Folia Biologica
Journal of Cellular and Molecular Biology, Charles University 

Crossref logo

Fol. Biol. 2003, 49, 1-8

https://doi.org/10.14712/fb2003049010001

What We Currently Know about the Structure and Function of the p53 Homologue - p73 Protein: Facts, Hypotheses and Expectations

P. Češková1, D. Valík2, Bořivoj Vojtěšek1

1Department of Experimental Oncology, Masaryk Memorial Cancer Institute, Brno, Czech Republic
2Department of Laboratory Medicine, Masaryk Memorial Cancer Institute, Brno, Czech Republic

Received October 2002
Accepted October 2002

References

1. Agami, R., Blandino, G., Oren, M., Shaul, Y. (1999) Interaction of c-Abl and p73alpha and their collaboration to induce apoptosis. Nature 399, 809-813. <https://doi.org/10.1038/21697>
2. Araki, D., Uzawa, K., Watanabe, T., Shiiba, M., Miyakawa, A., Yokoe, H., Tanzawa, H. (2002) Frequent allelic losses on the short arm of chromosome 1 and decreased expression of the p73 gene at 1p36.3 in squamous cell carcinoma of the oral cavity. Int. J. Oncol. 20, 355-360.
3. Balint, E., Bates, S., Vousden, K. H. (1999) Mdm2 binds p73 alpha without targeting degradation. Oncogene 18, 3923-3929. <https://doi.org/10.1038/sj.onc.1202781>
4. Baskaran, R., Wood, L. D., Whitaker, L. L., Canman, C. E., Morgan, S. E., Xu, Y., Barlow, C., Baltimore, D., Wynshaw-Boris, A., Kastan, M. B., Wang, J. Y. (1997) Ataxia telangiectasia mutant protein activates c-Abl tyrosine kinase in response to ionizing radiation. Nature 387, 516-519. <https://doi.org/10.1038/387516a0>
5. Cai, Y. C., Yang, G. Y., Nie, Y., Wang, L. D., Zhao, X., Song, Y. L., Seril, D. N., Liao, J., Xing, E. P., Yang, C. S. (2000) Molecular alterations of p73 in human esophageal squamous cell carcinomas: loss of heterozygosity occurs frequently; loss of imprinting and elevation of p73 expression may be related to defective p53. Carcinogenesis 21, 683-689. <https://doi.org/10.1093/carcin/21.4.683>
6. Chen, C. L., Ip, S. M., Cheng, D., Wong, L. C., Ngan, H. Y. (2000) P73 gene expression in ovarian cancer tissues and cell lines. Clin. Cancer Res. 6, 3910-3915.
7. Chi, S. W., Ayed, A., Arrowsmith, C. H. (1999) Solution structure of a conserved C-terminal domain of p73 with structural homology to the SAM domain. EMBO J. 18, 4438-4445. <https://doi.org/10.1093/emboj/18.16.4438>
8. Corn, P. G., Kuerbitz, S. J., van Noesel, M. M., Esteller, M., Compitello, N., Baylin, S. B., Herman, J. G. (1999) Transcriptional silencing of the p73 gene in acute lymphoblastic leukemia and Burkitt's lymphoma is associated with 5' CpG island methylation. Cancer Res. 59, 3352-3356.
9. Costanzo, A., Merlo, P., Pediconi, N., Fulco, M., Sartorelli, V., Cole, P. A., Fontemaggi, G., Fanciulli, M., Schiltz, L., Blandino, G., Balsano, C., Levrero, M. (2002) DNA damage-dependent acetylation of p73 dictates the selective activation of apoptotic target genes. Mol. Cell 9, 175-186. <https://doi.org/10.1016/S1097-2765(02)00431-8>
10. Davison, T. S., Vagner, C., Kaghad, M., Ayed, A., Caput, D., Arrowsmith, C. H. (1999) p73 and p63 are homotetramers capable of weak heterotypic interactions with each other but not with p53. J. Biol. Chem. 274, 18709-18714. <https://doi.org/10.1074/jbc.274.26.18709>
11. De Laurenzi, V., Costanzo, A., Barcaroli, D., Terrinoni, A., Falco, M., Annicchiarico-Petruzzelli, M., Levrero, M., Melino, G. (1998) Two new p73 splice variants, gamma and delta, with different transcriptional activity. J. Exp. Med. 188, 1763-1768. <https://doi.org/10.1084/jem.188.9.1763>
12. De Laurenzi, V. D., Catani, M. V., Terrinoni, A., Corazzari, M., Melino, G., Costanzo, A., Levrero, M., Knight, R. A. (1999) Additional complexity in p73: induction by mitogens in lymphoid cells and identification of two new splicing variants epsilon and zeta. Cell Death Differ. 6, 389-390. <https://doi.org/10.1038/sj.cdd.4400521>
13. Dobbelstein, M., Roth, J. (1998) The large T antigen of simian virus 40 binds and inactivates p53 but not p73. J. Gen. Virol. 79, 3079-3083. <https://doi.org/10.1099/0022-1317-79-12-3079>
14. Dong, S. M., Pang, J. C., Poon, W. S., Hu, J., To, K. F., Chang, A. R., Ng, H. K. (2001) Concurrent hypermethylation of multiple genes is associated with grade of oligodendroglial tumors. J. Neuropathol. Exp. Neurol. 60, 808-816. <https://doi.org/10.1093/jnen/60.8.808>
15. Flores, E. R., Tsai, K. Y., Crowley, D., Sengupta, S., Yang, A., McKeon, F., Jacks, T. (2002) p63 and p73 are required for p53-dependent apoptosis in response to DNA damage. Nature 416, 560-564. <https://doi.org/10.1038/416560a>
16. Gong, J. G., Costanzo, A., Yang, H. Q., Melino, G., Kaelin, W. G., Jr., Levrero, M., Wang, J. Y. (1999) The tyrosine kinase c-Abl regulates p73 in apoptotic response to cisplatin-induced DNA damage. Nature 399, 806-809. <https://doi.org/10.1038/21690>
17. Grob, T. J., Novak, U., Maisse, C., Barcaroli, D., Luthi, A. U., Pirnia, F., Hugli, B., Graber, H. U., De Laurenzi, V., Fey, M. F., Melino, G., Tobler, A. (2001) Human delta Np73 regulates a dominant negative feedback loop for TAp73 and p53. Cell Death Differ. 8, 1213-1223. <https://doi.org/10.1038/sj.cdd.4400962>
18. Han, S., Semba, S., Abe, T., Makino, N., Furukawa, T., Fukushige, S., Takahashi, H., Sakurada, A., Sato, M., Shiiba, K., Matsuno, S., Nimura, Y., Nakagawara, A., Horii, A. (1999) Infrequent somatic mutations of the p73 gene in various human cancers. Eur. J. Surg. Oncol. 25, 194-198. <https://doi.org/10.1053/ejso.1998.0626>
19. Hollstein, M., Sidransky, D., Vogelstein, B., Harris, C. C. (1991) p53 mutations in human cancers. Science 253, 49-53. <https://doi.org/10.1126/science.1905840>
20. Hollstein, M., Rice, K., Greenblatt, M. S., Soussi, T., Fuchs, R., Sorlie, T., Hovig, E., Smith-Sorensen, B., Montesano, R., Harris, C. C. (1994) Database of p53 gene somatic mutations in human tumors and cell lines. Nucleic Acids Res. 22, 3551-3555.
21. Hu, J. F., Ulaner, G. A., Oruganti, H., Ivaturi, R. D., Balagura, K. A., Pham, J., Vu, T. H., Hoffman, A. R. (2000) Allelic expression of the putative tumor suppressor gene p73 in human fetal tissues and tumor specimens. Biochim. Biophys. Acta 1491, 49-56. <https://doi.org/10.1016/S0167-4781(00)00017-8>
22. Ichimiya, S., Nimura, Y., Kageyama, H., Takada, N., Sunahara, M., Shishikura, T., Nakamura, Y., Sakiyama, S., Seki, N., Ohira, M., Kaneko, Y., McKeon, F., Caput, D., Nakagawara, A. (1999) p73 at chromosome 1p36.3 is lost in advanced stage neuroblastoma but its mutation is infrequent. Oncogene 18, 1061-1066. <https://doi.org/10.1038/sj.onc.1202390>
23. Ikawa, S., Nakagawara, A., Ikawa, Y. (1999) p53 family genes: structural comparison, expression and mutation. Cell Death Differ. 6, 1154-1161. <https://doi.org/10.1038/sj.cdd.4400631>
24. Ishimoto, O., Kawahara, C., Enjo, K., Obinata, M., Nukiwa, T.,Ikawa, S. (2002) Possible oncogenic potential of DeltaNp73: a newly identified isoform of human p73. Cancer Res. 62, 636-641.
25. Jost, C. A., Marin, M. C., Kaelin, W. G., Jr. (1997) p73 is a simian [correction of human] p53-related protein that can induce apoptosis. Nature 389, 191-194. <https://doi.org/10.1038/38298>
26. Kaghad, M., Bonnet, H., Yang, A., Creancier, L., Biscan, J. C., Valent, A., Minty, A., Chalon, P., Lelias, J. M., Dumont, X., Ferrara, P., McKeon, F., Caput, D. (1997) Monoallelically expressed gene related to p53 at 1p36, a region frequently deleted in neuroblastoma and other human cancers. Cell 90, 809-819. <https://doi.org/10.1016/S0092-8674(00)80540-1>
27. Kang, M. J., Park, B. J., Byun, D. S., Park, J. I., Kim, H. J., Park, J. H., Chi, S. G. (2000) Loss of imprinting and elevated expression of wild-type p73 in human gastric adenocarcinoma. Clin. Cancer Res. 6, 1767-1771.
28. Kawano, S., Miller, C. W., Gombart, A. F., Bartram, C. R., Matsuo, Y., Asou, H., Sakashita, A., Said, J., Tatsumi, E., Koeffler, H. P. (1999) Loss of p73 gene expression in leukemias/lymphomas due to hypermethylation. Blood 94, 1113-1120.
29. Kim, K. C., Kim, T. S., Kang, K. H., Choi, K. H. (2001) Amphiphysin IIb-1, a novel splicing variant of amphiphysin II, regulates p73beta function through protein-protein interactions. Oncogene 20, 6689-6699. <https://doi.org/10.1038/sj.onc.1204839>
30. Kojima, T., Ikawa, Y., Katoh, I. (2001) Analysis of molecular interactions of the p53-family p51(p63) gene products in a yeast two-hybrid system: homotypic and heterotypic interactions and association with p53-regulatory factors. Biochem. Biophys. Res. Commun. 281, 1170-1175. <https://doi.org/10.1006/bbrc.2001.4486>
31. Kovalev, S., Marchenko, N., Swendeman, S., LaQuaglia, M., Moll, U. M. (1998) Expression level, allelic origin, and mutation analysis of the p73 gene in neuroblastoma tumors and cell lines. Cell Growth Differ. 9, 897-903.
32. Kubbutat, M. H.,Vousden, K. H. (1998) Keeping an old friend under control: regulation of p53 stability. Mol. Med. Today 4, 250-256. <https://doi.org/10.1016/S1357-4310(98)01260-X>
33. Lane, D. P., Lain, S. (2002) Therapeutic exploitation of the p53 pathway. Trends Mol. Med. 8, S38-42. <https://doi.org/10.1016/S1471-4914(02)02309-2>
34. Lee, C. W., La Thangue, N. B. (1999) Promoter specificity and stability control of the p53-related protein p73. Oncogene 18, 4171-4181. <https://doi.org/10.1038/sj.onc.1202793>
35. Levrero, M., De Laurenzi, V., Costanzo, A., Gong, J., Melino, G., Wang, J. Y. (1999) Structure, function and regulation of p63 and p73. Cell Death Differ. 6, 1146-1153. <https://doi.org/10.1038/sj.cdd.4400624>
36. Levrero, M., De Laurenzi, V., Costanzo, A., Gong, J., Wang, J. Y., Melino, G. (2000) The p53/p63/p73 family of transcription factors: overlapping and distinct functions. J. Cell Sci. 113, 1661-1670. <https://doi.org/10.1242/jcs.113.10.1661>
37. Liu, M., Taketani, T., Li, R., Takita, J., Taki, T., Yang, H. W., Kawaguchi, H., Ida, K., Matsuo, Y., Hayashi, Y. (2001) Loss of p73 gene expression in lymphoid leukemia cell lines is associated with hypermethylation. Leuk. Res. 25, 441-447. <https://doi.org/10.1016/S0145-2126(00)00148-X>
38. Liu, Z. G., Baskaran, R., Lea-Chou, E. T., Wood, L. D., Chen, Y., Karin, M., Wang, J. Y. (1996) Three distinct signalling responses by murine fibroblasts to genotoxic stress. Nature 384, 273-276. <https://doi.org/10.1038/384273a0>
39. Liu, W., Mai, M., Yokomizo, A., Qian, C., Tindall, D. J., Smith, D. I., Thibodeau, S. N. (2000) Differential expression and allelotyping of the p73 gene in neuroblastoma. Int. J. Oncol. 16, 181-185.
40. Lomas, J., Bello, M. J., Arjona, D., Gonzalez-Gomez, P., Alonso, M. E., de Campos, J. M., Vaquero, J., RuizBarnes, P., Sarasa, J. L., Casartelli, C., Rey, J. A. (2001) Analysis of p73 gene in meningiomas with deletion at 1p. Cancer Genet. Cytogenet. 129, 88-91. <https://doi.org/10.1016/S0165-4608(01)00430-7>
41. Mai, M., Qian, C., Yokomizo, A., Tindall, D. J., Bostwick, D., Polychronakos, C., Smith, D. I., Liu, W. (1998) Loss of imprinting and allele switching of p73 in renal cell carcinoma. Oncogene 17, 1739-1741. <https://doi.org/10.1038/sj.onc.1202099>
42. Malkin, D., Li, F. P., Strong, L. C., Fraumeni, J. F., Jr., Nelson, C. E., Kim, D. H., Kassel, J., Gryka, M. A., Bischoff, F. Z., Tainsky, M. A., et al. (1990) Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250, 1233-1238. <https://doi.org/10.1126/science.1978757>
43. Minty, A., Dumont, X., Kaghad, M., Caput, D. (2000) Covalent modification of p73alpha by SUMO-1. Two-hybrid screening with p73 identifies novel SUMO-1-interacting proteins and a SUMO-1 interaction motif. J. Biol. Chem. 275, 36316-36323. <https://doi.org/10.1074/jbc.M004293200>
44. Nakagawa, T., Takahashi, M., Ozaki, T., Watanabe Ki, K., Todo, S., Mizuguchi, H., Hayakawa, T., Nakagawara, A. (2002) Autoinhibitory regulation of p73 by Delta Np73 to modulate cell survival and death through a p73-specific target element within the Delta Np73 promoter. Mol. Cell. Biol. 22, 2575-2585. <https://doi.org/10.1128/MCB.22.8.2575-2585.2002>
45. Nomoto, S., Haruki, N., Kondo, M., Konishi, H., Takahashi, T. (1998) Search for mutations and examination of allelic expression imbalance of the p73 gene at 1p36.33 in human lung cancers. Cancer Res. 58, 1380-1383.
46. Ongkeko, W. M., Wang, X. Q., Siu, W. Y., Lau, A. W., Yamashita, K., Harris, A. L., Cox, L. S., Poon, R. Y. (1999) MDM2 and MDMX bind and stabilize the p53-related protein p73. Curr. Biol. 9, 829-832. <https://doi.org/10.1016/S0960-9822(99)80367-4>
47. Pawson, T., Raina, M., Nash, P. (2002) Interaction domains: from simple binding events to complex cellular behavior. FEBS Lett 513, 2-10. <https://doi.org/10.1016/S0014-5793(01)03292-6>
48. Ponting, C. P. (1995) SAM: a novel motif in yeast sterile and Drosophila polyhomeotic proteins. Protein Sci. 4, 1928-1930. <https://doi.org/10.1002/pro.5560040927>
49. Schultz, J., Ponting, C. P., Hofmann, K., Bork, P. (1997) SAM as a protein interaction domain involved in developmental regulation. Protein Sci. 6, 249-253. <https://doi.org/10.1002/pro.5560060128>
50. Schwab, M., Praml, C., Amler, L. C. (1996) Genomic instability in 1p and human malignancies. Genes Chromosomes Cancer 16, 211-229. <https://doi.org/10.1002/(SICI)1098-2264(199608)16:4<211::AID-GCC1>3.0.CO;2-0>
51. Shaul, Y. (2000) c-Abl: activation and nuclear targets. Cell Death Differ. 7, 10-16. <https://doi.org/10.1038/sj.cdd.4400626>
52. Shvarts, A., Steegenga, W. T., Riteco, N., van Laar, T., Dekker, P., Bazuine, M., van Ham, R. C., van der Houven van Oordt, W., Hateboer, G., van der Eb, A. J., Jochemsen, A. G. (1996) MDMX: a novel p53-binding protein with some functional properties of MDM2. EMBO J. 15, 5349-5357. <https://doi.org/10.1002/j.1460-2075.1996.tb00919.x>
53. Stiewe, T., Putzer, B. M. (2002) Role of p73 in malignancy: tumor suppressor or oncogene? Cell Death Differ. 9, 237-245. <https://doi.org/10.1038/sj.cdd.4400995>
54. Strano, S., Munarriz, E., Rossi, M., Cristofanelli, B., Shaul, Y., Castagnoli, L., Levine, A. J., Sacchi, A., Cesareni, G., Oren, M., Blandino, G. (2000) Physical and functional interaction between p53 mutants and different isoforms of p73. J. Biol. Chem. 275, 29503-29512. <https://doi.org/10.1074/jbc.M003360200>
55. Strano, S., Munarriz, E., Rossi, M., Castagnoli, L., Shaul, Y., Sacchi, A., Oren, M., Sudol, M., Cesareni, G., Blandino, G. (2001) Physical interaction with Yes-associated protein enhances p73 transcriptional activity. J. Biol. Chem. 276, 15164-15173. <https://doi.org/10.1074/jbc.M010484200>
56. Takada, N., Ozaki, T., Ichimiya, S., Todo, S., Nakagawara, A. (1999) Identification of a transactivation activity in the COOH-terminal region of p73 which is impaired in the naturally occurring mutants found in human neuroblastomas. Cancer Res. 59, 2810-2814.
57. Ueda, Y., Hijikata, M., Takagi, S., Chiba, T., Shimotohno, K. (2001) Transcriptional activities of p73 splicing variants are regulated by inter-variant association. Biochem. J. 356, 859-866. <https://doi.org/10.1042/bj3560859>
58. Yang, A., Kaghad, M., Wang, Y., Gillett, E., Fleming, M. D., Dotsch, V., Andrews, N. C., Caput, D., McKeon, F. (1998) p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities. Mol. Cell 2, 305-316. <https://doi.org/10.1016/S1097-2765(00)80275-0>
59. Yang, A., McKeon, F. (2000) P63 and P73: P53 mimics, menaces and more. Nat. Rev. Mol. Cell Biol. 1, 199-207. <https://doi.org/10.1038/35043127>
60. Yang, A., Walker, N., Bronson, R., Kaghad, M., Oosterwegel, M., Bonnin, J., Vagner, C., Bonnet, H., Dikkes, P., Sharpe, A., McKeon, F.,Caput, D. (2000) p73-deficient mice have neurological, pheromonal and inflammatory defects but lack spontaneous tumours. Nature 404, 99-103. <https://doi.org/10.1038/35003607>
61. Yokomizo, A., Mai, M., Bostwick, D. G., Tindall, D. J., Qian, J., Cheng, L., Jenkins, R. B., Smith, D. I., Liu, W. (1999a) Mutation and expression analysis of the p73 gene in prostate cancer. Prostate 39, 94-100. <https://doi.org/10.1002/(SICI)1097-0045(19990501)39:2<94::AID-PROS3>3.0.CO;2-W>
62. Yokomizo, A., Mai, M., Tindall, D. J., Cheng, L., Bostwick, D. G., Naito, S., Smith, D. I., Liu, W. (1999b) Overexpression of the wild type p73 gene in human bladder cancer. Oncogene 18, 1629-1633. <https://doi.org/10.1038/sj.onc.1202474>
63. Yokozaki, H., Shitara, Y., Fujimoto, J., Hiyama, T., Yasui, W.,Tahara, E. (1999) Alterations of p73 preferentially occur in gastric adenocarcinomas with foveolar epithelial phenotype. Int. J. Cancer 83, 192-196. <https://doi.org/10.1002/(SICI)1097-0215(19991008)83:2<192::AID-IJC8>3.0.CO;2-E>
64. Zaika, A. I., Kovalev, S., Marchenko, N. D., Moll, U. M. (1999) Overexpression of the wild type p73 gene in breast cancer tissues and cell lines. Cancer Res. 59, 3257-3263.
65. Zeng, X., Chen, L., Jost, C. A., Maya, R., Keller, D., Wang, X., Kaelin, W. G., Jr., Oren, M., Chen, J., Lu, H. (1999) MDM2 suppresses p73 function without promoting p73 degradation. Mol. Cell Biol. 19, 3257-3266. <https://doi.org/10.1128/MCB.19.5.3257>
66. Zhao, R., Gish, K., Murphy, M., Yin, Y., Notterman, D., Hoffman, W. H., Tom, E., Mack, D. H., Levine, A. J. (2000) Analysis of p53-regulated gene expression patterns using oligonucleotide arrays. Genes Dev. 14, 981-993. <https://doi.org/10.1101/gad.14.8.981>
front cover

ISSN 0015-5500 (Print) ISSN 2533-7602 (Online)

Open access journal

Submissions

Archive