Journal of Life Science (생명과학회지)

Korean Society of Life Science (한국생명과학회)
권호 표지
DOI QR코드

DOI QR Code

The Structural and Functional Role of p53 as a Cancer Therapeutic Target

암 치료 표적으로서 p53의 구조적 및 기능적 역할

  • Han, Chang Woo (Department of Molecular Biology, College of Natural Sciences, Pusan National University) ;
  • Park, So Young (Department of Molecular Biology, College of Natural Sciences, Pusan National University) ;
  • Jeong, Mi Suk (Department of Molecular Biology, College of Natural Sciences, Pusan National University) ;
  • Jang, Se Bok (Department of Molecular Biology, College of Natural Sciences, Pusan National University)
  • 한창우 (부산대학교 자연과학대학 분자생물학과) ;
  • 박소영 (부산대학교 자연과학대학 분자생물학과) ;
  • 정미숙 (부산대학교 자연과학대학 분자생물학과) ;
  • 장세복 (부산대학교 자연과학대학 분자생물학과)
  • Received : 2018.03.14
  • Accepted : 2018.04.18
  • Published : 2018.04.30
Download PDF
⟨ Previous Next ⟩

Abstract

The p53 gene plays a critical role in the transcriptional regulation of cellular response to stress, DNA damage, hypoxia, and tumor development. Keeping in mind the recently discovered manifold physiological functions of p53, its involvement in the regulation of cancer is not surprising. In about 50% of all human cancers, inactivation of p53's protein function occurs either through mutations in the gene itself or defects in the mechanisms that activate it. This disorder plays a crucial role in tumor evolution by allowing the evasion of a p53-dependent response. Many recent studies have focused on directly targeting p53 mutants by identifying selective, small molecular compounds to deplete them or to restore their tumor-suppressive function. These small molecules should effectively regulate various interactions while maintaining good drug-like properties. Among them, the discovery of the key p53-negative regulator, MDM2, has led to the design of new small molecule inhibitors that block the interaction between p53 and MDM2. Some of these small molecule compounds have now moved from proof-of-concept studies into clinical trials, with prospects for further, more personalized anti-carcinogenic medicines. Here, we review the structural and functional consequences of wild type and mutant p53 as well as the development of therapeutic agents that directly target this gene, and compounds that inhibit the interaction between it and MDM2.

p53 유전자는 스트레스, DNA 손상, 저산소증 및 종양 발생에 대한 세포 반응의 전사 조절에서 중요한 역할을 담당한다. 최근에 발견된 다양한 종류의 p53의 생리 활성을 생각한다면 p53이 암 조절에 관여한다는 것은 놀랄만한 일이 아니다. 인간 암의 약 50%에는 p53 유전자의 돌연변이 또는 p53을 활성화시키는 기전의 결함을 통해 p53 단백질 기능의 불활성화가 나타난다. p53 기능의 이러한 장애는 p53 의존 반응으로부터 회피를 허용함으로써 종양의 진화에 결정적인 역할을 하게 된다. 최근의 많은 연구들은 p53의 돌연변이를 대폭 감소시키거나 p53의 종양 억제 기능을 복원하기 위하여 선택적인 저분자 화합물을 동정함으로써 p53의 돌연변이를 직접 표적하는 것에 초점을 두고 있다. 이들 저분자는 좋은 약물과 유사한 특성을 유지하면서 다양한 상호작용을 효과적으로 조절해야 한다. 이 중, p53의 음성조절인자 핵심인 MDM2의 발견은 p53과 MDM2 간의 상호작용을 차단하는 새로운 저분자 억제제의 설계를 제공하였다. 저분자 화합물 중 일부는 개념 증명 연구에서 임상 시험으로 옮겨졌으며 향후 맞춤형 항암제가 추가될 전망이다. 본 리뷰에서는 야생형 p53과 돌연변이 p53의 구조적 및 기능적 중요성과 p53을 직접 표적하는 치료제 개발, p53과 MDM2 간의 상호작용을 억제하는 화합물에 대하여 검토하였다.

Keywords

References

  1. Bochkareva, E., Kaustov, L., Ayed, A., Yi, G. S., Lu, Y., Pineda-Lucena, A., Liao, J. C., Okorokov, A. L., Milner, J., Arrowsmith, C. H. and Bochkarev, A. 2005. Single-stranded DNA mimicry in the p53 transactivation domain interaction with replication protein A. Proc. Natl. Acad. Sci. USA. 102, 15412-15417. https://doi.org/10.1073/pnas.0504614102
  2. Brown, C. J., Quah, S. T., Jong, J., Goh, A. M., Chiam, P. C., Khoo, K. H., Choong, M. L., Lee, M. A., Yurlova, L., Zolghadr, K., Joseph, T. L., Verma, C. S. and Lane, D. P. 2013. Stapled peptides with improved potency and specificity that activate p53. ACS Chem. Biol. 8, 506-512. https://doi.org/10.1021/cb3005148
  3. Burmakin, M., Shi, Y., Hedstrom, E., Kogner, P. and Selivanova, G. 2013. Dual targeting of wild-type and mutant p53 by small molecule RITA results in the inhibition of N-Myc and key survival oncogenes and kills neuroblastoma cells in vivo and in vitro. Clin. Cancer Res. 19, 5092-5103. https://doi.org/10.1158/1078-0432.CCR-12-2211
  4. Bykov, V. J. N., Eriksson, S. E., Bianchi, J. and Wiman, K. G. 2018. Targeting mutant p53 for efficient cancer therapy. Nat. Rev. Cancer 18, 89-102.
  5. Canadillas, J. M. P., Tidow, H., Freund, S. M. V., Rutherford, T. J., Ang, H. C. and Fersht, A. R. 2006. Solution structure of p53 core domain: Structural basis for its instability. Proc. Natl. Acad. Sci. USA. 103, 2109-2114. https://doi.org/10.1073/pnas.0510941103
  6. Chi, S. W. 2014. Structural insights into the transcription-independent apoptotic pathway of p53. BMB Rep. 47, 167-172. https://doi.org/10.5483/BMBRep.2014.47.3.261
  7. Chi, S. W., Lee, S. H., Kim, D. H., Ahn, M. J., Kim, J. S., Woo, J. Y., Torizawa, T., Kainosho, M. and Han, K. H. 2005. Structural details on mdm2-p53 interaction. J. Biol. Chem. 280, 38795-38802. https://doi.org/10.1074/jbc.M508578200
  8. Collavin, L., Lunardi, A. and Del, Sal G. 2010. p53-family proteins and their regulators: hubs and spokes in tumor suppression. Cell Death Differ. 17, 901-911. https://doi.org/10.1038/cdd.2010.35
  9. Demir, O., Ieong, P. U. and Amaro, R. E. 2017. Full-length p53 tetramer bound to DNA and its quaternary dynamics. Oncogene 36, 1451-1460. https://doi.org/10.1038/onc.2016.321
  10. Di Lello, P., Jenkins, L. M. M., Jones, T. N., Nguyen, B. D., Hara, T., Yamaguchi, H., Dikeakos, J. D., Appella, E., Legault, P. and Omichinski, J. G. 2006. Structure of the Tfb1/p53 complex: Insights into the interaction between the p62/Tfb1 subunit of TFIIH and the activation domain of p53. Mol. Cell 22, 731-740. https://doi.org/10.1016/j.molcel.2006.05.007
  11. Dornan, D., Shimizu, H., Burch, L., Smith, A. J. and Hupp, T. R. 2003. The proline repeat domain of p53 binds directly to the transcriptional coactivator p300 and allosterically controls DNA-dependent acetylation of p53. Mol. Cell. Biol. 23, 8846-8861. https://doi.org/10.1128/MCB.23.23.8846-8861.2003
  12. Duan, J. X. and Nilsson, L. 2006. Effect of $Zn^{2+}$ on DNA recognition and stability of the p53 DNA-binding domain. Biochemistry 45, 7483-7492. https://doi.org/10.1021/bi0603165
  13. Espinoza-Fonseca, L. M. and Trujillo-Ferrara, J. G. 2006. Transient stability of the helical pattern of region F19-L22 of the N-terminal domain of p53: a molecular dynamics simulation study. Biochem. Biophys. Res. Commun. 343, 110-116. https://doi.org/10.1016/j.bbrc.2006.02.129
  14. Feng, H. Q., Jenkins, L. M. M., Durell, S. R., Hayashi, R., Mazur, S. J., Cherry, S., Tropea, J. E., Miller, M., Wlodawer, A., Appella, E. and Bai, Y. 2009. Structural basis for p300 Taz2-p53 TAD1 binding and modulation by phosphorylation. Structure 17, 202-210. https://doi.org/10.1016/j.str.2008.12.009
  15. Fotouhi, N. and Graves, B. 2005. Small molecule inhibitors of p53/MDM2 interaction. Curr. Top. Med. Chem. 5, 159-165. https://doi.org/10.2174/1568026053507705
  16. Freed-Pastor, W. A. and Prives, C. 2012. Mutant p53: one name, many proteins. Genes Dev. 26, 1268-1286. https://doi.org/10.1101/gad.190678.112
  17. Grasberger, B. L., Lu, T., Schubert, C., Parks, D. J., Carver, T. E., Koblish, H. K., Cummings, M. D., LaFrance, L. V., Milkiewicz, K. L., Calvo, R. R., Maguire, D., Lattanze, J., Franks, C. F., Zhao, S., Ramachandren, K., Bylebyl, G. R., Zhang, M., Manthey, C. L., Petrella, E. C., Pantoliano, M. W., Deckman, I. C., Spurlino, J. C., Maroney, A. C., Tomczuk, B. E., Molloy, C. J. and Bone, R. F. 2005. Discovery and cocrystal structure of benzodiazepinedione HDM2 antagonists that activate p53 in cells. J. Med. Chem. 48, 909-912. https://doi.org/10.1021/jm049137g
  18. Halazonetis, T. D., Gorgoulis, V. G. and Bartek, J. 2008. An oncogene-induced DNA damage model for cancer development. Science 319, 1352-1355. https://doi.org/10.1126/science.1140735
  19. Hiraki, M., Hwang, S. Y., Cao, S., Ramadhar, T. R., Byun, S., Yoon, K. W., Lee, J. H., Chu, K., Gurkar, A. U., Kolev, V., Zhang, J., Namba, T., Murphy, M. E., Newman, D. J., Mandinova, A., Clardy, J. and Lee, S. W. 2015. Small- molecule reactivation of mutant p53 to wild-type-like p53 through the p53-Hsp40 regulatory axis. Chem. Biol. 22, 1206-1216. https://doi.org/10.1016/j.chembiol.2015.07.016
  20. Ho, W. C., Luo, C., Zhao, K., Chai, X., Fitzgerald, M. X. and Marmorstein, R. 2006. High-resolution structure of the p53 core domain: implications for binding small-molecule stabilizing compounds. Acta Crystallogr. D Biol. Crystallogr. 62, 1484-1493. https://doi.org/10.1107/S090744490603890X
  21. Hollstein, M., Sidransky, D., Vogelstein, B. and Harris, C. C. 1991. p53 mutations in human cancers. Science 253, 49-53. https://doi.org/10.1126/science.1905840
  22. Huang, L., Yan, Z., Liao, X. D., Li, Y., Yang, J., Wang, Z. G., Zuo, Y., Kawai, H., Shadfan, M., Ganapathy, S. and Yuan, Z. M. 2011. The p53 inhibitors MDM2/MDMX complex is required for control of p53 activity in vivo. Proc. Natl. Acad. Sci. USA. 108, 12001-12006. https://doi.org/10.1073/pnas.1102309108
  23. Issaeva, N., Bozko, P., Enge, M., Protopopova, M., Verhoef, L. G., Masucci, M., Pramanik, A. and Selivanova, G. 2004. Small molecule RITA binds to p53, blocks p53-HDM-2 interaction and activates p53 function in tumors. Nat. Med. 10, 1321-1328. https://doi.org/10.1038/nm1146
  24. Johnson, R. F. and Perkins, N. D. 2012. Nuclear $factor-{\kappa}B$, p53, and mitochondria: regulation of cellular metabolism and the Warburg effect. Trends Biochem. Sci. 37, 317-324 https://doi.org/10.1016/j.tibs.2012.04.002
  25. Jeffrey, P. D., Gorina, S. and Pavletich, N. P. 1995. Crystal structure of the tetramerization domain of the p53 tumor suppressor at 1.7 angstroms. Science 267, 1498-1502. https://doi.org/10.1126/science.7878469
  26. Joerger, A. C. and Fersht, A. R. 2010. The tumor suppressor p53: from structures to drug discovery. Cold Spring Harb. Perspect. Biol. 2, a000919.
  27. Kamada, R., Toguchi, Y., Nomura, T., Imagawa, T. and Sakaguchi, K. 2016. Tetramer formation of tumor suppressor protein p53: Structure, function, and applications. Biopolymers 106, 598-612. https://doi.org/10.1002/bip.22772
  28. Karlsson, G. B., Jensen, A., Stevenson, L. F., Woods, Y. L., Lane, D. P. and Sorensen, M. S. 2004. Activation of p53 by scaffold-stabilised expression of Mdm2-binding peptides: visualisation of reporter gene induction at the single-cell level. Br. J. Cancer 91, 1488-1494. https://doi.org/10.1038/sj.bjc.6602143
  29. Khoo, K. H., Andreeva, A. and Fersht, A. R. 2009. Adaptive evolution of p53 thermodynamic stability. J. Mol. Biol. 393, 161-175. https://doi.org/10.1016/j.jmb.2009.08.013
  30. Khoo, K. H., Verma, C. S. and Lane, D. P. 2014. Drugging the p53 pathway: understanding the route to clinical efficacy. Nat. Rev. Drug Discov. 13, 217-236. https://doi.org/10.1038/nrd4236
  31. Koblish, H. K, Zhao, S., Franks, C. F., Donatelli, R. R., Tominovich, R. M., LaFrance, L. V., Leonard, K. A., Gushue, J. M., Parks, D. J., Calvo, R. R., Milkiewicz, K. L., Marugan, J. J., Raboisson, P., Cummings, M. D., Grasberger, B. L., Johnson, D. L., Lu, T., Molloy, C. J. and Maroney, A. C. 2006. Benzodiazepinedione inhibitors of the Hdm2:p53 complex suppress human tumor cell proliferation in vitro and sensitize tumors to doxorubicin in vivo. Mol. Cancer Ther. 5, 160-169. https://doi.org/10.1158/1535-7163.MCT-05-0199
  32. Kussie, P. H., Gorina, S., Marechal, V., Elenbaas, B., Moreau, J., Levine, A. J. and Pavletich, N. P. 1996. Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain. Science 274, 948-953. https://doi.org/10.1126/science.274.5289.948
  33. Lambert, J. M., Gorzov, P., Veprintsev, D. B., Soderqvist, M., Segerback, D., Bergman, J., Fersht, A. R., Hainaut, P., Wiman, K. G. and Bykov, V. J. 2009. PRIMA-1 reactivates mutant p53 by covalent binding to the core domain. Cancer Cell 15, 376-388. https://doi.org/10.1016/j.ccr.2009.03.003
  34. Lane, D. P. and Verma, C. 2012. Mdm2 in evolution. Genes Cancer 3, 320-324. https://doi.org/10.1177/1947601912458285
  35. Lee, H., Mok, K. H., Muhandiram, R., Park, K. H., Suk, J. E., Kim, D. H., Chang, J., Sung, Y. C., Choi, K. Y. and Han, K. H. 2000. Local structural elements in the mostly unstructured transcriptional activation domain of human p53. J. Biol. Chem. 275, 29426-29432. https://doi.org/10.1074/jbc.M003107200
  36. Leroy, B., Anderson, M. and Soussi, T. 2014. TP53 mutations in human cancer: database reassessment and prospects for the next decade. Hum. Mutat. 35, 672-688. https://doi.org/10.1002/humu.22552
  37. Liu, X., Wilcken, R., Joerger, A. C., Chuckowree, I. S., Amin, J., Spencer, J. and Fersht, A. R. 2013. Small molecule induced reactivation of mutant p53 in cancer cells. Nucleic Acids Res. 41, 6034-6044. https://doi.org/10.1093/nar/gkt305
  38. Lucas, B. S., Fisher, B., McGee, L. R., Olson, S. H., Medina, J. C. and Cheung, E. 2012. An expeditious synthesis of the MDM2-p53 inhibitor AM-8553. J. Am. Chem. Soc. 134, 12855-12860. https://doi.org/10.1021/ja305123v
  39. Muller, P. A., Vousden, K. H. and Norman, J. C. 2011. p53 and its mutants in tumor cell migration and invasion. J. Cell Biol. 192, 209-218. https://doi.org/10.1083/jcb.201009059
  40. Olivier, M., Hollstein, M. and Hainaut, P. 2010. TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb. Perspect. Biol. 2, a001008.
  41. Oren, M. and Rotter, V. 1999. Introduction: p53 - the first twenty years. Cell. Mol. Life Sci. 55, 9-11. https://doi.org/10.1007/s000180050265
  42. Saha, T., Kar, R. K. and Sa, G. 2015. Structural and sequential context of p53: A review of experimental and theoretical evidence. Prog. Biophys. Mol. Biol. 117, 250-263. https://doi.org/10.1016/j.pbiomolbio.2014.12.002
  43. Shangary, S., Qin, D., McEachern, D., Liu, M., Miller, R. S., Qiu, S., Nikolovska-Coleska, Z., Ding, K., Wang, G., Chen, J., Bernard, D., Zhang, J., Lu, Y., Gu, Q., Shah, R. B., Pienta, K. J., Ling, X., Kang, S., Guo, M., Sun, Y., Yang, D. and Wang, S. 2008. Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition. Proc. Natl. Acad. Sci. USA. 105, 3933-3938. https://doi.org/10.1073/pnas.0708917105
  44. Takimoto, R., Wang, W., Dicker, D. T., Rastinejad, F., Lyssikatos, J. and el-Deiry, W. S. 2002. The mutant p53-conformation modifying drug, CP-31398, can induce apoptosis of human cancer cells and can stabilize wild-type p53 protein. Cancer Biol. Ther. 1, 47-55. https://doi.org/10.4161/cbt.1.1.41
  45. Tan, B. X., Liew, H. P., Chua, J. S., Ghadessy, F. J., Tan, Y. S., Lane, D. P. and Coffill, C. R. 2017. Anatomy of Mdm2 and Mdm4 in evolution. J. Mol. Cell Biol. 9, 3-15.
  46. Tang, X., Zhu, Y., Han, L., Kim, A. L., Kopelovich, L., Bickers, D. R. and Athar, M. 2007. CP-31398 restores mutant p53 tumor suppressor function and inhibits UVB-induced skin carcinogenesis in mice. J. Clin. Invest. 117, 3753-3764. https://doi.org/10.1172/JCI32481
  47. Tuncbag, N., Kar, G., Gursoy, A., Keskin, O. and Nussinov, R. 2009. Towards inferring time dimensionality in protein-protein interaction networks by integrating structures: the p53 example. Mol. Biosyst. 5, 1770-1778. https://doi.org/10.1039/b905661k
  48. Uversky, V. N. 2016. p53 Proteoforms and intrinsic disorder: an illustration of the protein structure-function continuum concept. Int. J. Mol. Sci. 17, 1874. https://doi.org/10.3390/ijms17111874
  49. Valente, L. J., Gray, D. H., Michalak, E. M., Pinon-Hofbauer, J., Egle, A., Scott, C. L., Janic, A. and Strasser, A. 2013. p53 efficiently suppresses tumor development in the complete absence of its cell-cycle inhibitory and proapoptotic effectors p21, Puma, and Noxa. Cell Rep. 3, 1339-1345. https://doi.org/10.1016/j.celrep.2013.04.012
  50. Vassilev, L. T., Vu, B. T., Graves, B., Carvajal, D., Podlaski, F., Filipovic, Z., Kong, N., Kammlott, U., Lukacs, C., Klein, C., Fotouhi, N. and Liu, E. A. 2004. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 303, 844-848. https://doi.org/10.1126/science.1092472
  51. Vogelstein, B., Lane, D. and Levine, A. J. 2000. Surfing the p53 network. Nature 408, 307-310. https://doi.org/10.1038/35042675
  52. Wallentine, B. D., Wang, Y., Tretyachenko-Ladokhina, V., Tan, M., Senear, D. F. and Luecke, H. 2013. Structures of oncogenic, suppressor and rescued p53 core-domain variants: mechanisms of mutant p53 rescue. Acta Crystallogr. D Biol. Crystallogr. 69, 2146-2156. https://doi.org/10.1107/S0907444913020830
  53. Wang, B., Fang, L., Zhao, H., Xiang, T. and Wang, D. 2012. MDM2 inhibitor Nutlin-3a suppresses proliferation and promotes apoptosis in osteosarcoma cells. Acta Biochim. Biophys. Sin. (Shanghai). 44, 685-691. https://doi.org/10.1093/abbs/gms053
  54. Wang, H., Nan, L., Yu, D., Agrawal, S. and Zhang, R. 2001. Antisense anti-MDM2 oligonucleotides as a novel therapeutic approach to human breast cancer: in vitro and in vivo activities and mechanisms. Clin. Cancer Res. 7, 3613-3624.
  55. Wang, S., Zhao, Y., Aguilar, A., Bernard, D. and Yang, C. Y. 2017. Targeting the MDM2-p53 protein-protein interaction for new cancer therapy: progress and challenges. Cold Spring Harb. Perspect. Med. 7, a026245. https://doi.org/10.1101/cshperspect.a026245
  56. Wang, Y., Rosengarth, A. and Luecke, H. 2007. Structure of the human p53 core domain in the absence of DNA. Acta Crystallogr. D Biol. Crystallogr. 63, 276-281. https://doi.org/10.1107/S0907444906048499
  57. Webster, G. A. and Perkins, N. D. 1999. Transcriptional Cross Talk between $NF-{\kappa}B$ and p53. Mol. Cell. Biol. 19, 3485-3495. https://doi.org/10.1128/MCB.19.5.3485
  58. Xu, J., Timares, L., Heilpern, C., Weng, Z., Li, C., Xu, H., Pressey, J. G., Elmets, C. A., Kopelovich, L. and Athar, M. 2010. Targeting wild-type and mutant p53 with small molecule CP-31398 blocks the growth of rhabdomyosarcoma by inducing reactive oxygen species-dependent apoptosis. Cancer Res. 70, 6566-6576. https://doi.org/10.1158/0008-5472.CAN-10-0942
  59. Zacchi, P., Gostissa, M., Uchida, T., Salvagno, C., Avolio, F., Volinia, S., Ronai, Z., Blandino, G., Schneider, C. and Del Sal, G. 2002. The prolyl isomerase Pin1 reveals a mechanism to control p53 functions after genotoxic insults. Nature 419, 853-857. https://doi.org/10.1038/nature01120
  60. Zhao, D., Tahaney, W. M., Mazumdar, A., Savage, M. I. and Brown, P. H. 2017. Molecularly targeted therapies for p53-mutant cancers. Cell. Mol. Life Sci. 74, 4171-4187. https://doi.org/10.1007/s00018-017-2575-0
  61. Zilfou, J. T. Hoffman, W. H., Sank, M., George, D. L. and Murphy, M. 2001. The corepressor mSin3a interacts with the proline-rich domain of p53 and protects p53 from proteasome-mediated degradation. Mol. Cell. Biol. 21, 3974-3985. https://doi.org/10.1128/MCB.21.12.3974-3985.2001