requires nuclear localization. Cell Growth Differ 1991; 2:661–667.PubMedGoogle Scholar
  9. 9.
    Liang SH, Clarke MF. A bipartite nuclear localization signal is required for p53 nuclear import regulated by a carboxyl-terminal domain. J Biol Chem 1999; 274:32699–32703.PubMedCrossRefGoogle Scholar
  10. 10.
    Liang SH, Clarke MF. The nuclear import of p53 is determined by the presence of a basic domain and its relative position to the nuclear localization signal. Oncogene 1999; 18:2163–2166.PubMedCrossRefGoogle Scholar
  11. 11.
    Liang SH, Hong D, Clarke MF. Cooperation of a single lysine mutation and a C-terminal domain in the cytoplasmic sequestration of the p53 protein. J Biol Chem 1998; 273:19817–19821.PubMedCrossRefGoogle Scholar
  12. 12.
    Stommel JM, Marchenko ND, Jimenez GS et al. A leucine-rich nuclear export signal in the p53 tetramerization domain: regulation of subcellular localization and p53 activity by NES masking. EMBO J 1999; 18:1660–1672.PubMedCrossRefGoogle Scholar
  13. 13.
    Gu J, Nie L, Wiederschain D et al. Identification of p53 sequence elements that are required for MDM2-mediated nuclear export. Mol Cell Biol 2001; 21:8533–8546.PubMedCrossRefGoogle Scholar
  14. 14.
    O’Keefe K, Li H, Zhang Y. Nucleocytoplasmic shuttling of p53 is essential for MDM2-mediated cytoplasmic degradation but not ubiquitination. Mol Cell Biol 2003; 23:6396–6405.PubMedCrossRefGoogle Scholar
  15. 15.
    Giannakakou P, Sackett DL, Ward Y et al. p53 is associated with cellular microtubules and is transported to the nucleus by dynein. Nat Cell Biol 2000; 2:709–717.PubMedCrossRefGoogle Scholar
  16. 16.
    Galigniana MD, Harrell JM, O’Hagen HM et al. Hsp90-binding immunophilins link p53 to dynein during p53 transport to the nucleus. J Biol Chem 2004; 279:22483–22489.PubMedCrossRefGoogle Scholar
  17. 17.
    Trostel SY, Sackett DL, Fojo T. Oligomerization of p53 precedes its association with dynein and nuclear accumulation. Cell Cycle 2006; 5:2253–2259.PubMedCrossRefGoogle Scholar
  18. 18.
    Vousden KH, Lu X. Live or let die: the cell’s response to p53. Nat Rev Cancer 2002; 2:594–604.PubMedCrossRefGoogle Scholar
  19. 19.
    Jensen K, Shiels C, Freemont PS. PML protein isoforms and the RBCC/TRIM motif. Oncogene 2001; 20:7223–7233.PubMedCrossRefGoogle Scholar
  20. 20.
    Fogal V, Gostissa M, Sandy P et al. Regulation of p53 activity in nuclear bodies by a specific PML isoform. EMBO J 2000; 19:6185–6195.PubMedCrossRefGoogle Scholar
  21. 21.
    Pearson M, Carbone R, Sebastiani C et al. PML regulates p53 acetylation and premature senescence induced by oncogenic Ras. Nature 2000; 406:207–210.PubMedCrossRefGoogle Scholar
  22. 22.
    Ferbeyre G, de Stanchina E, Querido E et al. PML is induced by oncogenic ras and promotes premature senescence. Genes Dev 2000; 14:2015–2027.PubMedGoogle Scholar
  23. 23.
    Seeler JS, Dejean A. SUMO: of branched proteins and nuclear bodies. Oncogene 2001; 20:7243–7249.PubMedCrossRefGoogle Scholar
  24. 24.
    Rodriguez MS, Desterro JM, Lain S et al. SUMO-1 modification activates the transcriptional response of p53. EMBO J 1999; 18:6455–6461.PubMedCrossRefGoogle Scholar
  25. 25.
    Mauri F, McNamee LM, Lunardi A et al. Modification of Drosophila p53 by SUMO Modulates Its Transactivation and Pro-apoptotic Functions. J Biol Chem 2008; 283:20848–20856.PubMedCrossRefGoogle Scholar
  26. 26.
    Li T, Santockyte R, Shen RF et al. Expression of SUMO-2/3 induced senescence through p53-and pRB-mediated pathways. J Biol Chem 2006; 281:36221–36227.PubMedCrossRefGoogle Scholar
  27. 27.
    Zhang Y, Xiong Y. A p53 amino-terminal nuclear export signal inhibited by DNA damage-induced phosphorylation. Science 2001; 292:1910–1915.PubMedCrossRefGoogle Scholar
  28. 28.
    Freedman DA, Levine AJ. Nuclear export is required for degradation of endogenous p53 by MDM2 and human papillomavirus E6. Mol Cell Biol 1998; 18:7288–7293.PubMedGoogle Scholar
  29. 29.
    Roth J, Dobbelstein M, Freedman DA et al. 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 1998; 17:554–564.PubMedCrossRefGoogle Scholar
  30. 30.
    Tao W, Levine AJ. Nucleocytoplasmic shuttling of oncoprotein Hdm2 is required for Hdm2-mediated degradation of p53. Proc Natl Acad Sci USA 1999; 96:3077–3080.PubMedCrossRefGoogle Scholar
  31. 31.
    Geyer RK, Yu ZK, Maki CG. The MDM2 RING-finger domain is required to promote p53 nuclear export. Nat Cell Biol 2000; 2:569–573.PubMedCrossRefGoogle Scholar
  32. 32.
    Boyd SD, Tsai KY, Jacks T. An intact HDM2 RING-finger domain is required for nuclear exclusion of p53. Nat Cell Biol 2000; 2:563–568.PubMedCrossRefGoogle Scholar
  33. 33.
    Lohrum MA, Woods DB, Ludwig RL et al. C-terminal ubiquitination of p53 contributes to nuclear export. Mol Cell Biol 2001; 21:8521–8532.PubMedCrossRefGoogle Scholar
  34. 34.
    Li M, Brooks CL, Wu-Baer F et al. Mono-versus polyubiquitination: differential control of p53 fate by Mdm2. Science 2003; 302:1972–1975.PubMedCrossRefGoogle Scholar
  35. 35.
    Brooks CL, Li M, Gu W. Mechanistic studies of MDM2-mediated ubiquitination in p53 regulation. J Biol Chem 2007; 282:22804–22815.PubMedCrossRefGoogle Scholar
  36. 36.
    Chau V, Tobias JW, Bachmair A et al. A multiubiquitin chain is confined to specific lysine in a targeted short-lived protein. Science 1989; 243:1576–1583.PubMedCrossRefGoogle Scholar
  37. 37.
    Grossman SR, Deato ME, Brignone C et al. Polyubiquitination of p53 by a ubiquitin ligase activity of p300. Science 2003; 300:342–344.PubMedCrossRefGoogle Scholar
  38. 38.
    Grossman SR, Perez M, Kung AL et al. p300/MDM2 complexes participate in MDM2-mediated p53 degradation. Mol Cell 1998; 2:405–415.PubMedCrossRefGoogle Scholar
  39. 39.
    Grossman SR. p300/CBP/p53 interaction and regulation of the p53 response. Eur J Biochem 2001; 268:2773–2778.PubMedCrossRefGoogle Scholar
  40. 40.
    Gannon JV, Greaves R, Iggo R et al. Activating mutations in p53 produce a common conformational effect. A monoclonal antibody specific for the mutant form. EMBO J 1990; 9:1595–1602.PubMedGoogle Scholar
  41. 41.
    Milner J, Cook A, Sheldon M. A new anti-p53 monoclonal antibody, previously reported to be directed against the large T antigen of simian virus 40. Oncogene 1987; 1:453–455.PubMedGoogle Scholar
  42. 42.
    Nie L, Sasaki M, Maki CG. Regulation of p53 nuclear export through sequential changes in conformation and ubiquitination. J Biol Chem 2007; 282:14616–14625.PubMedCrossRefGoogle Scholar
  43. 43.
    Yu ZK, Geyer RK, Maki CG. MDM2-dependent ubiquitination of nuclear and cytoplasmic p53. Oncogene 2000; 19:5892–5897.PubMedCrossRefGoogle Scholar
  44. 44.
    Xirodimas DP, Stephen CW, Lane DP. Cocompartmentalization of p53 and Mdm2 is a major determinant for Mdm2-mediated degradation of p53. Exp Cell Res 2001; 270:66–77.PubMedCrossRefGoogle Scholar
  45. 45.
    Shirangi TR, Zaika A, Moll UM. Nuclear degradation of p53 occurs during down-regulation of the p53 response after DNA damage. FASEB J 2002; 16:420–422.PubMedGoogle Scholar
  46. 46.
    Dumont P, Leu JI, Della Pietra AC 3rd et al. The codon 72 polymorphic variants of p53 have markedly different apoptotic potential. Nat Genet 2003; 33:357–365.PubMedCrossRefGoogle Scholar
  47. 47.
    Nikolaev AY, Li M, Puskas N et al. Parc: a cytoplasmic anchor for p53. Cell 2003; 112:29–40.PubMedCrossRefGoogle Scholar
  48. 48.
    Sengupta S, Vonesch JL, Waltzinger C et al. Negative cross-talk between p53 and the glucocorticoid receptor and its role in neuroblastoma cells. EMBO J 2000; 19:6051–6064.PubMedCrossRefGoogle Scholar
  49. 49.
    Sengupta S, Wasylyk B. Ligand-dependent interaction of the glucocorticoid receptor with p53 enhances their degradation by Hdm2. Genes Dev 2001; 15:2367–2380.PubMedCrossRefGoogle Scholar
  50. 50.
    Wadhwa R, Takano S, Robert M et al. Inactivation of tumor suppressor p53 by mot-2, a hsp70 family member. J Biol Chem 1998; 273:29586–29591.PubMedCrossRefGoogle Scholar
  51. 51.
    Lu W, Pochampally R, Chen L et al. Nuclear exclusion of p53 in a subset of tumors requires MDM2 function. Oncogene 2000; 19:232–240.PubMedCrossRefGoogle Scholar
  52. 52.
    Rodriguez-Lopez AM, Xenaki D, Eden TO et al. MDM2 mediated nuclear exclusion of p53 attenuates etoposide-induced apoptosis in neuroblastoma cells. Mol Pharmacol 2001; 59:135–143.PubMedGoogle Scholar
  53. 53.
    Fontoura BM, Atienza CA, Sorokina EA et al. Cytoplasmic p53 polypeptide is associated with ribosomes. Mol Cell Biol 1997; 17:3146–3154.PubMedGoogle Scholar
  54. 54.
    Guerra B, Issinger OG. p53 and the ribosomal protein L5 participate in high molecular mass complex formation with protein kinase CK2 in murine teratocarcinoma cell line F9 after serum stimulation and cisplatin treatment. FEBS Lett 1998; 434:115–120.PubMedCrossRefGoogle Scholar
  55. 55.
    Marchenko ND, Moll UM. The role of ubiquitination in the direct mitochondrial death program of p53. Cell Cycle 2007; 6:1718–1723.PubMedCrossRefGoogle Scholar
  56. 56.
    Carter S, Bischof O, Dejean A et al. C-terminal modifications regulate MDM2 dissociation and nuclear export of p53. Nat Cell Biol 2007; 9:428–435.PubMedCrossRefGoogle Scholar
  57. 57.
    Wang X, Zalcenstein A, Oren M. Nitric oxide promotes p53 nuclear retention and sensitizes neuroblastoma cells to apoptosis by ionizing radiation. Cell Death Differ 2003; 10:468–476.PubMedCrossRefGoogle Scholar
  58. 58.
    Schneiderhan N, Budde A, Zhang Y et al. Nitric oxide induces phosphorylation of p53 and impairs nuclear export. Oncogene 2003; 22:2857–2868.PubMedCrossRefGoogle Scholar
  59. 59.
    Kawaguchi Y, Ito A, Appella E et al. Charge modification at multiple C-terminal lysine residues regulates p53 oligomerization and its nucleus-cytoplasm trafficking. J Biol Chem 2006; 281: 1394–1400.PubMedCrossRefGoogle Scholar
  60. 60.
    Li M, Luo J, Brooks CL et al. Acetylation of p53 inhibits its ubiquitination by Mdm2. J Biol Chem 2002; 277:50607–50611.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Carl G. Maki
    • 1
  1. 1.Department of Radiation and Cellular OncologyUniversity of ChicagoChicagoUSA

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