Nucleic Acids Research Advance Access published online on February 11, 2008
Nucleic Acids Research, doi:10.1093/nar/gkn044
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Molecular Biology |
C-terminal diversity within the p53 family accounts for differences in DNA binding and transcriptional activity
1Department of Hematology, Oncology and Immunology, Institute for Molecular Biology and Tumor Research, Philipps-University Marburg, 35033 Marburg, Germany, 2Rudolf-Virchow-Center (DFG Research Center for Experimental Biomedicine) and 3Department of Pathology, University of Würzburg, 97078 Würzburg, Germany
*To whom correspondence should be addressed. Tel: +49 6421 2826280; Fax: +49 6421 2824292; Email: thorsten.stiewe{at}staff.uni-marburg.de
Received December 18, 2007. Revised January 22, 2008. Accepted January 23, 2008.
The p53 family is known as a family of transcription factors with functions in tumor suppression and development. Whereas the central DNA-binding domain is highly conserved among the three family members p53, p63 and p73, the C-terminal domains (CTDs) are diverse and subject to alternative splicing and post-translational modification. Here we demonstrate that the CTDs strongly influence DNA binding and transcriptional activity: while p53 and the p73 isoform p73
have basic CTDs and form weak sequence-specific protein–DNA complexes, the major p73 isoforms have neutral CTDs and bind DNA strongly. A basic CTD has been previously shown to enable sliding along the DNA backbone and to facilitate the search for binding sites in the complex genome. Our experiments, however, reveal that a basic CTD also reduces protein–DNA complex stability, intranuclear mobility, promoter occupancy in vivo, target gene activation and induction of cell cycle arrest or apoptosis. A basic CTD therefore provides both positive and negative regulatory functions presumably to enable rapid switching of protein activity in response to stress. The different DNA-binding characteristics of the p53 family members could therefore reflect their predominant role in the cellular stress response (p53) or developmental processes (p73).
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