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 Dornan, D.
Right arrow Articles by Hupp, T. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Dornan, D.
Right arrow Articles by Hupp, T. R.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, December 2003, p. 8846-8861, Vol. 23, No. 23
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.23.8846-8861.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

The Proline Repeat Domain of p53 Binds Directly to the Transcriptional Coactivator p300 and Allosterically Controls DNA-Dependent Acetylation of p53

David Dornan, Harumi Shimizu, Lindsay Burch, Amanda J. Smith, and Ted R. Hupp*

Cancer Research UK Laboratories, P53 Signal Transduction Group, Department of Molecular and Cellular Pathology, University of Dundee, Dundee DD1 9SY, United Kingdom

Received 24 March 2003/ Returned for modification 5 May 2003/ Accepted 29 July 2003

The transcription coactivator p300 cannot acetylate native p53 tetramers, thus revealing intrinsic conformational constraints on p300-catalyzed acetylation. Consensus site DNA is an allosteric effector that promotes acetylation of p53, suggesting that p300 has an undefined conformationally flexible interface within the p53 tetramer. To identify such conformationally responsive p300-binding sites, p300 was subjected to peptide selection from a phage-peptide display library, a technique that can define novel protein-protein interfaces. The enriched p300-binding peptides contained a proline repeat (PXXP/PXPXP) motif, and five proline repeat motifs actually reside within the p53 transactivation domain, suggesting that this region of p53 may harbor the second p300 contact site. p300 binds in vitro to PXXP-containing peptides derived from the proline repeat domain, and PXXP-containing peptides inhibit sequence-specific DNA-dependent acetylation of p53, indicating that p300 docking to both the LXXLL and contiguous PXXP motif in p53 is required for p53 acetylation. Deletion of the proline repeat motif of p53 prevents DNA-dependent acetylation of p53 by occluding p300 from the p53-DNA complex. Sequence-specific DNA places an absolute requirement for the proline repeat domain to drive p53 acetylation in vivo. Chromatin immunoprecipitation was used to show that the proline repeat deletion mutant p53 is bound to the p21 promoter in vivo, but it is not acetylated, indicating that proline-directed acetylation of p53 is a post-DNA binding event. The PXXP repeat expands the basic interface of a p300-targeted transactivation domain, and proline-directed acetylation of p53 at promoters indicates that p300-mediated acetylation can be highly constrained by substrate conformation in vivo.

* Corresponding author. Mailing address: Cancer Research UK Laboratories, P53 Signal Transduction Group, Department of Molecular and Cellular Pathology, University of Dundee, Dundee DD1 9SY, United Kingdom. Phone: 44-0-1382-496430. Fax: 44-0-1382-633952. E-mail: t.r.hupp{at}dundee.ac.uk.

Molecular and Cellular Biology, December 2003, p. 8846-8861, Vol. 23, No. 23
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.23.8846-8861.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Kimbrel, E. A., Kung, A. L. (2009). The F-box Protein {beta}-TrCp1/Fbw1a Interacts with p300 to Enhance {beta}-Catenin Transcriptional Activity. J. Biol. Chem. 284: 13033-13044 [Abstract] [Full Text]  
  • MacLaine, N. J., Oster, B., Bundgaard, B., Fraser, J. A., Buckner, C., Lazo, P. A., Meek, D. W., Hollsberg, P., Hupp, T. R. (2008). A Central Role for CK1 in Catalyzing Phosphorylation of the p53 Transactivation Domain at Serine 20 after HHV-6B Viral Infection. J. Biol. Chem. 283: 28563-28573 [Abstract] [Full Text]  
  • Harrison, B., Kraus, M., Burch, L., Stevens, C., Craig, A., Gordon-Weeks, P., Hupp, T. R. (2008). DAPK-1 Binding to a Linear Peptide Motif in MAP1B Stimulates Autophagy and Membrane Blebbing. J. Biol. Chem. 283: 9999-10014 [Abstract] [Full Text]  
  • Napolitano, M. A., Cipollaro, M., Cascino, A., Melone, M. A. B., Giordano, A., Galderisi, U. (2007). Brg1 chromatin remodeling factor is involved in cell growth arrest, apoptosis and senescence of rat mesenchymal stem cells. J. Cell Sci. 120: 2904-2911 [Abstract] [Full Text]  
  • Stevens, C., Lin, Y., Sanchez, M., Amin, E., Copson, E., White, H., Durston, V., Eccles, D. M., Hupp, T. (2007). A Germ Line Mutation in the Death Domain of DAPK-1 Inactivates ERK-induced Apoptosis. J. Biol. Chem. 282: 13791-13803 [Abstract] [Full Text]  
  • Craig, A. L., Chrystal, J. A., Fraser, J. A., Sphyris, N., Lin, Y., Harrison, B. J., Scott, M. T., Dornreiter, I., Hupp, T. R. (2007). The MDM2 Ubiquitination Signal in the DNA-Binding Domain of p53 Forms a Docking Site for Calcium Calmodulin Kinase Superfamily Members. Mol. Cell. Biol. 27: 3542-3555 [Abstract] [Full Text]  
  • Teufel, D. P., Freund, S. M., Bycroft, M., Fersht, A. R. (2007). Four domains of p300 each bind tightly to a sequence spanning both transactivation subdomains of p53. Proc. Natl. Acad. Sci. USA 104: 7009-7014 [Abstract] [Full Text]  
  • Toledo, F., Lee, C. J., Krummel, K. A., Rodewald, L.-W., Liu, C.-W., Wahl, G. M. (2007). Mouse Mutants Reveal that Putative Protein Interaction Sites in the p53 Proline-Rich Domain Are Dispensable for Tumor Suppression. Mol. Cell. Biol. 27: 1425-1432 [Abstract] [Full Text]  
  • Lacroix, M., Toillon, R.-A., Leclercq, G. (2006). p53 and breast cancer, an update.. Endocr Relat Cancer 13: 293-325 [Abstract] [Full Text]  
  • Zhao, Y., Lu, S., Wu, L., Chai, G., Wang, H., Chen, Y., Sun, J., Yu, Y., Zhou, W., Zheng, Q., Wu, M., Otterson, G. A., Zhu, W.-G. (2006). Acetylation of p53 at Lysine 373/382 by the Histone Deacetylase Inhibitor Depsipeptide Induces Expression of p21Waf1/Cip1.. Mol. Cell. Biol. 26: 2782-2790 [Abstract] [Full Text]  
  • Kim, J. H., Yang, C. K., Stallcup, M. R. (2006). Downstream signaling mechanism of the C-terminal activation domain of transcriptional coactivator CoCoA.. Nucleic Acids Res 34: 2736-2750 [Abstract] [Full Text]  
  • Vega, F. M., Sevilla, A., Lazo, P. A. (2004). p53 Stabilization and Accumulation Induced by Human Vaccinia-Related Kinase 1. Mol. Cell. Biol. 24: 10366-10380 [Abstract] [Full Text]  
  • Finlan, L., Hupp, T. R. (2004). The N-terminal Interferon-binding Domain (IBiD) Homology Domain of p300 Binds to Peptides with Homology to the p53 Transactivation Domain. J. Biol. Chem. 279: 49395-49405 [Abstract] [Full Text]  
  • Dornan, D., Eckert, M., Wallace, M., Shimizu, H., Ramsay, E., Hupp, T. R., Ball, K. L. (2004). Interferon Regulatory Factor 1 Binding to p300 Stimulates DNA-Dependent Acetylation of p53. Mol. Cell. Biol. 24: 10083-10098 [Abstract] [Full Text]  
  • Gronroos, E., Terentiev, A. A., Punga, T., Ericsson, J. (2004). YY1 inhibits the activation of the p53 tumor suppressor in response to genotoxic stress. Proc. Natl. Acad. Sci. USA 101: 12165-12170 [Abstract] [Full Text]  
  • Pohler, E., Craig, A. L., Cotton, J., Lawrie, L., Dillon, J. F., Ross, P., Kernohan, N., Hupp, T. R. (2004). The Barrett's Antigen Anterior Gradient-2 Silences the p53 Transcriptional Response to DNA Damage. Mol. Cell. Proteomics 3: 534-547 [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»