Journal of Biological Chemistry
Volume 277, Issue 15, 12 April 2002, Pages 12937-12945
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MOLECULAR BASIS OF CELL AND DEVELOPMENTAL BIOLOGY
Biogenesis of p53 Involves Cotranslational Dimerization of Monomers and Posttranslational Dimerization of Dimers: IMPLICATIONS ON THE DOMINANT NEGATIVE EFFECT

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Precisely how mutant p53 exerts a dominant negative effect over wild type p53 has been an enigma. To understand how wild type and mutant p53 form hetero-oligomers, we studied p53 biogenesis in vitro. We show here that p53 dimers are formed cotranslationally (on the polysome), whereas tetramers are formed posttranslationally (by the dimerization of dimers in solution). Coexpression of wild type and mutant p53 therefore results in 50% of the p53 generated being heterotetramers comprised of a single species: wild type dimer/mutant dimer. Using hot spot mutants of p53 and a variety of natural target sites, we show that all wild type/mutant heterotetramers manifest impaired DNA binding activity. This impairment is not due to the mutant dimeric subunit inhibiting association of the complex with DNA but rather due to the lack of significant contribution (positive cooperativity) from the mutant partner. For all heterotetramers, bias in binding is particularly pronounced against those sequences in genes responsible for apoptosis rather than cell growth arrest. These results explain the molecular basis of p53 dominant negative effect and suggest a functional role in the regulation of p53 tetramerization.

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Published, JBC Papers in Press, January 22, 2002, DOI 10.1074/jbc.M108815200

This work was supported by the National Cancer Institute of Canada with funds from the Canadian Cancer Society (to P. W. K. L.). The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of studentships from the National Sciences and Engineering Research Council and Alberta Heritage Foundation for Medical Research.

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Present address: Dept. of Hematology and Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105.