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The P53 Tumor Suppressor Protein

Biophysical Characterization of the Carboxy-Terminal Oligomerization Domain
  • Ettore Appella
  • Kazuyasu Sakaguchi
  • Hiroshi Sakamoto
  • Marc S. Lewis
  • James G. Omichinski
  • Angela M. Gronenborn
  • G. Marius Clore
  • Carl W. Anderson

Abstract

In response to damaged DNA, mammalian cell growth is arrested at cell cycle checkpoints in Gl, near the border of S phase, or in G2, before mitosis (Murray, 1992; Hunter, 1993; Weinert and Lydall, 1993). In some circumstances, DNA damage initiates apoptosis, a program that results in cell death. Recent studies have shown that the p53 tumor suppressor protein is an essential component of the G1 checkpoint pathway (Kastan et al., 1991); it also modulates the initiation of apoptosis (Oren, 1994). The arrest of cell cycle progression provides time for DNA damage to be repaired, whereas apoptosis may insure the death of more severely damaged cells that are at risk of loss of growth control through genome rearrangements. Thus, these functions account, at least in part, for the importance of p53 in suppressing or eliminating preneoplastic or neoplastic cells in the human and other vertebrate species. In turn, p53 function is mediated through its physical characteristics, and these may be modulated by post-translational mechanisms (Ullrich et al., 1992; Meek, 1994). Thus, biophysical studies of p53 and its functional domains are fundamental to an understanding of those properties that are important for normal p53 function.

Keywords

Casein Kinase Mutant P53s Tetramerization Domain Leucine Zipper Dimerization Domain 
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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References

  1. Addison, C., Jenkins, J. R. and Sturzbecher, H.-W., 1990. The p53 nuclear-localization signal is structurally linked to a p34cdc2 kinase motif. Oncogene 5: 423.PubMedGoogle Scholar
  2. Bakalkin, G., Yakovleva, T., Selivanova, G., Magnusson, K. P., Szekely, L.. Kiseleva, E., Klein, G., Terenius, L. and Wiman, K. G., 1994. p53 binds single-stranded DNA ends and catalyzes DNA renaturation and strand transfer. Proc. Natl. Acad. Sci. USA 91: 413.Google Scholar
  3. Bargonetti, J., Friedman, P. N., Kern, S. E., Vogelstein, B. and Prives, C., 1991. Wild-type but not mutant p53 immunopurified proteins bind to sequences adjacent to the SV40 origin of replication. Cell 65: 1083.PubMedCrossRefGoogle Scholar
  4. Bargonetti, J., Manfredi, J. J., Chen, X., Marshak, D. R. and Prives, C., 1993. A proteolytic fragment from the central region of p53 has marked sequence-specific DNA-binding activity when generated from wild-type but not from oncogenic mutant p53 protein. Genes Dey. 7: 2565.CrossRefGoogle Scholar
  5. Bax, A. and Grzesiek, S., 1993. Methodological advances in protein NMR. Acc. Chem. Res. 26: 131. Bischoff, J. R., Friedman, P. N., Marshak, D. R., Prives, C., and Beach, D., 1990 Human p53 is phosphorylated by p60-cdc2 and cyclin B-cdc2. Proc. Natl. Acad. Sci. USA 87: 4766.Google Scholar
  6. Cho, Y., Gorina, S., Jeffrey, P. D. and Pavletich, N. P., 1994. Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations. Science 265: 346.PubMedCrossRefGoogle Scholar
  7. Clarke, E. C. W. and Glew, D. N., 1966. Evaluation of thermodynamic function from equilibrium constants. Trans. Farady Soc. 62: 539.CrossRefGoogle Scholar
  8. Clore, G. M. and Gronenborn, A. M., 1994. Multidimensional heteronuclear magnetic resonance of proteins. Methods Enzymol. 239: 349.PubMedCrossRefGoogle Scholar
  9. Clore, G. M., Omichinski, J. G., Sakaguchi, K., Zambrano, N., Sakamoto, H., Appella, E. and Gronenborn, A. M., 1994. High-resolution structure of the oligomerization domain of p53 by multidimensional NMR. Science 265: 386.PubMedCrossRefGoogle Scholar
  10. De’rijard, B., Hibi, M., Wu, I.-H., Barrett, T., Su, B., Deng, T., Karin, M. and Davis, R. J., 1994. JNK1: a protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain. Cell 76: 1025.CrossRefGoogle Scholar
  11. El-Deiry, W. S., Tokino, T., Velculescu, V. E., Levy, D. B., Parsons, R., Trent, J. M., Lin, D., Mercer, W. E., Kinzler, K. W. and Vogelstein, B., 1993. WAF1, a potential mediator of p53 tumor suppression. Cell 75: 817.Google Scholar
  12. El-Deiry, W. S., Harper, J. W., O’Connor, P. M., Velculescu, V. E., Carman, C. E., Jackman, J., Pietenpol, J. A., Burrell, M., Hill, D. E., Wang, Y., Wiman, K. G., Mercer, W. E., Kastan, M. B., Kohn, K. W., Elledge, S. J., Kinzler, K. W. and Vogelstain B., 1994. WAF1/CIPI is induced in p53-mediated G1 arrest and apoptosis. Cancer Res. 54: 1169.Google Scholar
  13. Farmer, G., Bargonetti, J., Zhu, H., Friedman, P., Prywes, R. and Prives, C., 1992 Wild-type p53 activates transcription in vitro. Nature 358: 83.CrossRefGoogle Scholar
  14. Fields, S. and Jang, S. K., 1990. Presence of a potent transcription activating sequence in the p53 protein. Science 249: 1046.PubMedCrossRefGoogle Scholar
  15. Fiscella, M., Zambrano, N., Ullrich, S. J., Ungar, T., Lin, D., Cho, B., Mercer, W. E., Anderson, C. W. and Appella, E., 1994. The carboxy-terminal serine 392 phosphorylation site of human p53 is not required for wild-type activities. Oncogene 9: 3249.PubMedGoogle Scholar
  16. Funk, W. D., Pak, D. T., Karas, R. H., Wright, W. E. and Shay, J. W., 1992. A transcriptionally active DNA-binding site for human p53 protein complexes. Mol. Cell. Biol. 12: 2866.PubMedGoogle Scholar
  17. Greenblatt, M. S., Bennett, W. P., Hollstein, M. and Harris, C. C., 1994. Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res. 54: 4855.PubMedGoogle Scholar
  18. Halazonetis, T. D., Davis, L. J. and Kandil, A. N., 1993. Wild-type p53 adopts a ‘mutant’-like conformation when bound to DNA. EMBO J. 12: 1021.Google Scholar
  19. Halazonetis, T. D. and Kandil, A. N., 1993. Conformational shifts propagate from the oligomerization domain of p53 to its tetrameric DNA binding domain and restore DNA binding to select p53 mutants. EMBO J. 12: 5057.Google Scholar
  20. Harrington, R. E. and Winicov, I., 1994. New concepts in protein-DNA recognition: sequence-directed DNA bending and flexibility. Prog.Nucleic Acid Res. Mol. Biol. 47: 195.PubMedCrossRefGoogle Scholar
  21. Hojo, H. and Aimoto, S., 1992. Protein synthesis using S-alkyl thioester of partially protected peptide segments. synthesis of DNA-binding protein of Bacillus sterothermophilus. Bull. Chem. Soc. Jpn. 65: 3055.CrossRefGoogle Scholar
  22. Hollstein, M., Sidransky, D., Vogelstein, B. and Harris, C. C. 1991. p53 mutations in human cancers. Science 253: 49.Google Scholar
  23. Hunter, T., 1993. Braking the cycle. Cell 75: 839.PubMedCrossRefGoogle Scholar
  24. Hunter, T., and Karin, M., 1992. The regulation of transcription by phosphorylation. Cell 70: 375.PubMedCrossRefGoogle Scholar
  25. Hupp, T. R., Meek, D. W., Midgley, C. A. and Lane, D. P., 1992. Regulation of the specific DNA binding function of p53. Cell 71: 875.PubMedCrossRefGoogle Scholar
  26. Jackson, S. P., 1992. Regulating transcription factor activity by phosphorylation. Trends Cell Biol. 2: 104. Johnson, Jr., W. C., 1988. Secondary structure of proteins through circular dichroism spectroscopy. Annu. Rev. Biophys. Biochem. 17: 145.Google Scholar
  27. Kastan, M. B., Onyekwere, O., Sidransky, D., Vogelstein, B. and Craig, R. W., 1991. Participation of p53 protein in cellular response to DNA damage. Cancer Res. 51: 6304.PubMedGoogle Scholar
  28. Kastan, M. B., Zhan, Q., El-Deiry, W. S., Camer, F., Jacks, T., Walsh, W. V., Plunkett, B. S., Vogelstein, B. and Fornace, Jr., A. J., 1992. A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia. Cell 71: 587.PubMedCrossRefGoogle Scholar
  29. Kern, S. E., Pietenpol, J. A., Thiagalingam, S., Seymour, A., Kinzler, K. W. and Vogelstein, B., 1992. Oncogenic forms of p53 inhibit p53-regulated gene expression. Science 256: 827.PubMedCrossRefGoogle Scholar
  30. Kuerbitz, S. J., Plunkett, B. S., Walsh, W. V. and Kastan, M. B., 1992. Wild-type p53 is a cell cycle checkpoint determinant following irradiation. Proc. Natl. Acad. Sci. USA 89: 7491.PubMedCrossRefGoogle Scholar
  31. Lamb, P. and Crawford, L., 1986. Characterization of the human p53 gene. Mol Cell Biol 6: 1379.PubMedGoogle Scholar
  32. Lees-Miller, S. P., Sakaguchi, K., Ullrich, S. J., Appella, E. and Anderson, C. W., 1992. Human DNA-activated protein kinase phosphorylates serines 15 and 37 in the amino-terminal transactivation domain of human p53. Mol Cell Biol 12: 5041.PubMedGoogle Scholar
  33. Levine, A. J., 1993. The tumor suppressor genes. Annu. Rev. Biochem, 62: 623.PubMedCrossRefGoogle Scholar
  34. Lu, X. and Lane, D. P., 1993. Differential induction of transcriptionally active p53 following UV or ionizing radiation: defects in chromosome instability syndromes? Cell 75: 765.PubMedCrossRefGoogle Scholar
  35. Maltzman, W. and Czyzyk, L., 1984. UV irradiation stimulates levels of p53 cellular tumor antigen in nontransformed mouse cells. Mol. Cell. Biol. 4: 1689.PubMedGoogle Scholar
  36. Meek, D., 1994. Post-translational modification of p53. Semin. Cancer Biol. 5: 203.PubMedGoogle Scholar
  37. Meek, D. W., Simon, S., Kikkawa, U. and Eckhart, W., 1990. The p53 tumor suppressor protein is phosphorylated at serine 389 by casein kinase II. EMBO J. 9: 3253.Google Scholar
  38. Mercer, W. E., Shields, M. T., Amin, M., Sauve, G. J., Appella, E., Romano, J. W. and Ullrich, S. J., 1990. Negative growth regulation in a glioblastoma tumor cell line that conditionally expresses human wild-type p53. Proc. Natl. Acad. Sci. USA 87: 6166.PubMedCrossRefGoogle Scholar
  39. Milne, D. M., Palmer, R. H., Campbell, D. G. and Meek, D. W., 1992. Phosphorylation of the p53 tumor-sup-pressor protein at 3 N-terminal sites by a novel casein kinase I-like enzyme. Oncogene 7: 1361.PubMedGoogle Scholar
  40. Milne, D. M., Campbell, D. G., Caudwell, F. B. and Meek, D. W., 1994. Phosphorylation of the tumor suppressor protein p53 by mitogen-activated protein kinases. J. Biol. Chem. 269: 9253.PubMedGoogle Scholar
  41. Milner, J., and Medcalf, E. A., 1991. Cotranslation of activated mutant p53 with wild-type drives the wild-type 53 protein into the mutant p53 conformation. Cell 65: 765.PubMedCrossRefGoogle Scholar
  42. Murray, A. W., 1992. Creative blocks: cell-cycle checkpoints and feedback controls. Nature 359: 599. Nelson, W. G. and Kastan, M. B., 1994. DNA strand breaks: the DNA template alterations that trigger p53-dependent DNA damage response pathways. Mol. Cell. Biol. 14: 1815.Google Scholar
  43. Oberosler, P., Hloch, P., Ramsperger, U. and Stahl, H., 1993. p53-catalyzed annealing of complementary single-stranded nucleic acids. EMBO J. 12: 2389.Google Scholar
  44. Oren, M., 1994. Relationship of p53 to the control of apoptotic cell death. Semin. Cancer Biol. 5: 221. Pavletich, N. P., Chambers, K. A. and Pabo, C. 0., 1993. The DNA-binding domain of p53 contains the four conserved regions and the major mutation hot spots. Genes Dey. 7: 2556.Google Scholar
  45. Pietenpol, J. A., Tokino, T., Thiagalingam, S., El-Deity, W. S., Kinzler, K. W. and Vogelstein, B., 1994. Sequence-specific transcriptional activation is essential for growth suppression by p53. Proc. Natl. Acad. Sci. USA 91: 1998.Google Scholar
  46. Raycroft, L., Wu, H. and Lozano, G., 1990. Transcriptional activation by wild-type but not transforming mutants of the p53 anti-oncogene. Science 249: 1049.PubMedCrossRefGoogle Scholar
  47. Reed, M., Wang, Y., Mayr, G., Anderson, M. E., Schwedes, J. F., and Tegtmeyer, E, 1993. p53 domains: suppression, transformation, and transactivation. Gene Expression 3: 95.Google Scholar
  48. Sakamoto, H., Lewis, M. S., Kodama, H, Appella, E., and Sakaguchi, K., 1994. Specific sequences from the carboxy-terminus of human p53 form anti-parallel tetramers in solution. Proc. Natl. Acad. Sci. USA 91: 8974.PubMedCrossRefGoogle Scholar
  49. Soussi, T., Caron de Fromentel, C. and May, P., 1990 Structural aspects of the p53 protein in relation to gene evolution. Oncogene 5: 945.PubMedGoogle Scholar
  50. Stenger, J. E., Mayr, G. A., Mann, K. and Tegtmeyer, P., 1992. p53 forms stable homotetramers and multiples of tetramers. Mol. Carcinog. 5: 102.Google Scholar
  51. Ullrich, S. J., Anderson, C. W., Mercer, W. E. and Appella, E., 1992. The p53 tumor suppressor protein, a modulator of cell proliferation. J. Biol. Chem. 267: 15259.PubMedGoogle Scholar
  52. Ullrich, S. J., Sakaguchi, K., Lees-Miller, S. P., Fiscella, M., Mercer, W. E., Anderson, C. W. and Appella, E., 1993. Phosphorylation at serine 15 and 392 in mutant p53s from human tumors is altered compared to wild-type p53. Proc. Natl. Acad. Sci. USA 90: 5954.PubMedCrossRefGoogle Scholar
  53. Unger, T., Nau, M. M., Segal, S. & Minna, J.D., 1992. p53: a transdominant regulator of transcription whose function is ablated by mutations occurring in human cancer. EMBO J. 11: 1383.Google Scholar
  54. Wang, Y., and Eckhart, W., 1992. Phosphorylation sites in the amino-terminal region of mouse p53. Proc. Natl. Acad. Sci. USA 89: 4231.PubMedCrossRefGoogle Scholar
  55. Wang, Y., Reed, M., Wang, P., Stenger, J. E., Mayr, G., Anderson, M. E., Schwedes, J. F. and Tegtmeyer,P., 1993. p53 domains: identification and characterization of two autonomous DNA-binding regions. Genes Dey. 7: 2575.Google Scholar
  56. Wang, Y., Reed, M., Wang, Y., Mayr, G., Stenger, J. E., Anderson, M. E., Schwedes, J. F. and Tegtmeyer, P., 994. p53 domains. structure, oligomerization, and transformation. Mol. Cell. Biol. 14: 5182.Google Scholar
  57. Weinert, T. and Lydall, D., 1993. Cell cycle checkpoints, genetic instability and cancer. Semin. Cancer Biol. 4: 129.PubMedGoogle Scholar
  58. Xiong, Y., Hannon, G. J., Zhang, H., Casso, D., Kobayashi, R. and Beach, D., 1993. p21 is a universal inhibitor of cyclin kinases. Nature 366: 701.Google Scholar
  59. Zambetti, G. P., Bargonetti, J., Walker, K., Prives, C. and Levine, A. J., 1992. Wild-type p53 mediates positive regulation of gene expression through a specific DNA sequence element. Genes Dey. 6: 1143.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1995

Authors and Affiliations

  • Ettore Appella
    • 1
  • Kazuyasu Sakaguchi
    • 1
  • Hiroshi Sakamoto
    • 1
  • Marc S. Lewis
    • 2
  • James G. Omichinski
    • 3
  • Angela M. Gronenborn
    • 3
  • G. Marius Clore
    • 3
  • Carl W. Anderson
    • 4
  1. 1.Laboratory of Cell BiologyNational Cancer Institute, National Institutes of HealthBethesdaUSA
  2. 2.Biomedical Engineering and Instrumentation ProgramNational Center for Research ResourcesBethesdaUSA
  3. 3.Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney DiseasesNational Institutes of HealthBethesdaUSA
  4. 4.Biology DepartmentBrookhaven National LaboratoryUptonUSA

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