Abstract
Single mutations in the DNA binding domain of p53 cause a radical shift in function from tumor suppressor to oncogene. The mutated proteins lose the negative feedback regulation mediated by MDM2. Their oncogenic activity consists of a dominant negative inhibition of the remaining wild-type p53 protein, and a gain of function (GOF) activity independent of wild-type p53 inhibition. An understanding of the properties of these very common oncogenes is yielding promising therapeutic approaches, and is predicted to offer more clinical applications as the field develops.
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Aas, T., Borresen, A.-L., Geisler, S., Smith-Sorensen, B., Johnsen, H., Varhaug, J. E., Akslen, L. A., and Lonning, P. E. (1996). Specific p53 mutations are associated with de novo resistance to doxorubicin in breast cancer patients. Nat Med 2:811–814.
Abarzua, P., LoSardo, J. E., Gubler, M. L., and Neri, A. (1995). Microinjection of monoclonal antibody PAb421 into human SW480 colorectal carcinoma cells restores the transcription activation function to mutant p53. Cancer Res 55:3490–3494.
Abarzua, P., LoSardo, J. E., Gubler, M. L., Spathis, R., Lu, Y. A., Felix, A., and Neri, A. (1996). Restoration of the transcription activation function to mutant p53 in human cancer cells. Oncogene 13:2477–2482.
Agami, R., Blandino, G., Oren, M., and Shaul, Y. (1999). Interaction of c-Abl and p73alpha and their collaboration to induce apoptosis. Nature 399:809–813.
Almog, N., Goldfinger, N., and Rotter, V. (2000). p53-dependent apoptosis is regulated by a C-terminally alternatively spliced form of murine p53. Oncogene 19:3395–3403.
Aloni-Grinstein, R., Schwartz, D., and Rotter, V. (1995). Accumulation of wild-type p53 protein upon gamma-irradiation induces a G2 arrest-dependent immunoglobulin kappa light chain gene expression. EMBO J 14:1392–1401.
Aloni-Grinstein, R., Zan-Bar, I., Alboum, I., Goldfinger, N., and Rotter, V. (1993). Wild type p53 functions as a control protein in the differentiation pathway of the B-cell lineage. Oncogene 8:3297–3305.
Atema, A., and Chene, P. (2002). The gain of function of the p53 mutant Asp281Gly is dependent on its ability to form tetramers. Cancer Lett 185:103–109.
Bartek, J., Iggo, R., Gannon, J., and Lane, D. P. (1990). Genetic and immunochemical analysis of mutant p53 in human breast cancer cell lines. Oncogene 5:893–899.
Bergh, J., Norberg, T., Sjogren, S., Lindgren, A., and Holmberg, L. (1995). Complete sequencing of the p53 gene provides prognostic information in breast cancer patients, particularly in relation to adjuvant systemic therapy and radiotherapy. Nat Med 1:1029–1034.
Birch, J. M., Blair, V., Kelsey, A. M., Evans, D. G., Harris, M., Tricker, K. J., and Varley, J. M. (1998). Cancer phenotype correlates with constitutional TP53 genotype in families with the Li-Fraumeni syndrome. Oncogene 17:1061–1068.
Blagosklonny, M.V. (2000). p53 from complexity to simplicity: mutant p53 stabilization, gain-of-function, and dominant-negative effect. FASEB J 14:1901–1907.
Blagosklonny, M. V. (2002). P53: an ubiquitous target of anticancer drugs. Int J Cancer 98:161–166.
Blandino, G., Levine, A. J., and Oren, M. (1999). Mutant p53 gain of function: differential effects of different p53 mutants on resistance of cultured cells to chemotherapy [In Process Citation]. Oncogene 18:477–485.
Brachmann, R. K., Yu, K., Eby, Y., Pavletich, N. P., and Boeke, J. D. (1998). Genetic selection of intragenic suppressor mutations that reverse the effect of common p53 cancer mutations. EMBOJ 17:1847–1859.
Bressac, B., Galvin, K. M., Liang, T. J., Isselbacher, K. J., Wands, J. R., and Ozturk, M. (1990). Abnormal structure and expression of p53 gene in human hepatocellular carcinoma. Proc Natl Acad Sci USA 87:1973–1977.
Bullock, A. N., and Fersht, A. R. (2001). Rescuing the function of mutant p53. Nat Rev Cancer 1:68–76.
Bullock, A. N., Henckel, J., and Fersht, A. R. (2000). Quantitative analysis of residual folding and DNA binding in mutant p53 core domain: definition of mutant states for rescue in cancer therapy. Oncogene 19:1245–1256.
Bunz, F., Dutriaux, A., Lengauer, C., Waldman, T., Zhou, S., Brown, J. P., Sedivy, J. M., Kinzler, K. W., and Vogelstein, B. (1998). Requirement for p53 and p21 to sustain G2 arrest after DNA damage. Science 282:1497–1501.
Bykov, V. J., Issaeva, N., Shilov, A., Hultcrantz, M., Pugacheva, E., Chumakov, P., Bergman, J., Wiman, K. G., and Selivanova, G. (2002). Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound. Nat Med 8:282–288.
Cadwell, C., and Zambetti, G. P. (2001). The effects of wild-type p53 tumor suppressor activity and mutant p53 gain-of-function on cell growth. Gene 277:15–30.
Cao, Y., Gao, Q., Wazer, D. E., and Band, V. (1997). Abrogation of wild-type p53-mediated transactivation is insufficient for mutant p53-induced immortalization of normal human mammary epithelial cells. Cancer Res 57:5584–5589.
Carroll, A. G., Voeller, H. J., Sugars, L., and Gelmann, E. P. (1993). p53 oncogene mutations in three human prostate cancer cell lines. Prostate 23:123–134.
Chene, P. (1998). In vitro analysis of the dominant negative effect of p53 mutants. J Mol Biol 281:205–209.
Chene, P., and Bechter, E. (1999). p53 mutants without a functional tetramerisation domain are not oncogenic. J Mol Biol 286:1269–1274.
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 265:346–355.
Crook, T., and Vousden, K. H. (1992). Properties of p53 mutations detected in primary and secondary cervical cancers suggest mechanisms of metastasis and involvement of environmental carcinogens. EMBO J 11:3935–3940.
Davison, T. S., Vagner, C., Kaghad, M., Ayed, A., Caput, D., and 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.
Deb, S., Jackson, C. T., Subler, M. A., and Martin, D.W. (1992). Modulation of cellular and viral promoters by mutant human p53 proteins found in tumor cells. J Virol 66:6164–6170.
Denissenko, M. F., Chen, J. X., Tang, M. S., and Pfeifer, G. P. (1997). Cytosine methylation determines hot spots of DNA damage in the human P53 gene. Proc Natl Acad Sci USA 94:3893–3898.
Denissenko, M. F., Koudriakova, T. B., Smith, L., O’Connor, T. R., Riggs, A. D., and Pfeifer, G. P. (1998). The p53 codon 249 mutational hotspot in hepatocellular carcinoma is not related to selective formation or persistence of aflatoxin B-1 adducts. Oncogene 17:3007–3014.
Denissenko, M. F., Pao, A., Tang, M., and Pfeifer, G. P. (1996). Preferential formation of benzo[a]pyrene adducts at lung cancer mutational hotspots in P53. Science 274:430–432.
Di Como, C. J., Gaiddon, C., and Prives, C. (1999). p73 function is inhibited by tumor-derived p53 mutants in mammalian cells. Mol Cell Biol 19:1438–1449.
DiGiammarino, E. L., Lee, A. S., Cadwell, C., Zhang, W., Bothner, B., Ribeiro, R. C., Zambetti, G., and Kriwacki, R.W. (2002). Anovel mechanism of tumorigenesis involving pH-dependent destabilization of a mutant p53 tetramer. Nat Struct Biol 9:12–16.
Dittmer, D., Pati, S., Zambetti, G., Chu, S., Teresky, A., Moore, M., Finlay, C., and Levine, A. (1993). Gain of function mutations in p53. Nat Genet 4:42–46.
Djelloul, S., Forgue-Lafitte, M. E., Hermelin, B., Mareel, M., Bruyneel, E., Baldi, A., Giordano, A., Chastre, E., and Gespach, C. (1997). Enterocyte differentiation is compatible with SV40 large T expression and loss of p53 function in human colonic Caco-2 cells. Status of the pRb1 and pRb2 tumor suppressor gene products. FEBS Lett 406:234–242.
El-Hizawi, S., Lagowski, J. P., Kulesz-Martin, M., and Albor, A. (2002). Induction of gene amplification as a gain-of-function phenotype of mutant p53 proteins. Cancer Res 62:3264–3270.
Eliyahu, D., Goldfinger, N., Pinhasi-Kimhi, O., Shaulsky, G., Skurnik, Y., Arai, N., Rotter, V., and Oren, M. (1988). Meth A fibrosarcoma cells express two transforming mutant p53 species. Oncogene 3:313–321.
Erber, R., Conradt, C., Homann, N., Enders, C., Finckh, M., Dietz, A., Weidauer, H., and Bosch, F. X. (1998). TP53 DNA contact mutations are selectively associated with allelic loss and have a strong clinical impact in head and neck cancer. Oncogene 16:1671–1679.
Finlay, C. A., Hinds, P. W., and Levine, A. J. (1989). The p53 proto-oncogene can act as a suppressor of transformation. Cell 57:1083–1093.
Foster, B. A., Coffey, H. A., Morin, M. J., and Rastinejad, F. (1999). Pharmacological rescue of mutant p53 conformation and function. Science 286:2507–2510.
Frazier, M.W., He, X., Wang, J., Gu, Z., Cleveland, J. L., and Zambetti, G. P. (1998). Activation of C-myc gene expression by tumor-derived p53 mutants requires a descrete C-terminal domain. Mol Cell Biol 18:3735–3743.
Gaiddon, C., Lokshin, M., Ahn, J., Zhang, T., and Prives, C. (2001). A subset of tumor-derived mutant forms of p53 down-regulate p63 and p73 through a direct interaction with the p53 core domain. Mol Cell Biol 21:1874–1887.
Gong, J. G., Costanzo, A., Yang, H. Q., Melino, G., Kaelin, W. G., Jr., Levrero, M., and Wang, J. Y. (1999). The tyrosine kinase c-Abl regulates p73 in apoptotic response to cisplatin-induced DNA damage. Nature 399:806–809.
Gottlieb, E., Haffner, R., von, R. T., Wagner, E. F., and Oren, M. (1994). Down-regulation of wild-type p53 activity interferes with apoptosis of IL-3-dependent hematopoietic cells following IL-3 withdrawal. EMBO J 13:1368–1374.
Grant, S. W., Kyshtoobayeva, A. S., Kurosaki, T., Jakowatz, J., and Fruehauf, J. P. (1998). Mutant p53 correlates with reduced expression of thrombospondin-1, increased angiogenesis, and metastatic progression in melanoma. Cancer Detect Prev 22:185–194.
Gualberto, A., Aldape, K., Kozakiewicz, K., and Tlsty, T.D. (1998). An oncogenic form of p53 confers a dominant gain of function phenotype that disrupts spindle checkpoint control. Natl Acad Sci USA 95, 5166–5171.
Harris, N., Brill, E., Shohat, O., Prokocimer, M., Wolf, D., Arai, N., and Rotter, V. (1986). Molecular basis for heterogeneity of the human p53 protein. Mol Cell Biol 6:4650–4656.
Harvey, M., Vogel, H., Morris, D., Bradley, A., Bernstein, A., and Donehower, L. A. (1995). A mutant p53 transgene accelerates tumour development in heterozygous but not nullizygous p53-deficient mice. Nat Genet 9:305–311.
Haupt, Y., Maya, R., Kazaz, A., and Oren, M. (1997). Mdm2 promotes the rapid degradation of p53. Nature 387:296–299.
Hernandez-Boussard, T., Rodriguez-Tome, P., Montesano, R., and Hainaut, P. (1999). IARC p53 mutation database: a relational database to compile and analyze p53 mutations in human tumors and cell lines. International Agency for Research on Cancer. Hum Mutat 14:1–8.
Hinds, P., W., F., C., A., Frey, A., B., and L., A., J. (1987). Immunological evidence for the association of p53 with a heat shock protein, hsc70, in p53-plus-ras-transformed cell lines. Mol Cell Biol 7:2863–2869.
Hinds, P. W., Finlay, C. A., Frey, A. B., and Levine, A. J. (1989). Mutation is required to activate the p53 gene for cooperation with the ras oncogene and transformation. J Virol 63:739–746.
Hinds, P. W., Finlay, C. A., Quartin, R. S., Baker, S. J., Fearon, E. R., Vogelstein, B., and Levine, A. J. (1990). Mutant p53 DNA clones from human colon carcinomas cooperate with ras in transforming primary rat cells: a comparison of the “hot spot” mutant phenotypes. Cell Growth Differ 1:571–580.
Hsiao, M., Low, J., Dorn, E., Ku, D., Pattengale, P., Yeargin, J., and Haas, M. (1994). Gain-of-function mutations of the p53 gene induce lymphhematopoietic metastatic potential and tissue invasiveness. Am J Pathol 145:702–714.
Hsu, I. C., Metcalf, R. A., Sun, T., Welsh, J. A., Wang, N. J., and Harris, C. C. (1991). Mutational hotspot in the p53 gene in human hepatocellular carcinomas. Nature 350:427–431.
Hupp, T. R., Meek, D. W., Midgley, C. A., and Lane, D. P. (1993). Activation of the cryptic DNA binding function of mutant forms of p53. Nucleic Acids Res 21:3167–3174.
Hussain, S. P., and Harris, C. C. (1998a). Molecular Epidemiology of Human Cancer: Contribution of Mutation Spectra Studies of Tumor Suppressor Genes. Cancer Res 58:4023–4037.
Hussain, S. P., and Harris, C. C. (1998b). Molecular epidemiology of human cancer: contribution of mutation spectra studies of tumor suppressor genes. Cancer Res 58:4023–4037.
Isaacs, W. B., Carter, B. S., and Ewing, C. M. (1991). Wild-type p53 suppresses growth of human prostate cancer cells containing mutant p53 alleles. Cancer Res 51:4716–4720.
Iwamoto, K. S., Mizuno, T., Ito, T., Tsuyama, N., Kyoizumi, S., and Seyama, T. (1996). Gain-of-function p53 mutations enhance alteration of the T-cell receptor following X-irradiation, independently of the cell cycle and cell survival. Canc Res 56:3862–3865.
Joers, A., Kristjuhan, A., Kadaja, L., and Maimets, T. (1998). Tumour associated mutants of p53 can inhibit transcriptional activity of p53 without heterooligomerization. Oncogene 17:2351–2358.
Jost, C. A., Marin, M. C., and Kaelin, W. G., Jr. (1997). p73 is a human p53-related protein that can induce apoptosis. Nature 389:191–194.
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 256:827–830.
Kieser, A., Weich, H. A., Brandner, G., Marme, D., and Kolch, W. (1994). Mutant p53 potentiates protein kinase C induction of vascular endothelial growth factor expression. Oncogene 9:963–969.
Kim, A. L., Raffo, A. J., Brandt-Rauf, P. W., Pincus, M. R., Monaco, R., Abarzua, P., and Fine, R. L. (1999). Conformational and molecular basis for induction of apoptosis by a p53 C-terminal peptide in human cancer cells. J Biol Chem 274:34924–34931.
Koga, H., and Deppert, W. (2000). Identification of genomic DNA sequences bound by mutant p53 protein (Gly245->Ser) in vivo. Oncogene 19:4178–4183.
Lane, D., and Crawford, L. (1979). T antigen is bound to a host protein in SV40-transformed cells. Nature 278:261–263.
Lanyi, A., Deb, D., Seymour, R. C., Ludes-Meyers, J. H., Subler, M. A., and Deb, S. (1998). ‘Gain of function’ phenotype of tumor-derived mutant p53 requires the oligomerization/nonsequence-specific nucleic acid-binding domain. Oncogene 16:3169–3176.
Lassus, P., Bertrand, C., Zugasti, O., Chambon, J. P., Soussi, T., Mathieu-Mahul, D., and Hibner, U. (1999). Anti-apoptotic activity of p53 maps to the COOH-terminal domain and is retained in a highly oncogenic natural mutant. Oncogene 18:4699–4709.
Lassus, P., Ferlin, M., Piette, J., and Hibner, U. (1996). Anti-apoptotic activity of low levels of wild-type p53. EMBO J 15:4566–4573.
Lavigueur, A., Maltby, V., Mock, D., Rossant, J., Pawson, T., and Bernstein, A. (1989). High incidence of lung, bone, and lymphoid tumors in transgenic mice overexpressing mutant alleles of the p53 oncogene. Mol Cell Biol 9:3982–3991.
Lee, Y. I., Lee, S., Das, G. C., Park, U. S., Park, S. M., and Lee, Y. I. (2000). Activation of the insulin-like growth factor II transcription by aflatoxin B1 induced p53 mutant 249 is caused by activation of transcription complexes; implications for a gain-of-function during the formation of hepatocellular carcinoma. Oncogene 19:3717–3726.
Li, R., Sutphin, P. D., Schwartz, D., Matas, D., Almog, N., Wolkowicz, R., Goldfinger, N., Pei, H., Prokocimer, M., and Rotter, V. (1998). Mutant p53 protein expression interferes with p53-independent apoptotic pathways. Oncogene 16:3269–3277.
Lin, J., Chen, J., Elenbaas, B., and Levine, A. J. (1994). Several hydrophobic amino acids in the p53 aminoterminal domain are required for transcriptional activation, binding to mdm-2 and the adenovirus 5 E1B 55-kD protein. Genes Dev 8:1235–1246.
Lin, J., Teresky, A. K., and Levine, A. J. (1995). Two critical hydrophobic amino acids in the N-terminal domain of the p53 protein are required for the gain of function phenotypes of human p53 mutants. Oncogene 10:2387–2390.
Linzer, D. I. H., and Levine, A. J. (1979). Characterization of a 54K dalton cellular SV40 tumor antigen present in SV40-transformed cells and uninfected embryonal carcinoma cells. Cell 17:43–52.
Liu, P. K., Kraus, E., Wu, T. A., Strong, L. C., and Tainsky, M. A. (1996). Analysis of genomic instablity in Li-Fraumeni fibroblasts with germline p53 mutations. Oncogene 12:2267–2278.
Lomax, M. E., Barnes, D. M., Gilchrist, R., Picksley, S. M., Varley, J. M., and Camplejohn, R. S. (1997). Two functional assays employed to detect an unusual mutation in the oligomerisation domain of p53 in a Li-Fraumeni like family. Oncogene 14:1869–1874.
Lotem, J., and Sachs, L. (1993). Regulation by bcl-2, c-myc, and p53 of susceptibility to induction of apoptosis by heat shock and cancer chemotherapy compounds in differentiation-competent and-defective myeloid leukemic cells. Cell Growth Differ 4:41–47.
Ludes-Meyers, J. H., Subler, M. A., Shivakumar, V., Munoz, R. M., Jiang, P., Bigger, J. E., Brown, D. R., Deb, S. P., and Deb, S. (1996). Transcriptional activation of the human epidermal growth factor receptor promotor by human p53. Mol Cell Biol 16:6009–6019.
Margulies, L., and Sehgal, P. B. (1993). Modulation of the human interleukin-6 promoter (IL-6) and transcription factor C/EBPb (NF-IL6) activity by p53 species. J Biol Chem 268:15096–15100.
Marin, M. C., Jost, C. A., Brooks, L. A., Irwin, M. S., O’Nions, J., Tidy, J. A., James, N., McGregor, J. M., Harwood, C. A., Yulug, I. G., et al. (2000). A common polymorphism acts as an intragenic modifier of mutant p53 behaviour. Nat Genet 25:47–54.
Matas, D., Sigal, A., Stambolsky, P., Milyavsky, M., Weisz, L., Schwartz, D., Goldfinger, N., and Rotter, V. (2001). Integrity of the N-terminal transcription domain of p53 is required for mutant p53 interference with drug-induced apoptosis. EMBO J 20:4163–4172.
Mazzaro, G., Bossi, G., Coen, S., Sacchi, A., and Soddu, S. (1999). The role of wild-type p53 in the differentiation of primary hemopoietic and muscle cells. Oncogene 18:5831–5835.
McGregor, J. M., Harwood, C. A., Brooks, L., Fisher, S. A., Kelly, D. A., O’Nions, J., Young, A. R., Surentheran, T., Breuer, J., Millard, T. P.,et al. (2002). Relationship Between p53 Codon 72 Polymorphism and Susceptibility to Sunburn and Skin Cancer. J Invest Dermatol 119:84–90.
Mekeel, K. L., Tang, W., Kachnic, L. A., Luo, C.-M., DeFrank, J. S., and Powell, S. N. (1997). Inactivation of p53 results in high rates of homologous recombination. Oncogene 14:1847–1857.
Midgley, C. A., and Lane, D. P. (1997). p53 protein stability in tumour cells is not determined by mutation but is dependent on Mdm2 binding. Oncogene 15:1179–1189.
Milner, J., and Medcalf, E. A. (1991). Cotranslation of activated mutant p53 with wild type drives the wild-type p53 protein into the mutant conformation. Cell 65:765–774.
Mitsudomi, T., Steinberg, S. M., Nau, M. M., Carbone, D., D’Amico, D., Bodner, S., Oie, H. K., Linnoila, R. I., Mulshine, J. L., Minna, J. D., and et al. (1992). p53 gene mutations in non-small-cell lung cancer cell lines and their correlation with the presence of ras mutations and clinical features. Oncogene 7:171–180.
Mukhopadhyay, D., Tsiokas, L., and Sukhateme, V. P. (1995). Wild-type p53 and v-Src exert opposing influences on human vascular endothelial growth factor gene expression. Cancer Res 55:6161–6165.
Murphy, K. L., Dennis, A. P., and Rosen, J. M. (2000). A gain of function p53 mutant promotes both genomic instability and cell survival in a novel p53-null mammary epithelial cell model. FASEB J 14:2291–2302.
Nagata, Y., Anan, T., Yoshida, T., Mizukami, T., Taya, Y., Fujiwara, T., Kato, H., Saya, H., and Nakao, M. (1999). The stabilization mechanism of mutant-type p53 by impaired ubiquitination: the loss of wild-type p53 function and the hsp90 association. Oncogene 18:6037–6049.
Niewolik, D., Vojtesek, B., and Kovarik, J. (1995). p53 derived from human tumour cell lines and containing distinct point mutations can be activated to bind to its consensus target sequence. Oncogene 10:881–890.
Nikolova, P. V., Wong, K. B., DeDecker, B., Henckel, J., and Fersht, A. R. (2000). Mechanism of rescue of common p53 cancer mutations by second-site suppressor mutations. EMBO J 19:370–378.
Osada, M., Ohba, M., Kawahara, C., Ishioka, C., Kanamaru, R., Katoh, I., Ikawa, Y., Nimura, Y., Nakagawara, A., and Obinata, M., Ikawa, S., (1998). Cloning and functional analysis of human p51, which stracturally and functionally resmbles p53. Nat Med 4:839–843.
Peled, A., Zipori, D., and Rotter, V. (1996a). Cooperation between p53-dependent and p53-independent apoptotic pathway of myloid cells. Cancer Res 56:2148–2156.
Peled, A., Zipori, D., and Rotter, V. (1996b). Cooperation between p53-dependent and p53-independent apoptotic pathways in myeloid cells. Cancer Res 56:2148–2156.
Peng, Y., Chen, L., Li, C., Lu, W., Agrawal, S., and Chen, J. (2001a). Stabilization of the MDM2 oncoprotein by mutant p53. J Biol Chem 276:6874–6878.
Peng, Y., Chen, L., Li, C., Lu, W., and Chen, J. (2001b). Inhibition of MDM2 by hsp90 contributes to mutant p53 stabilization. J Biol Chem 276:40583–40590.
Pfeifer, G. P., and Holmquist, G. P. (1997). Mutagenesis in the p53 gene. Biochim Biophys Acta 1333:M1–M8.
Pugacheva, E. N., Ivanov, A. V., Kravchenko, J. E., Kopnin, B. P., Levine, A. J., and Chumakov, P. M. (2002). Novel gain of function activity of p53 mutants: activation of the dUTPase gene expression leading to resistance to 5-fluorouracil. Oncogene 21:4595–4600.
Ribeiro, R. C., Sandrini, F., Figueiredo, B., Zambetti, G. P., Michalkiewicz, E., Lafferty, A. R., DeLacerda, L., Rabin, M., Cadwell, C., Sampaio, G.,et al. (2001). An inherited p53 mutation that contributes in a tissue-specific manner to pediatric adrenal cortical carcinoma. Proc Natl Acad Sci USA 98:9330–9335.
Righetti, S. C., Torre, G. D., Pilotti, S., Menard, S., Ottone, F., Colnaghi, M. I., Pierotti, M. A., Lavarino, C., Cornarotti, M., Oriana, S.,et al. (1996). Comparative study of p53 gene mutations, protein accumulation and response to cisplatin-based chemotherapy in advanced ovarian carcinoma. Canc Res 56:689–693.
Rippin, T. M., Bykov, V. J., Freund, S. M., Selivanova, G., Wiman, K. G., and Fersht, A. R. (2002). Characterization of the p53-rescue drug CP-31398 in vitro and in living cells. Oncogene 21:2119–2129.
Rodin, S. N., and Rodin, A. S. (2000). Human lung cancer and p53: the interplay between mutagenesis and selection. Proc Natl Acad Sci USA 97:12244–12249.
Roemer, K. (1999). Mutant p53: gain-of-function oncoproteins and wild-type p53 inactivators. Biol Chem 380:879–887.
Rolley, N., Butcher, S., and Milner, J. (1995). Specific DNA binding by different classes of human p53 mutants. Oncogene 11:763–770.
Rotter, V. (1983). p53, a transformation-related cellular-encoded protein, can be used as a biochemical marker for the detection of primary mouse tumor cells. Proc Natl Acad Sci USA 80:2613–2617.
Rotter, V., Abutbul, H., and Wolf, D. (1983). The presence of p53 transformation-related protein in Ab-MuLV transformed cells is required for their development into lethal tumors in mice. Int J Cancer 31:315–320.
Rusch, V., Klimstra, D., Venkatraman, E., Oliver, J., Martini, N., Gralla, R., Kris, M., and Dmitrovsky, E. (1995). Aberrant p53 expression predicts clinical resistance to cisplatin-based chemotherapy in locally advanced non-small-cell lung-cancer. Cancer Res 55:5038–5042.
Sampath, J., Sun, D., Kidd, V. J., Grenet, J., Gandhi, A., Shapiro, L. H., Wang, Q., Zambetti, G. P., and Schuetz, J. D. (2001). Mutant p53 cooperates with ETS and selectively up-regulates human MDR1 not MRP1. J Biol Chem 276:39359–39367.
Selivanova, G., Iotsova, V., Okan, I., Fritsche, M., Strome, M., Groner, B., Graftstrom, R. C., and Wiman, K. G. (1997). Restoration of the growth suppression function of mutant p53 by a synthetic peptide derived from the p53 C-terminal domain. Nat Med 3:632–638.
Selivanova, G., Kawasaki, T., Ryabchenko, L., and Wiman, K. G. (1998). Reactivation of mutant p53: a new strategy for cancer therapy. Semin Cancer Biol 8:369–378.
Selivanova, G., Ryabchenko, L., Jansson, E., Iotsova, V., and Wiman, K. G. (1999). Reactivation of mutant p53 through interaction of a C-terminal peptide with the core domain. Mol Cell Biol 19:3395–3402.
Shaulian, E., Zauberman, A., Ginsberg, D., and Oren, M. (1992a). Identification of a minimal transforming domain of p53: negative dominance through abrogation of sequence-specific DNA binding. Mol Cell Biol 12:5581–5592.
Shaulian, E., Zauberman, A., Ginsberg, D., and Oren, M. (1992b). Identification of minimal transforming domain of p53: negative dominance through abrogation of sequence-specific DNA binding. Mol Cell Biol 12:5581–5592.
Shaulian, E., Zauberman, A., Milner, J., Davies, E. A., and Oren, M. (1993). Tight DNA binding and oligomerization are dispensable for the ability of p53 to transactivate target genes and suppress transformation. EMBO J 12:2789–2797.
Shaulsky, G., Goldfinger, N., and Rotter, V. (1991). Alterations in tumor development in vivo mediated by expression of wild type or mutant p53 proteins. Cancer Res 51:5232–5237.
Sigal, A., Matas, D., Almog, N., Goldfinger, N., and Rotter, V. (2001). The C-terminus of mutant p53 is necessary for its ability to interfere with growth arrest or apoptosis. Oncogene 20:4891–4898.
Sigal, A., and Rotter, V. (2000). Oncogenic mutations of the p53 tumor suppressor: the demons of the guardian of the genome. Cancer Res 60:6788–6793.
Slingerland, J. M., Jenkins, J. R., and Benchimol, S. (1993). The transforming and suppressor functions of p53 alleles: effects of mutations that disrupt phosphorylation, oligomerization and nuclear translocation. EMBO J 12, 1029–1037.
Soddu, S., Blandino, G., Scardigli, R., Coen, S., Marchetti, A., Rizzo, M. G., Bossi, G., Cimino, L., Crescenzi, M., and Sacchi, A. (1996). Interference with p53 protein inhibits hematopoietic and muscle differentiation. J Cell Biol 134:1–12.
Srivastava, S., Wang, S., Tong, Y. O., Hao, Z. M., and Chang, E. (1993). Dominant negative effect of a germ-line mutant p53: A step fostering tumorigenesis. Cancer Res 53:4452–4455.
Strano, S., Fontemaggi, G., Costanzo, A., Rizzo, M. G., Monti, O., Baccarini, A., Del Sal, G., Levrero, M., Sacchi, A., Oren, M., and Blandino, G. (2002). Physical interaction with human tumor-derived p53 mutants inhibits p63 activities. J Biol Chem 277:18817–18826.
Strano, S., Munarriz, E., Rossi, M., Cristofanelli, B., Shaul, Y., Castagnoli, L., Levine, A. J., Sacchi, A., Cesareni, G., Oren, M., and Blandino, G. (2000). Physical and functional interaction between p53 mutants and different isoforms of p73. J Biol Chem 275:29503–29512.
Subler, M. A., Martin, D. W., and Deb, S. (1994). Activation of the human immunodeficiency virus type 1 long terminal repeat by transforming mutants of human p53. J Virol 68:103–110.
Takahashi, T., Nau, M. M., Chiba, I., Birrer, M. J., Rosenberg, R. K., Vinocour, M., Levitt, M., Pass, H., Gazdar, A. F., and Minna, J. D. (1989). p53: a frequent target for genetic abnormalities in lung cancer. Science 246:491–494.
Takahashi, Y., Bucana, C. D., Cleary, K. R., and Ellis, L. M. (1998). p53, vessel count, and vascular endothelial growth factor expression in human colon cancer. Int J Cancer 79:34–38.
Tang, H. Y., Zhao, K., Pizzolato, J. F., Fonarev, M., Langer, J. C., and Manfredi, J. J. (1998). Constitutive expression of the cyclin-dependent kinase inhibitor p21 is transcriptionally regulated by the tumor suppressor protein p53. J Biol Chem 273:29156–29163.
Telerman, A., Tuynder, M., Dupressoir, T., Robaye, B., Sigaux, F., Shaulian, E., Oren, M., Rommelaere, J., and Amson, R. (1993). A model for tumor suppression using H-1 parvovirus. Proc Natl Acad Sci USA 90:8702–8706.
Tsutsumi-Ishii, Y., Todakoro, K., Hanaoka, F., and Tsuchida, N. (1995). Response of heat shock element within the human HSP70 promotor to mutated p53 genes. Cell Growth Differ 6:1–8.
Ueba, T., Nosaka, T., Takahashi, J. A., Shibata, F., Florkiewicz, R. Z., Vogelstein, B., Oda, Y., Kikuchi, H., and Hatanaka, M. (1994). Transcriptional regulation of basic fibroblast growth factor gene by p53 in human glioblastoma and hepatocellular carcinoma cells. Proc Natl Acad Sci USA 91:9009–9013.
Unger, T., Mietz, J. A., Scheffner, M., Yee, C. L., and Howley, P. M. (1993). Functional domains of wild-type and mutant p53 proteins involved in transcriptional regulation, transdominant inhibition and transformation suppression. Mol Cell Biol 13:5186–5194.
Van Meir, E. G., Polverini, P. J., Chazin, V. R., Huang, H.-J., de Tribolet, N., and Cavenee, W. K. (1994). Release of an inhibitor of angiogenesis upon induction of wild type p53 expression in glioblastoma cells. Nat Genet 8:171–176.
van Oijen, M. G., and Slootweg, P. J. (2000). Gain-of-function mutations in the tumor suppressor gene p53. Clin Cancer Res 6:2138–2145.
Varley, J. M., McGown, G., Thorncroft, M., Cochrane, S., Morrison, P., Woll, P., Kelsey, A. M., Mitchell, E. L., Boyle, J., Birch, J. M., and Evans, D. G. (1996). A previously undescribed mutation within the tetramerisation domain of TP53 in a family with Li-Fraumeni syndrome. Oncogene 12:2437–2442.
Vogelstein, B., and Kinzler, K. W. (1993). The multistep nature of cancer. Trends Genet 9:138–141.
Vollmer, C. M., Ribas, A., Butterfield, L. H., Dissette, V. B., Andrews, K. J., Eilber, F. C., Montejo, L. D., Chen, A. Y., Hu, B., Glaspy, J. A., et al. (1999). p53 selective and nonselective replication of an E1B-deleted adenovirus in hepatocellular carcinoma. Cancer Res 59:4369–4374.
Wallingford, J. B., Seufert, D. W., Virta, V. C., and Vize, P. D. (1997). p53 activity is essential for normal development in Xenopus. Curr Biol 7:747–757.
Whitesell, L., Sutphin, P. D., Pulcini, E. J., Martinez, J. D., and Cook, P. H. (1998). The physical association of multiple molecular chaperone proteins with mutant p53 is altered by geldanamycin, an hsp90-binding agent. Mol Cell Biol 18:1517–1524.
Wieczorek, A. M., Waterman, J. L. F., Waterman, M. J. F., and Halazonetis, T. D. (1996). Structure-based rescue of common tumor-derived p53 mutants. Nat Med 2:1143–1146.
Wolf, D., Harris, N., and Rotter, V. (1984a). Reconstitution of p53 expression in a nonproducer Ab-MuLV-transformed cell line by transfection of a functional p53 gene. Cell 38:119–126.
Wolf, D., Harris, N., and Rotter, V. (1984b). Reconstitution of p53 expression in a nonproducer Ab-MuLV-transformed cell line by transfection of a functional p53 gene. Cell 38:119–126.
Wong, K. B., DeDecker, B. S., Freund, S. M., Proctor, M. R., Bycroft, M., and Fersht, A. R. (1999). Hot-spot mutants of p53 core domain evince characteristic local structural changes. Proc Natl Acad Sci USA 96:8438–8442.
Yang, A., Kaghad, M., Wang, Y., Gillett, E., Fleming, M. D., Dotsch, V., Andrews, N. C., Caput, D., and 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.
Yang, A., Schweitzer, R., Sun, D. Q., Kaghad, M., Walker, N., Bronson, R. T., Tabin, C., Sharpe, A., Caput, D., Crum, C., and McKeon, F. (1999). p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Nature 398:714–718.
Yang, A., Walker, N., Bronson, R., Kaghad, M., Oosterwegel, M., Bonnin, J., Vagner, C., Bonnet, H., Dikkes, P., Sharpe, A., et al. (2000). p73-deficient mice have neurological, pheromonal and inflammatory defects but lack spontaneous tumours. Nature 404:99–103.
Yuan, Z. M., Shioya, H., Ishiko, T., Sun, X., Gu, J., Huang, Y. Y., Lu, H., Kharbanda, S., Weichselbaum, R., and Kufe, D. (1999). p73 is regulated by tyrosine kinase c-Abl in the apoptotic response to DNA damage. Nature 399:814–817.
Zhu, J., Jiang, J., Zhou, W., and Chen, X. (1998). The potential tumor suppressor p73 differentially regulates cellular p53 target genes. Cancer Res 58:5061–5065.
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Sigal, A., Rotter, V. (2005). The Oncogenic Activity of p53 Mutants. In: Zambetti, G.P. (eds) The p53 Tumor Suppressor Pathway and Cancer. Protein Reviews, vol 2. Springer, Boston, MA. https://doi.org/10.1007/0-387-30127-5_9
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