HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 48, 50566-50579, November 26, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/48/50566    most recent M406743200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zhao, L. Y. Articles by Liao, D. Search for Related Content PubMed PubMed Citation Articles by Zhao, L. Y. Articles by Liao, D. Social Bookmarking                      What's this?

Negative Regulation of p53 Functions by Daxx and the Involvement of MDM2^*

Lisa Y. Zhao, Jilin Liu, Gurjit S. Sidhu, Yuxin Niu, Yue Liu¶, Ruipeng Wang, and Daiqing Liao||**

From the Department of Anatomy and Cell Biology, and ^||Shands Cancer Center, University of Florida College of Medicine, Gainesville, Florida 32610-0235 and the Department of Microbiology and Infectious Diseases, Faculty of Medicine, Université de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada

In normal cells p53 activity is tightly controlled and MDM2 is a known negative regulator. Here we show that via its acidic domain, Daxx binds to the COOH-terminal domain of p53, whose positive charges are critical for this interaction, as Lys to Arg mutations preserved, but Lys to Ala or Ser to Glu mutations abolished Daxx-p53 interaction. These results thus implicate acetylation and phosphorylation of p53 in regulating its binding to Daxx. Interestingly, whereas Daxx did not bind to p53 in cells as assessed by immunoprecipitation, MDM2 expression restored p53-Daxx interaction, and this correlated with deacetylation of p53. In p53/MDM2-null mouse embryonic fibroblasts (DKO MEF), Daxx repressed p53 target promoters whose p53-binding elements were required for the repression. Coexpression of Daxx and MDM2 led to further repression. p53 expression in DKO MEF induced apoptosis and Daxx expression relieved this effect. Similarly, in HCT116 cells, Daxx conferred striking resistance to 5-fluorouracil-induced apoptosis. As p53 is required for 5-fluorouracil-induced cell death, our data show that Daxx can suppress cell death induced by p53 overexpression and p53-dependent stress response. Collectively, our data reveal Daxx as a novel negative regulator of p53. Importantly, posttranslational modifications of p53 inhibit Daxx-p53 interaction, thereby relieving negative regulation of p53 by Daxx.

Received for publication, June 16, 2004 , and in revised form, September 7, 2004.

^* This work was supported by National Institutes of Health Grant RO1 CA92236) (to D. L.), Canadian Institutes for Health Research Grants MOP-14109 and MOP-42429, a Career Investigator Award from American Lung Association Florida Inc., and the Howard Hughes Medical Institute Biomedical Research Support Program for Medical Schools to the University of Florida College of Medicine. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Current address: Molecular Biology Institute, University of California, 611 Charles Young Dr. East, Los Angeles, CA 90095.

^** To whom correspondence should be addressed: Dept. of Anatomy and Cell Biology, University of Florida College of Medicine, 1600 SW Archer Rd., Gainesville, FL 32610-0235. Tel.: 352-294-7976; Fax: 352-392-3305; E-mail: dliao{at}ufl.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				L. Bodai, N. Pardi, Z. Ujfaludi, O. Bereczki, O. Komonyi, E. Balint, and I. M. Boros Daxx-like Protein of Drosophila Interacts with Dmp53 and Affects Longevity and Ark mRNA Level J. Biol. Chem., December 14, 2007; 282(50): 36386 - 36393. [Abstract] [Full Text] [PDF]

				P. Fisher, C. Hedeler, K. Wolstencroft, H. Hulme, H. Noyes, S. Kemp, R. Stevens, and A. Brass A systematic strategy for large-scale analysis of genotype phenotype correlations: identification of candidate genes involved in African trypanosomiasis Nucleic Acids Res., August 20, 2007; (2007) gkm623v1. [Abstract] [Full Text] [PDF]

				L. Y. Zhao, A. Santiago, J. Liu, and D. Liao Repression of p53-mediated Transcription by Adenovirus E1B 55-kDa Does Not Require Corepressor mSin3A and Histone Deacetylases J. Biol. Chem., March 9, 2007; 282(10): 7001 - 7010. [Abstract] [Full Text] [PDF]

				L. Y. Zhao, Y. Niu, A. Santiago, J. Liu, S. H. Albert, K. D. Robertson, and D. Liao An EBF3-Mediated Transcriptional Program That Induces Cell Cycle Arrest and Apoptosis Cancer Res., October 1, 2006; 66(19): 9445 - 9452. [Abstract] [Full Text] [PDF]

				V. G. Karur, C. A. Lowell, P. Besmer, V. Agosti, and D. M. Wojchowski Lyn kinase promotes erythroblast expansion and late-stage development Blood, September 1, 2006; 108(5): 1524 - 1532. [Abstract] [Full Text] [PDF]

				J. E. Kwon, M. La, K. H. Oh, Y. M. Oh, G. R. Kim, J. H. Seol, S. H. Baek, T. Chiba, K. Tanaka, O. S. Bang, et al. BTB Domain-containing Speckle-type POZ Protein (SPOP) Serves as an Adaptor of Daxx for Ubiquitination by Cul3-based Ubiquitin Ligase J. Biol. Chem., May 5, 2006; 281(18): 12664 - 12672. [Abstract] [Full Text] [PDF]

				H.-Y. Kuo, C.-C. Chang, J.-C. Jeng, H.-M. Hu, D.-Y. Lin, G. G. Maul, R. P. S. Kwok, and H.-M. Shih SUMO modification negatively modulates the transcriptional activity of CREB-binding protein via the recruitment of Daxx PNAS, November 22, 2005; 102(47): 16973 - 16978. [Abstract] [Full Text] [PDF]