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 Ryan, K. M.
Right arrow Articles by Vousden, K. H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ryan, K. M.
Right arrow Articles by Vousden, K. H.

 Previous Article  |  Next Article 

Mol Cell Biol, July 1998, p. 3692-3698, Vol. 18, No. 7
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Characterization of Structural p53 Mutants Which Show Selective Defects in Apoptosis but Not Cell Cycle Arrest

Kevin M. Ryan and Karen H. Vousden*

ABL Basic Research Program, NCI-FCRDC, Frederick, Maryland 21702

Received 24 November 1997/Returned for modification 5 January 1998/Accepted 8 April 1998

Suppression of tumor cell growth by p53 results from the activation of both apoptosis and cell cycle arrest, functions which have been shown to be separable activities of p53. We have characterized a series of p53 mutants with amino acid substitutions at residue 175 and show that these mutants fall into one of three classes: class I, which is essentially wild type for apoptotic and cell cycle arrest functions; class II, which retains cell cycle arrest activity but is impaired in the induction of apoptosis; and class III, which is defective in both activities. Several residue 175 mutants which retain cell cycle arrest function have been detected in cancers, and we show that these have lost apoptotic function. Furthermore, several class II mutants have been found to be temperature sensitive for apoptotic activity while showing constitutive cell cycle arrest function. Taken together, these mutants comprise an excellent system with which to investigate the biochemical nature of p53-mediated apoptosis, the function of principal importance in tumor suppression. All of the mutants that showed loss of apoptotic function also showed defects in the activation of promoters from the potential apoptotic targets Bax and the insulin-like growth factor-binding protein 3 gene (IGF-BP3), and a correlation between full apoptotic activity and activation of both of these promoters was also seen with the temperature-sensitive mutants. However, a role for additional apoptotic activities of p53 was suggested by the observation that some mutants retained significant apoptotic function despite being impaired in the activation of Bax- and IGF-BP3-derived promoters. In contrast to the case of transcriptional activation, a perfect correlation between transcriptional repression of the c-fos promoter and the ability to induce apoptosis was seen, although the observation that Bax expression induced a similar repression of transcription from this promoter suggests that this may be a consequence, rather than a cause, of apoptotic death.

* Corresponding author. Mailing address: ABL Basic Research Program, NCI-FCRDC, Building 560, Room 22-96, West 7th St., Frederick, MD 21702-1201. Phone: (301) 846-1726. Fax: (301) 846-1666. E-mail: vousden{at}ncifcrf.gov.

Mol Cell Biol, July 1998, p. 3692-3698, Vol. 18, No. 7
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Ahn, J., Byeon, I.-J. L., Byeon, C.-H., Gronenborn, A. M. (2009). Insight into the Structural Basis of Pro- and Antiapoptotic p53 Modulation by ASPP Proteins. J. Biol. Chem. 284: 13812-13822 [Abstract] [Full Text]  
  • Nyman, U., Vlachos, P., Cascante, A., Hermanson, O., Zhivotovsky, B., Joseph, B. (2009). Protein Kinase C-Dependent Phosphorylation Regulates the Cell Cycle-Inhibitory Function of the p73 Carboxy Terminus Transactivation Domain. Mol. Cell. Biol. 29: 1814-1825 [Abstract] [Full Text]  
  • Garrison, S. P., Jeffers, J. R., Yang, C., Nilsson, J. A., Hall, M. A., Rehg, J. E., Yue, W., Yu, J., Zhang, L., Onciu, M., Sample, J. T., Cleveland, J. L., Zambetti, G. P. (2008). Selection against PUMA Gene Expression in Myc-Driven B-Cell Lymphomagenesis. Mol. Cell. Biol. 28: 5391-5402 [Abstract] [Full Text]  
  • O'Prey, J., Wilkinson, S., Ryan, K. M. (2008). Tumor Antigen LRRC15 Impedes Adenoviral Infection: Implications for Virus-Based Cancer Therapy. J. Virol. 82: 5933-5939 [Abstract] [Full Text]  
  • Bhattacharyya, N., Pechhold, K., Shahjee, H., Zappala, G., Elbi, C., Raaka, B., Wiench, M., Hong, J., Rechler, M. M. (2006). Nonsecreted Insulin-like Growth Factor Binding Protein-3 (IGFBP-3) Can Induce Apoptosis in Human Prostate Cancer Cells by IGF-independent Mechanisms without Being Concentrated in the Nucleus. J. Biol. Chem. 281: 24588-24601 [Abstract] [Full Text]  
  • Ang, H. C., Joerger, A. C., Mayer, S., Fersht, A. R. (2006). Effects of Common Cancer Mutations on Stability and DNA Binding of Full-length p53 Compared with Isolated Core Domains. J. Biol. Chem. 281: 21934-21941 [Abstract] [Full Text]  
  • Gonin-Laurent, N., Gibaud, A., Huygue, M., Lefevre, S. H., Le Bras, M., Chauveinc, L., Sastre-Garau, X., Doz, F., Lumbroso, L., Chevillard, S., Malfoy, B. (2006). Specific TP53 mutation pattern in radiation-induced sarcomas. Carcinogenesis 27: 1266-1272 [Abstract] [Full Text]  
  • West, A. N., Ribeiro, R. C., Jenkins, J., Rodriguez-Galindo, C., Figueiredo, B. C., Kriwacki, R., Zambetti, G. P. (2006). Identification of a Novel Germ Line Variant Hotspot Mutant p53-R175L in Pediatric Adrenal Cortical Carcinoma.. Cancer Res. 66: 5056-5062 [Abstract] [Full Text]  
  • Menendez, D., Inga, A., Resnick, M. A. (2006). The Biological Impact of the Human Master Regulator p53 Can Be Altered by Mutations That Change the Spectrum and Expression of Its Target Genes.. Mol. Cell. Biol. 26: 2297-2308 [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]  
  • Hublitz, P., Kunowska, N., Mayer, U. P., Muller, J. M., Heyne, K., Yin, N., Fritzsche, C., Poli, C., Miguet, L., Schupp, I. W., van Grunsven, L. A., Potiers, N., van Dorsselaer, A., Metzger, E., Roemer, K., Schule, R. (2005). NIR is a novel INHAT repressor that modulates the transcriptional activity of p53. Genes Dev. 19: 2912-2924 [Abstract] [Full Text]  
  • McDermott, U., Longley, D. B., Galligan, L., Allen, W., Wilson, T., Johnston, P. G. (2005). Effect of p53 Status and STAT1 on Chemotherapy-Induced, Fas-Mediated Apoptosis in Colorectal Cancer. Cancer Res. 65: 8951-8960 [Abstract] [Full Text]  
  • Yee, K. S., Vousden, K. H. (2005). Complicating the complexity of p53. Carcinogenesis 26: 1317-1322 [Abstract] [Full Text]  
  • Grimberg, A., Coleman, C. M., Burns, T. F., Himelstein, B. P., Koch, C. J., Cohen, P., El-Deiry, W. S. (2005). p53-Dependent and p53-Independent Induction of Insulin-Like Growth Factor Binding Protein-3 by Deoxyribonucleic Acid Damage and Hypoxia. J. Clin. Endocrinol. Metab. 90: 3568-3574 [Abstract] [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]  
  • Tanikawa, J., Nomura, T., Macmillan, E. M., Shinagawa, T., Jin, W., Kokura, K., Baba, D., Shirakawa, M., Gonda, T. J., Ishii, S. (2004). p53 Suppresses c-Myb-induced trans-Activation and Transformation by Recruiting the Corepressor mSin3A. J. Biol. Chem. 279: 55393-55400 [Abstract] [Full Text]  
  • Pizzoferrato, E., Liu, Y., Gambotto, A., Armstrong, M. J., Stang, M. T., Gooding, W. E., Alber, S. M., Shand, S. H., Watkins, S. C., Storkus, W. J., Yim, J. H. (2004). Ectopic Expression of Interferon Regulatory Factor-1 Promotes Human Breast Cancer Cell Death and Results in Reduced Expression of Survivin. Cancer Res. 64: 8381-8388 [Abstract] [Full Text]  
  • Godefroy, N., Bouleau, S., Gruel, G., Renaud, F., Rincheval, V., Mignotte, B., Tronik-Le Roux, D., Vayssiere, J.-L. (2004). Transcriptional repression by p53 promotes a Bcl-2-insensitive and mitochondria-independent pathway of apoptosis. Nucleic Acids Res 32: 4480-4490 [Abstract] [Full Text]  
  • Ashur-Fabian, O., Avivi, A., Trakhtenbrot, L., Adamsky, K., Cohen, M., Kajakaro, G., Joel, A., Amariglio, N., Nevo, E., Rechavi, G. (2004). Evolution of p53 in hypoxia-stressed Spalax mimics human tumor mutation. Proc. Natl. Acad. Sci. USA 101: 12236-12241 [Abstract] [Full Text]  
  • Nakade, K., Zheng, H., Ganguli, G., Buchwalter, G., Gross, C., Wasylyk, B. (2004). The Tumor Suppressor p53 Inhibits Net, an Effector of Ras/Extracellular Signal-Regulated Kinase Signaling. Mol. Cell. Biol. 24: 1132-1142 [Abstract] [Full Text]  
  • Shiraishi, K., Kato, S., Han, S.-Y., Liu, W., Otsuka, K., Sakayori, M., Ishida, T., Takeda, M., Kanamaru, R., Ohuchi, N., Ishioka, C. (2004). Isolation of Temperature-sensitive p53 Mutations from a Comprehensive Missense Mutation Library. J. Biol. Chem. 279: 348-355 [Abstract] [Full Text]  
  • Reczek, E. E., Flores, E. R., Tsay, A. S., Attardi, L. D., Jacks, T. (2003). Multiple Response Elements and Differential p53 Binding Control Perp Expression During Apoptosis. Mol Cancer Res 1: 1048-1057 [Abstract] [Full Text]  
  • Lohr, K., Moritz, C., Contente, A., Dobbelstein, M. (2003). p21/CDKN1A Mediates Negative Regulation of Transcription by p53. J. Biol. Chem. 278: 32507-32516 [Abstract] [Full Text]  
  • Ruiz-Ruiz, C., Robledo, G., Cano, E., Redondo, J. M., Lopez-Rivas, A. (2003). Characterization of p53-mediated Up-regulation of CD95 Gene Expression upon Genotoxic Treatment in Human Breast Tumor Cells. J. Biol. Chem. 278: 31667-31675 [Abstract] [Full Text]  
  • Zhou, J., Prives, C. (2003). Replication of damaged DNA in vitro is blocked by p53. Nucleic Acids Res 31: 3881-3892 [Abstract] [Full Text]  
  • Chung, T.-W., Lee, Y.-C., Ko, J.-H., Kim, C.-H. (2003). Hepatitis B Virus X Protein Modulates the Expression of PTEN by Inhibiting the Function of p53, a Transcriptional Activator in Liver Cells. Cancer Res. 63: 3453-3458 [Abstract] [Full Text]  
  • Vasilevskaya, I. A., Rakitina, T. V., O'Dwyer, P. J. (2003). Geldanamycin and its 17-Allylamino-17-Demethoxy Analogue Antagonize the Action of Cisplatin in Human Colon Adenocarcinoma Cells: Differential Caspase Activation as a Basis for Interaction. Cancer Res. 63: 3241-3246 [Abstract] [Full Text]  
  • Ha, L., Ceryak, S., Patierno, S. R. (2003). Chromium (VI) Activates Ataxia Telangiectasia Mutated (ATM) Protein. REQUIREMENT OF ATM FOR BOTH APOPTOSIS AND RECOVERY FROM TERMINAL GROWTH ARREST. J. Biol. Chem. 278: 17885-17894 [Abstract] [Full Text]  
  • Guo, F., Gao, Y., Wang, L., Zheng, Y. (2003). p19Arf-p53 Tumor Suppressor Pathway Regulates Cell Motility by Suppression of Phosphoinositide 3-Kinase and Rac1 GTPase Activities. J. Biol. Chem. 278: 14414-14419 [Abstract] [Full Text]  
  • Lee, S., Tarn, C., Wang, W.-H., Chen, S., Hullinger, R. L., Andrisani, O. M. (2002). Hepatitis B Virus X Protein Differentially Regulates Cell Cycle Progression in X-transforming Versus Nontransforming Hepatocyte (AML12) Cell Lines. J. Biol. Chem. 277: 8730-8740 [Abstract] [Full Text]  
  • Crawford, K. W., Bowen, W. D. (2002). Sigma-2 Receptor Agonists Activate a Novel Apoptotic Pathway and Potentiate Antineoplastic Drugs in Breast Tumor Cell Lines. Cancer Res. 62: 313-322 [Abstract] [Full Text]  
  • Dubrez, L., Coll, J.-L., Hurbin, A., Solary, E., Favrot, M.-C. (2001). Caffeine Sensitizes Human H358 Cell Line to p53-mediated Apoptosis by Inducing Mitochondrial Translocation and Conformational Change of BAX Protein. J. Biol. Chem. 276: 38980-38987 [Abstract] [Full Text]  
  • Pritchard, D. E., Ceryak, S., Ha, L., Fornsaglio, J. L., Hartman, S. K., O'Brien, T. J., Patierno, S. R. (2001). Mechanism of Apoptosis and Determination of Cellular Fate in Chromium(VI)-exposed Populations of Telomerase-immortalized Human Fibroblasts. Cell Growth Differ. 12: 487-496 [Abstract] [Full Text]  
  • Abeysinghe, R. D., Greene, B. T., Haynes, R., Willingham, M. C., Turner, J., Planalp, R. P., Brechbiel, M.W., Torti, F. M., Torti, S. V. (2001). p53-independent apoptosis mediated by tachpyridine, an anti-cancer iron chelator. Carcinogenesis 22: 1607-1614 [Abstract] [Full Text]  
  • Peng, Y.-C., Kuo, F., Breiding, D. E., Wang, Y.-F., Mansur, C. P., Androphy, E. J. (2001). AMF1 (GPS2) Modulates p53 Transactivation. Mol. Cell. Biol. 21: 5913-5924 [Abstract] [Full Text]  
  • Blagosklonny, M. V., Giannakakou, P., Romanova, L. Y., Ryan, K. M., Vousden, K. H., Fojo, T. (2001). Inhibition of HIF-1- and wild-type p53-stimulated transcription by codon Arg175 p53 mutants with selective loss of functions. Carcinogenesis 22: 861-867 [Abstract] [Full Text]  
  • Koumenis, C., Alarcon, R., Hammond, E., Sutphin, P., Hoffman, W., Murphy, M., Derr, J., Taya, Y., Lowe, S. W., Kastan, M., Giaccia, A. (2001). Regulation of p53 by Hypoxia: Dissociation of Transcriptional Repression and Apoptosis from p53-Dependent Transactivation. Mol. Cell. Biol. 21: 1297-1310 [Abstract] [Full Text]  
  • BLAGOSKLONNY, M. V. (2000). p53 from complexity to simplicity: mutant p53 stabilization, gain-of-function, and dominant-negative effect. FASEB J. 14: 1901-1907 [Abstract] [Full Text]  
  • Attardi, L. D., Reczek, E. E., Cosmas, C., Demicco, E. G., McCurrach, M. E., Lowe, S. W., Jacks, T. (2000). PERP, an apoptosis-associated target of p53, is a novel member of the PMP-22/gas3 family. Genes Dev. 14: 704-718 [Abstract] [Full Text]  
  • Munsch, D., Watanabe-Fukunaga, R., Bourdon, J.-C., Nagata, S., May, E., Yonish-Rouach, E., Reisdorf, P. (2000). Human and Mouse Fas (APO-1/CD95) Death Receptor Genes Each Contain a p53-responsive Element That Is Activated by p53 Mutants Unable to Induce Apoptosis. J. Biol. Chem. 275: 3867-3872 [Abstract] [Full Text]  
  • Aurelio, O. N., Kong, X.-T., Gupta, S., Stanbridge, E. J. (2000). p53 Mutants Have Selective Dominant-Negative Effects on Apoptosis but Not Growth Arrest in Human Cancer Cell Lines. Mol. Cell. Biol. 20: 770-778 [Abstract] [Full Text]  
  • Scotto, C., Delphin, C., Deloulme, J. C., Baudier, J. (1999). Concerted Regulation of Wild-Type p53 Nuclear Accumulation and Activation by S100B and Calcium-Dependent Protein Kinase C. Mol. Cell. Biol. 19: 7168-7180 [Abstract] [Full Text]  
  • Murphy, M., Ahn, J., Walker, K. K., Hoffman, W. H., Evans, R. M., Levine, A. J., George, D. L. (1999). Transcriptional repression by wild-type p53 utilizes histone deacetylases, mediated by interaction with mSin3a. Genes Dev. 13: 2490-2501 [Abstract] [Full Text]  
  • Unnikrishnan, I., Radfar, A., Jenab-Wolcott, J., Rosenberg, N. (1999). p53 Mediates Apoptotic Crisis in Primary Abelson Virus-Transformed Pre-B Cells. Mol. Cell. Biol. 19: 4825-4831 [Abstract] [Full Text]  
  • Ashcroft, M., Kubbutat, M. H. G., Vousden, K. H. (1999). Regulation of p53 Function and Stability by Phosphorylation. Mol. Cell. Biol. 19: 1751-1758 [Abstract] [Full Text]  
  • Yap, D. B. S., Hsieh, J.-K., Lu, X. (2000). Mdm2 Inhibits the Apoptotic Function of p53 Mainly by Targeting It for Degradation. J. Biol. Chem. 275: 37296-37302 [Abstract] [Full Text]  
  • Kong, X.-T., Gao, H., Stanbridge, E. J. (2001). Mechanisms of Differential Activation of Target Gene Promoters by p53 Hinge Domain Mutants with Impaired Apoptotic Function. J. Biol. Chem. 276: 32990-33000 [Abstract] [Full Text]  
  • Hoffman, W. H., Biade, S., Zilfou, J. T., Chen, J., Murphy, M. (2002). Transcriptional Repression of the Anti-apoptotic survivin Gene by Wild Type p53. J. Biol. Chem. 277: 3247-3257 [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»