C-terminal diversity within the p53 family accounts for differences in DNA binding and transcriptional activity

被引:50
作者
Sauer, Markus [1 ,3 ]
Bretz, Anne Catherine [1 ,3 ]
Beinoraviciute-Kellner, Rasa [3 ]
Beitzinger, Michaela [3 ]
Burek, Christof [2 ]
Rosenwald, Andreas [2 ]
Harms, Gregory S. [3 ]
Stiewe, Thorsten [1 ,3 ]
机构
[1] Univ Marburg, Dept Hematol Oncol & Immunol, Inst Mol Biol & Tumor Res, D-35033 Marburg, Germany
[2] Univ Wurzburg, Dept Pathol, D-97078 Wurzburg, Germany
[3] Univ Wurzburg, DFG Ctr Expt Biomed, Rudolf Virchow Ctr, D-97078 Wurzburg, Germany
关键词
D O I
10.1093/nar/gkn044
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 proteinDNA 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 proteinDNA 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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页码:1900 / 1912
页数:13
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