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Transcriptional Regulation

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

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Pages 3735-3743 | Received 19 Aug 1997, Accepted 27 Mar 1998, Published online: 28 Mar 2023
 

ABSTRACT

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-mycgene 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.

ACKNOWLEDGMENTS

We thank James Ihle and Amy Frazier for critically reading the manuscript and for their helpful suggestions. We thank Moshe Oren (Rehovot, Israel) for kindly providing the p53 miniprotein expression vectors.

This work was supported by NIH/NCI grant CA63230 (G.P.Z.), NIH/NIDDK grant DK44158 (J.L.C.), NIH/NCI Cancer Center Support CORE grant 5 P30 CA21765, and the American Lebanese Syrian Associated Charities of St. Jude Children’s Research Hospital.

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