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Mol Cell Biol, July 1998, p. 3735-3743, Vol. 18, No. 7
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Activation of c-myc Gene Expression by Tumor-Derived p53 Mutants Requires a Discrete C-Terminal Domain

Mark W. Frazier,1 dagger Xiaoping He,1 JinLing Wang,1 Zhengming Gu,1 John L. Cleveland,1 2 and Gerard P. Zambetti1 *

Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, Tennessee 38105,1 and Department of Biochemistry, University of Tennessee, Memphis, Tennessee 381632

Received 19 August 1997/Returned for modification 28 September 1997/Accepted 27 March 1998

Mutation of the p53 tumor suppressor gene is the most common genetic alteration in human cancer, and tumors that express mutant p53 may be more aggressive and have a worse prognosis than p53-null cancers. Mutant p53 enhances tumorigenicity in the absence of a transdominant negative mechanism, and this tumor-promoting activity correlates with its ability to transactivate reporter genes in transient transfection assays. However, the mechanism by which mutant p53 functions in transactivation and its endogenous cellular targets that promote tumorigenicity are unknown. Here we report that (i) mutant p53 can regulate the expression of the endogenous c-myc gene and is a potent activator of the c-myc promoter; (ii) the region of mutant p53 responsiveness in the c-myc gene has been mapped to the 3' end of exon 1; (iii) the mutant p53 response region is position and orientation dependent and therefore does not function as an enhancer; and (iv) transactivation by mutant p53 requires the C terminus, which is not essential for wild-type p53 transactivation. These data suggest that it may be possible to selectively inhibit mutant p53 gain of function and consequently reduce the tumorigenic potential of cancer cells. A possible mechanism for transactivation of the c-myc gene by mutant p53 is proposed.

* Corresponding author. Mailing address: Department of Biochemistry, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105-2794. Phone: (901) 495-3429. Fax: (901) 525-8025. E-mail: gerard.zambetti{at}stjude.org.

dagger Present address: Department of Clinical Chemistry, St. Jude Children's Research Hospital, Memphis, TN 38105.

Mol Cell Biol, July 1998, p. 3735-3743, Vol. 18, No. 7
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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