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Volume 271, Number 41, Issue of October 11, 1996 pp. 25468-25478
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

Regulation of Mutant p53 Temperature-sensitive DNA Binding

(Received for publication, March 28, 1996, and in revised form, July 9, 1996)

Philip Friedlander , Yann Legros Dagger , Thierry Soussi Dagger and Carol Prives

From the Department of Biological Sciences, Columbia University, New York, New York 10027 and the Dagger  Institut de Genetique Moleculaire, INSERM, 75010 Paris, France

We have examined in detail the DNA binding properties of several immunopurified tumor-derived mutant p53 proteins (Val-143 right-arrow Ala, Arg-175 right-arrow His, Arg-248 right-arrow Trp, Arg-249 right-arrow Ser, and Arg-273 right-arrow His). While all mutants were defective for binding to DNA at 37 °C, each bound specifically to several cognate p53 binding sites at sub-physiological temperatures (25-33 °C), and several mutants activated transcription from a p53-responsive promoter at 26 °C in transfected H1299 cells. Heating mutant p53 proteins at 37 °C irreversibly destroyed their ability to subsequently bind at 25 °C. However, several different monoclonal antibodies that each share the ability to recognize an epitope encompassing amino acids 46-55 markedly stabilized binding by mutant p53 proteins at 37 °C. Both intact antibody and FAb fragments allowed mutant p53 to bind to DNA. By contrast, antibodies that recognize epitopes located elsewhere within p53 stabilized mutant p53 binding significantly less effectively. Our data show that the major hot-spot p53 mutants have the intrinsic ability to bind to DNA and that a unique region within the N terminus of p53 may be critical for rescuing them from loss of binding at physiological temperatures. This suggests the possibility of developing small molecules that can stabilize mutant p53 proteins under physiological conditions.


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