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Molecular and Cellular Biology, December 2002, p. 8612-8625, Vol. 22, No. 24
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.24.8612-8625.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Differential Transactivation by the p53 Transcription Factor Is Highly Dependent on p53 Level and Promoter Target Sequence

Alberto Inga,1 Francesca Storici,1 Thomas A. Darden,2 and Michael A. Resnick1*

Laboratory of Molecular Genetics,1 Laboratory of Structural Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 277092

Received 24 May 2002/ Returned for modification 14 August 2002/ Accepted 10 September 2002

Little is known about the mechanisms that regulate differential transactivation by p53. We developed a system in the yeast Saccharomyces cerevisiae that addresses p53 transactivation capacity from 26 different p53 response elements (REs) under conditions where all other factors, such as chromatin, are kept constant. The system relies on a tightly regulated promoter (rheostatable) that can provide for a broad range of p53 expression. The p53 transactivation capacity toward each 20- to 22-bp-long RE could be ranked by using a simple phenotypic assay. Surprisingly, there was as much as a 1,000-fold difference in transactivation. There was no correlation between the functional rank and statistical predictions of binding energy of the REs. Instead we found that the central sequence element in an RE greatly affects p53 transactivation capacity, possibly because of DNA structural properties. Our results suggest that intrinsic DNA binding affinity and p53 protein levels are important contributors to p53-induced differential transactivation. These results are also relevant to understanding the regulation by other families of transcription factors that recognize several sequence-related response elements and/or have tightly regulated expression. We found that p53 had weak activity towards half the apoptotic REs. In addition, p53 alleles associated with familial breast cancer, previously classified as wild type, showed subtle differences in transactivation capacity towards several REs.

* Corresponding author. Mailing address: National Institute of Environmental Health Sciences (NIEHS), Mail drop D3-01, TW Alexander Dr., P.O. Box 12233, Research Triangle Park, NC 27709. Phone: (919) 541-4480. Fax: (919) 541-7593. E-mail: Resnick{at}NIEHS.NIH.GOV.

Molecular and Cellular Biology, December 2002, p. 8612-8625, Vol. 22, No. 24
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.24.8612-8625.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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