This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Gaiddon, C.
Right arrow Articles by Prives, C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gaiddon, C.
Right arrow Articles by Prives, C.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, March 2001, p. 1874-1887, Vol. 21, No. 5
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.5.1874-1887.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

A Subset of Tumor-Derived Mutant Forms of p53 Down-Regulate p63 and p73 through a Direct Interaction with the p53 Core Domain

C. Gaiddon,dagger M. Lokshin, J. Ahn, T. Zhang, and C. Prives*

Department of Biological Sciences, Columbia University, New York, New York 10027

Received 17 August 2000/Returned for modification 29 September 2000/Accepted 4 December 2000

The p53 protein is related by sequence homology and function to the products of two other genes, p63 and p73, that each encode several isoforms. We and others have discovered previously that certain tumor-derived mutants of p53 can associate and inhibit transcriptional activation by the alpha  and beta  isoforms of p73. In this study we have extended these observations to show that in transfected cells a number of mutant p53 proteins could bind and down-regulate several isoforms not only of p73 (p73alpha , -beta , -gamma , and -delta ) but also of p63 (p63alpha and -gamma ; Delta Np63alpha and -gamma ). Moreover, a correlation existed between the efficiency of p53 binding and the inhibition of p63 or p73 function. We also found that wild-type p63 and p73 interact efficiently with each other when coexpressed in mammalian cells. The interaction between p53 mutants and p63 or p73 was confirmed in a physiological setting by examining tumor cell lines that endogenously express these proteins. We also demonstrated that purified p53 and p73 proteins interact directly and that the p53 core domain, but not the tetramerization domain, mediates this interaction. Using a monoclonal antibody (PAb240) that recognizes an epitope within the core domain of a subset of p53 mutants, we found a correlation between the ability of p53 proteins to be immunoprecipitated by this antibody and their ability to interact with p73 or p63 in vitro and in transfected cells. Based on these results and those of others, we propose that interactions between the members of the p53 family are likely to be widespread and may account in some cases for the ability of tumor-derived p53 mutants to promote tumorigenesis.

* Corresponding author. Mailing address: Department of Biological Sciences, Columbia University, 1212 Amsterdam Ave., New York, NY 10027. Phone: (212) 854-2557. Fax: (212) 865-8246. E-mail: prives{at}cubsps.bio.columbia.edu.

dagger Present address: UMR 7519 CNRS-Université Louis Pasteur, Strasbourg 67084, France.

Molecular and Cellular Biology, March 2001, p. 1874-1887, Vol. 21, No. 5
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.5.1874-1887.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Roperch, J.-P., El Ouadrani, K., Hendrix, A., Emami, S., De Wever, O., Melino, G., Gespach, C. (2008). Netrin-1 Induces Apoptosis in Human Cervical Tumor Cells via the TAp73{alpha} Tumor Suppressor. Cancer Res. 68: 8231-8239 [Abstract] [Full Text]  
  • Tozluoglu, M., Karaca, E., Haliloglu, T., Nussinov, R. (2008). Cataloging and organizing p73 interactions in cell cycle arrest and apoptosis. Nucleic Acids Res 36: 5033-5049 [Abstract] [Full Text]  
  • Kravchenko, J. E., Ilyinskaya, G. V., Komarov, P. G., Agapova, L. S., Kochetkov, D. V., Strom, E., Frolova, E. I., Kovriga, I., Gudkov, A. V., Feinstein, E., Chumakov, P. M. (2008). Small-molecule RETRA suppresses mutant p53-bearing cancer cells through a p73-dependent salvage pathway. Proc. Natl. Acad. Sci. USA 105: 6302-6307 [Abstract] [Full Text]  
  • Livera, G., Petre-Lazar, B., Guerquin, M.-J., Trautmann, E., Coffigny, H., Habert, R. (2008). p63 null mutation protects mouse oocytes from radio-induced apoptosis. Reproduction 135: 3-12 [Abstract] [Full Text]  
  • Kommagani, R., Payal, V., Kadakia, M. P. (2007). Differential Regulation of Vitamin D Receptor (VDR) by the p53 Family: p73-DEPENDENT INDUCTION OF VDR UPON DNA DAMAGE. J. Biol. Chem. 282: 29847-29854 [Abstract] [Full Text]  
  • Johnson, J., Lagowski, J., Sundberg, A., Lawson, S., Liu, Y., Kulesz-Martin, M. (2007). p73 Loss Triggers Conversion to Squamous Cell Carcinoma Reversible upon Reconstitution with TAp73{alpha}. Cancer Res. 67: 7723-7730 [Abstract] [Full Text]  
  • Marusyk, A., Wheeler, L. J., Mathews, C. K., DeGregori, J. (2007). p53 Mediates Senescence-Like Arrest Induced by Chronic Replicational Stress. Mol. Cell. Biol. 27: 5336-5351 [Abstract] [Full Text]  
  • Malaguarnera, R, Vella, V, Vigneri, R, Frasca, F (2007). p53 family proteins in thyroid cancer. Endocr Relat Cancer 14: 43-60 [Abstract] [Full Text]  
  • Keyes, W. M., Vogel, H., Koster, M. I., Guo, X., Qi, Y., Petherbridge, K. M., Roop, D. R., Bradley, A., Mills, A. A. (2006). p63 heterozygous mutant mice are not prone to spontaneous or chemically induced tumors. Proc. Natl. Acad. Sci. USA 103: 8435-8440 [Abstract] [Full Text]  
  • Takaoka, M., Smith, C. E., Mashiba, M. K., Okawa, T., Andl, C. D., El-Deiry, W. S., Nakagawa, H. (2006). EGF-mediated regulation of IGFBP-3 determines esophageal epithelial cellular response to IGF-I. Am. J. Physiol. Gastrointest. Liver Physiol. 290: G404-G416 [Abstract] [Full Text]  
  • Malaguarnera, R., Mandarino, A., Mazzon, E., Vella, V., Gangemi, P., Vancheri, C., Vigneri, P., Aloisi, A., Vigneri, R., Frasca, F. (2005). The p53-homologue p63 may promote thyroid cancer progression. Endocr Relat Cancer 12: 953-971 [Abstract] [Full Text]  
  • Gaiddon, C., Jeannequin, P., Bischoff, P., Pfeffer, M., Sirlin, C., Loeffler, J. P. (2005). Ruthenium (II)-Derived Organometallic Compounds Induce Cytostatic and Cytotoxic Effects on Mammalian Cancer Cell Lines through p53-Dependent and p53-Independent Mechanisms. J. Pharmacol. Exp. Ther. 315: 1403-1411 [Abstract] [Full Text]  
  • Concin, N., Hofstetter, G., Berger, A., Gehmacher, A., Reimer, D., Watrowski, R., Tong, D., Schuster, E., Hefler, L., Heim, K., Mueller-Holzner, E., Marth, C., Moll, U. M., Zeimet, A. G., Zeillinger, R. (2005). Clinical Relevance of Dominant-Negative p73 Isoforms for Responsiveness to Chemotherapy and Survival in Ovarian Cancer: Evidence for a Crucial p53-p73 Cross-talk In vivo. Clin. Cancer Res. 11: 8372-8383 [Abstract] [Full Text]  
  • Cui, R., Nguyen, T. T., Taube, J. H., Stratton, S. A., Feuerman, M. H., Barton, M. C. (2005). Family Members p53 and p73 Act Together in Chromatin Modification and Direct Repression of {alpha}-Fetoprotein Transcription. J. Biol. Chem. 280: 39152-39160 [Abstract] [Full Text]  
  • Scian, M. J., Stagliano, K. E. R., Anderson, M. A. E., Hassan, S., Bowman, M., Miles, M. F., Deb, S. P., Deb, S. (2005). Tumor-Derived p53 Mutants Induce NF-{kappa}B2 Gene Expression. Mol. Cell. Biol. 25: 10097-10110 [Abstract] [Full Text]  
  • Nelson, H. H., Wilkojmen, M., Marsit, C. J., Kelsey, K. T. (2005). TP53 mutation, allelism and survival in non-small cell lung cancer. Carcinogenesis 26: 1770-1773 [Abstract] [Full Text]  
  • Mills, A. A. (2005). p53: link to the past, bridge to the future. Genes Dev. 19: 2091-2099 [Full Text]  
  • Harms, K. L., Chen, X. (2005). The C Terminus of p53 Family Proteins Is a Cell Fate Determinant. Mol. Cell. Biol. 25: 2014-2030 [Abstract] [Full Text]  
  • Urist, M., Tanaka, T., Poyurovsky, M. V., Prives, C. (2004). p73 induction after DNA damage is regulated by checkpoint kinases Chk1 and Chk2. Genes Dev. 18: 3041-3054 [Abstract] [Full Text]  
  • Tomkova, K., Belkhiri, A., El-Rifai, W., Zaika, A. I. (2004). p73 Isoforms Can Induce T-Cell Factor-Dependent Transcription in Gastrointestinal Cells. Cancer Res. 64: 6390-6393 [Abstract] [Full Text]  
  • Moll, U. M., Slade, N. (2004). p63 and p73: Roles in Development and Tumor Formation. Mol Cancer Res 2: 371-386 [Abstract] [Full Text]  
  • Concin, N., Becker, K., Slade, N., Erster, S., Mueller-Holzner, E., Ulmer, H., Daxenbichler, G., Zeimet, A., Zeillinger, R., Marth, C., Moll, U. M. (2004). Transdominant {Delta}TAp73 Isoforms Are Frequently Up-regulated in Ovarian Cancer. Evidence for Their Role as Epigenetic p53 Inhibitors in Vivo. Cancer Res. 64: 2449-2460 [Abstract] [Full Text]  
  • Billon, N., Terrinoni, A., Jolicoeur, C., McCarthy, A., Richardson, W. D., Melino, G., Raff, M. (2004). Roles for p53 and p73 during oligodendrocyte development. Development 131: 1211-1220 [Abstract] [Full Text]  
  • Fulco, M., Costanzo, A., Merlo, P., Mangiacasale, R., Strano, S., Blandino, G., Balsano, C., Lavia, P., Levrero, M. (2003). p73 Is Regulated by Phosphorylation at the G2/M Transition. J. Biol. Chem. 278: 49196-49202 [Abstract] [Full Text]  
  • Gonzalez, S., Prives, C., Cordon-Cardo, C. (2003). p73{alpha} Regulation by Chk1 in Response to DNA Damage. Mol. Cell. Biol. 23: 8161-8171 [Abstract] [Full Text]  
  • Hann, B., Balmain, A. (2003). Replication of an E1B 55-Kilodalton Protein-Deficient Adenovirus (ONYX-015) Is Restored by Gain-of-Function Rather than Loss-of-Function p53 Mutants. J. Virol. 77: 11588-11595 [Abstract] [Full Text]  
  • Sheard, M. A., Uldrijan, S., Vojtesek, B. (2003). Role of p53 in Regulating Constitutive and X-Radiation-Inducible CD95 Expression and Function in Carcinoma Cells. Cancer Res. 63: 7176-7184 [Abstract] [Full Text]  
  • Frasca, F., Vella, V., Aloisi, A., Mandarino, A., Mazzon, E., Vigneri, R., Vigneri, P. (2003). p73 Tumor-Suppressor Activity Is Impaired in Human Thyroid Cancer. Cancer Res. 63: 5829-5837 [Abstract] [Full Text]  
  • Gaiddon, C., Lokshin, M., Gross, I., Levasseur, D., Taya, Y., Loeffler, J.-P., Prives, C. (2003). Cyclin-dependent Kinases Phosphorylate p73 at Threonine 86 in a Cell Cycle-dependent Manner and Negatively Regulate p73. J. Biol. Chem. 278: 27421-27431 [Abstract] [Full Text]  
  • Kaye, F. J., Komiya, T. (2003). New Leads Suggest a Clinically Relevant Genotype-Phenotype Relationship for the p53 Gene. JNCI J Natl Cancer Inst 95: 926-927 [Full Text]  
  • Stiewe, T., Stanelle, J., Theseling, C. C., Pollmeier, B., Beitzinger, M., Putzer, B. M. (2003). Inactivation of Retinoblastoma (RB) Tumor Suppressor by Oncogenic Isoforms of the p53 Family Member p73. J. Biol. Chem. 278: 14230-14236 [Abstract] [Full Text]  
  • Westfall, M. D., Mays, D. J., Sniezek, J. C., Pietenpol, J. A. (2003). The {Delta}Np63{alpha} Phosphoprotein Binds the p21 and 14-3-3{sigma} Promoters In Vivo and Has Transcriptional Repressor Activity That Is Reduced by Hay-Wells Syndrome-Derived Mutations. Mol. Cell. Biol. 23: 2264-2276 [Abstract] [Full Text]  
  • Bensaad, K., Le Bras, M., Unsal, K., Strano, S., Blandino, G., Tominaga, O., Rouillard, D., Soussi, T. (2003). Change of Conformation of the DNA-binding Domain of p53 Is the Only Key Element for Binding of and Interference with p73. J. Biol. Chem. 278: 10546-10555 [Abstract] [Full Text]  
  • Ghioni, P., Bolognese, F., Duijf, P. H. G., van Bokhoven, H., Mantovani, R., Guerrini, L. (2002). Complex Transcriptional Effects of p63 Isoforms: Identification of Novel Activation and Repression Domains{dagger}. Mol. Cell. Biol. 22: 8659-8668 [Abstract] [Full Text]  
  • Fontemaggi, G., Kela, I., Amariglio, N., Rechavi, G., Krishnamurthy, J., Strano, S., Sacchi, A., Givol, D., Blandino, G. (2002). Identification of Direct p73 Target Genes Combining DNA Microarray and Chromatin Immunoprecipitation Analyses. J. Biol. Chem. 277: 43359-43368 [Abstract] [Full Text]  
  • Hackzell, A., Uramoto, H., Izumi, H., Kohno, K., Funa, K. (2002). p73 Independent of c-Myc Represses Transcription of Platelet-derived Growth Factor beta -Receptor through Interaction with NF-Y. J. Biol. Chem. 277: 39769-39776 [Abstract] [Full Text]  
  • Strano, S., Fontemaggi, G., Costanzo, A., Rizzo, M. G., Monti, O., Baccarini, A., Del Sal, G., Levrero, M., Sacchi, A., Oren, M., Blandino, G. (2002). Physical Interaction with Human Tumor-derived p53 Mutants Inhibits p63 Activities. J. Biol. Chem. 277: 18817-18826 [Abstract] [Full Text]  
  • Stiewe, T., Theseling, C. C., Putzer, B. M. (2002). Transactivation-deficient Delta TA-p73 Inhibits p53 by Direct Competition for DNA Binding. IMPLICATIONS FOR TUMORIGENESIS. J. Biol. Chem. 277: 14177-14185 [Abstract] [Full Text]  
  • Balint, E., Phillips, A. C., Kozlov, S., Stewart, C. L., Vousden, K. H. (2002). Induction of p57KIP2 expression by p73beta. Proc. Natl. Acad. Sci. USA 99: 3529-3534 [Abstract] [Full Text]  
  • Ishimoto, O., Kawahara, C., Enjo, K., Obinata, M., Nukiwa, T., Ikawa, S. (2002). Possible Oncogenic Potential of {Delta}Np73: A Newly Identified Isoform of Human p73. Cancer Res. 62: 636-641 [Abstract] [Full Text]  
  • Di Como, C. J., Urist, M. J., Babayan, I., Drobnjak, M., Hedvat, C. V., Teruya-Feldstein, J., Pohar, K., Hoos, A., Cordon-Cardo, C. (2002). p63 Expression Profiles in Human Normal and Tumor Tissues. Clin. Cancer Res. 8: 494-501 [Abstract] [Full Text]  
  • Fontemaggi, G., Gurtner, A., Strano, S., Higashi, Y., Sacchi, A., Piaggio, G., Blandino, G. (2001). The Transcriptional Repressor ZEB Regulates p73 Expression at the Crossroad between Proliferation and Differentiation. Mol. Cell. Biol. 21: 8461-8470 [Abstract] [Full Text]  
  • Suliman, Y., Opitz, O. G., Avadhani, A., Burns, T. C., El-Deiry, W., Wong, D. T., Rustgi, A. K. (2001). p63 Expression Is Associated with p53 Loss in Oral-Esophageal Epithelia of p53-deficient Mice. Cancer Res. 61: 6467-6473 [Abstract] [Full Text]  
  • Irwin, M. S., Kaelin, W. G. (2001). p53 Family Update: p73 and p63 Develop Their Own Identities. Cell Growth Differ. 12: 337-349 [Full Text]  
  • Klein, C., Georges, G., Kunkele, K.-P., Huber, R., Engh, R. A., Hansen, S. (2001). High Thermostability and Lack of Cooperative DNA Binding Distinguish the p63 Core Domain from the Homologous Tumor Suppressor p53. J. Biol. Chem. 276: 37390-37401 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»