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Equal Transcription of Wild-Type and Mutant p53 Using Bicistronic Vectors Results in the Wild-Type Phenotype¹

Division of Molecular Genetics, Massachusetts General Hospital Cancer Center, MGH East, Charlestown, Massachusetts 02129 [T. F., Y-S. N., J. K., S. H. F.]; Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142 [M. S.]; Department of Pediatrics, Division of Hematology-Oncology, The Children's Hospital, Dana-Farber Institute, Harvard Medical School, Boston, Massachusetts 02114 [S. H. F.]

³ To whom requests for reprints should be addressed.

Somatic and germ-line mutations of p53 alleles inactivate the function of the protein. It has been suggested that mutant p53 can inactivate the wild-type protein and therefore have a trans-dominant negative effect. To investigate the interaction between wild-type and mutant proteins when both alleles are equally transcribed, we designed bicistronic vectors containing the internal ribosome entry site of the encephalomyocarditis virus and expressing wild-type and mutant p53. Analysis of the transcriptional activity and of the effect on cell growth of these plasmids indicates that the mutant protein is unable to completely suppress wild-type function. These results could explain why the inactivation of both p53 alleles is required in cancer development.

¹ This work was supported in part by the Robert Steel Foundation, the John T. Merk Fund, and the Lucille P. Markey Foundation.

² Present address: Unité de Génétique Moléculaire, CHU de Rouen, 1 rue de Germont, 76000 Rouen, France.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 9/23/93. Accepted 1/ 5/94.

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