Skip Navigation

This Article
Right arrow Full Text Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (21)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Blagosklonny, M. V.
Right arrow Articles by Fojo, T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Blagosklonny, M. V.
Right arrow Articles by Fojo, T.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Carcinogenesis, Vol. 22, No. 6, 861-867, June 2001
© 2001 Oxford University Press

ACCELERATED PAPER

Inhibition of HIF-1- and wild-type p53-stimulated transcription by codon Arg175 p53 mutants with selective loss of functions

Mikhail V. Blagosklonny,1, Paraskevi Giannakakou, Larisa Y. Romanova,2, Kevin M. Ryan,3, Karen H. Vousden,3 and Tito Fojo

Medicine Branch and
2 Laboratory of Genetics, National Cancer Institute, NIH, Bethesda, MD 20892, USA and
3 ABL Basic Research Program, NCI–FCRDC, Frederick, MD 21702, USA

Overexpression of ectopic mutant p53 represses wild-type p53-stimulated transcription, known as a dominant negative effect. On the other hand, overexpression of wild-type p53 can repress transcription stimulated by several transcription factors, including hypoxia-inducible factor-1 (HIF-1). Using a panel of well-characterized Arg175 p53 mutants we found that only mutants (Tyr175, Trp175, Asp175 and Phe175) which have completely lost their ability to transactivate repress wild-type p53-stimulated Bax, p21 and PG13 promoter constructs. In contrast, Asn175, Gln175, Leu175 and Pro175 mutants which partially retained transactivating functions did not exert dominant negative effects against PG13 and p21 promoter constructs. However, these latter mutants failed to activate Bax and, instead, exerted a dominant negative effect on a Bax-Luc promoter construct. We conclude that a dominant negative effect is promoter selective as a consequence of selective loss of transactivating function. Albeit less potent than wild-type p53, all Arg175 p53 mutants retained partial ability to repress HIF-1-stimulated transcription. We propose that transrepression and the dominant negative effect have similar mechanisms and may involve competition with transcription factors (wild-type p53, HIF-1, etc.) for cofactors such as p300. Thus, a p53(22/23) mutant, which is deficient in p300 binding, did not exert dominant negative effects. Like transrepression, the dominant negative effect required overexpression of mutant p53 and, therefore, is not dominant. In the presence of a wild-type p53 allele, levels of endogenous mutant p53 protein were low in heterozygous cells. Endogenous mutant p53 became overexpressed only after loss of the second p53 allele. Therefore, endogenous mutant p53s are unable to display a dominant negative effect. This explains why loss of the second p53 allele is required to eliminate p53 functions in cancer cells.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 J. Biol. Chem.Home page
L. M. Huff, J.-S. Lee, R. W. Robey, and T. Fojo
Characterization of Gene Rearrangements Leading to Activation of MDR-1
J. Biol. Chem., December 1, 2006; 281(48): 36501 - 36509.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
P. Bryant, Q. Zheng, and K. Pumiglia
Focal Adhesion Kinase Controls Cellular Levels of p27/Kip1 and p21/Cip1 through Skp2-Dependent and -Independent Mechanisms.
Mol. Cell. Biol., June 1, 2006; 26(11): 4201 - 4213.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
B. S. Sayan, A. E. Sayan, R. A. Knight, G. Melino, and G. M. Cohen
p53 Is Cleaved by Caspases Generating Fragments Localizing to Mitochondria
J. Biol. Chem., May 12, 2006; 281(19): 13566 - 13573.
[Abstract] [Full Text] [PDF]

Home page
 J. Virol.Home page
H. Si and E. S. Robertson
Kaposi's Sarcoma-Associated Herpesvirus-Encoded Latency-Associated Nuclear Antigen Induces Chromosomal Instability through Inhibition of p53 Function
J. Virol., January 15, 2006; 80(2): 697 - 709.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
L. Mickley Huff, Z. Wang, A. Iglesias, T. Fojo, and J.-S. Lee
Aberrant Transcription from an Unrelated Promoter Can Result in MDR-1 Expression following Drug Selection In vitro and in Relapsed Lymphoma Samples
Cancer Res., December 15, 2005; 65(24): 11694 - 11703.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
M. V. Blagosklonny, S. Trostel, G. Kayastha, Z. N. Demidenko, L. T. Vassilev, L. Y. Romanova, S. Bates, and T. Fojo
Depletion of Mutant p53 and Cytotoxicity of Histone Deacetylase Inhibitors
Cancer Res., August 15, 2005; 65(16): 7386 - 7392.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
Z. N. Demidenko and M. V. Blagosklonny
Flavopiridol Induces p53 via Initial Inhibition of Mdm2 and p21 and, Independently of p53, Sensitizes Apoptosis-Reluctant Cells to Tumor Necrosis Factor
Cancer Res., May 15, 2004; 64(10): 3653 - 3660.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.