Selenomethionine regulation of p53 by a ref1-dependent redox mechanism
- *Department of Microbiology, Walther Oncology Center, and Walther Cancer Institute, and †Herman B. Wells Center for Pediatric Research, Section of Pediatric Hematology/Oncology, Department of Biochemistry and Molecular Biology, Indiana University Cancer Center and Indiana University School of Medicine, Indianapolis, IN 46208
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Edited by Philip C. Hanawalt, Stanford University, Stanford, CA, and approved August 16, 2002 (received for review May 28, 2002)
Abstract
The cancer chemopreventive properties of selenium compounds are well documented, yet little is known of the mechanism(s) by which these agents inhibit carcinogenesis. We show that selenium in the form of selenomethionine (SeMet) can activate the p53 tumor suppressor protein by a redox mechanism that requires the redox factor Ref1. Assays to measure direct reduction/oxidation of p53 showed a SeMet-dependent response that was blocked by a dominant–negative Ref1. By using a peptide containing only p53 cysteine residues 275 and 277, we demonstrate the importance of these residues in the SeMet-induced response. SeMet induced sequence-specific DNA binding and transactivation by p53. Finally, cellular responses to SeMet were determined in mouse embryo fibroblasts wild-type or null for p53 genes. The evidence suggests that the DNA repair branch of the p53 pathway was activated. The central relevance of DNA repair to cancer prevention is discussed.
Footnotes
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↵ ‡ To whom correspondence should be addressed at: Indiana University Cancer Center, 1044 West Walnut, Room 155, Indianapolis, IN 46202. E-mail: marlsmit{at}iupui.edu.
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This paper was submitted directly (Track II) to the PNAS office.
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See commentary on page 13969.
- Abbreviations:
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SeMet, selenomethionine
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Ref1, bifunctional protein encoding redox factor-1
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MEF, mouse embryo fibroblasts
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PDTC, pyrrolidine dithiocarbamate
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Ref-DN, dominant–negative mutant redox-factor-1
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CMV, cytomegalovirus
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NEM, N-ethylmaleimide
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MPB, 3-(maleimido-propioryl)-biocytin
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CAT, chloramphenicol acetyltransferase
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HCR, host-cell reactivation
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PDTC, pyrrolidine dithiocarbamate
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NER, nucleotide excision repair
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GGR, global genomic repair
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AP, alkaline phosphatase
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- Copyright © 2002, The National Academy of Sciences
