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Molecular and Cellular Biology, January 2003, p. 322-334, Vol. 23, No. 1
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.1.322-334.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Inhibition of Stress-Inducible Kinase Pathways by Tumorigenic Mutant p53

Yoichi Ohiro,1,1 Anny Usheva,1 Shinichiro Kobayashi,2 Shannon L. Duffy,1 Regan Nantz,2 David Gius,3 and Nobuo Horikoshi2*

Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215,1 Department of Radiation Oncology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri 63108,2 Radiation Oncology Sciences Program, Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 208923

Received 19 March 2002/ Returned for modification 24 May 2002/ Accepted 30 September 2002

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.

* Corresponding author. Mailing address: Department of Radiation Oncology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, 4511 Forest Park Blvd., St. Louis, MO 63108. Phone: (314) 362-9787. Fax: (314) 362-9790. E-mail: horikoshi{at}radonc.wustl.edu.

{dagger} Present address: Hokkaido University Graduate School of Dental Medicine, Sapporo 060-8685, Japan.

Molecular and Cellular Biology, January 2003, p. 322-334, Vol. 23, No. 1
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.1.322-334.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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