Inhibition of Stress-Inducible Kinase Pathways by Tumorigenic Mutant p53

Abstract

More than 50% of human cancers contain p53 gene mutations and as a result accumulate altered forms of the full-length p53 protein. Although certain tumor types expressing mutant p53 protein have a poor prognostic process, the precise role of mutant p53 protein in highly malignant tumor cells is not well defined. Some p53 mutants, but not wild-type p53, are shown here to interact with Daxx, a Fas-binding protein that activates stress-inducible kinase pathways. Interaction of Daxx with p53 is highly dependent upon the specific mutation of p53. Tumorigenic mutants of p53 bind to Daxx and inhibit Daxx-dependent activation of the apoptosis signal-regulating kinase 1 stress-inducible kinases and Jun NH₂-terminal kinase. Mutant p53 forms complexes with Daxx in cells, and consequently, mutant p53 is able to rescue cells from Daxx-dependent inhibition of proliferation. Thus, the accumulation of mutant p53 in tumor cells may contribute to tumorigenesis by inhibiting stress-inducible kinase pathways.

ACKNOWLEDGMENTS

We thank R. Davis, H. Ichijo, A. J. Levine, H. Saito, and L. Zon for the plasmids used in the experiments. We also thank T. Hupp, M. Romanowski, R. Higashikubo, and T. Pandita for helpful comments and critical reading of the manuscript.

This work was partly supported by grants from the American Cancer Society (RPG0029201 to N.H.), American Heart Association (9930031 to A.U.), and National Institutes of Health (HL62458 to A.U. and CA75556 to N.H.).