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Molecular and Cellular Biology, November 2005, p. 10097-10110, Vol. 25, No. 22
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.22.10097-10110.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Tumor-Derived p53 Mutants Induce NF-{kappa}B2 Gene Expression

Mariano J. Scian,1 Katherine E. R. Stagliano,1 Michelle A. E. Anderson,1 Sajida Hassan,2 Melissa Bowman,2 Mike F. Miles,2 Swati Palit Deb,1 and Sumitra Deb1*

Department of Biochemistry and Massey Cancer Center,1 Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia 232982

Received 16 November 2004/ Returned for modification 20 December 2004/ Accepted 8 August 2005

Overexpression of mutant p53 is a common theme in tumors, suggesting a selective pressure for p53 mutation in cancer development and progression. To determine how mutant p53 expression may lead to survival advantage in human cancer cells, we generated stable cell lines expressing p53 mutants p53-R175H, -R273H, and -D281G by use of p53-null human H1299 (lung carcinoma) cells. Compared to vector-transfected cells, H1299 cells expressing mutant p53 showed a survival advantage when treated with etoposide, a common chemotherapeutic agent; however, cells expressing the transactivation-deficient triple mutant p53-D281G (L22Q/W23S) had significantly lower resistance to etoposide. Gene expression profiling of cells expressing transcriptionally active mutant p53 proteins revealed the striking pattern that all three p53 mutants induced expression of approximately 100 genes involved in cell growth, survival, and adhesion. The gene NF-{kappa}B2 is a prominent member of this group, whose overexpression in H1299 cells also leads to chemoresistance. Treatment of H1299 cells expressing p53-R175H with small interfering RNA specific for NF-{kappa}B2 made these cells more sensitive to etoposide. We have also observed activation of the NF-{kappa}B2 pathway in mutant p53-expressing cells. Thus, one possible pathway through which mutants of p53 may induce loss of drug sensitivity is via the NF-{kappa}B2 pathway.

* Corresponding author. Mailing address: Virginia Commonwealth University, Department of Biochemistry, P.O. Box 980614, Richmond, VA 23298. Phone: (804) 827-1375. Fax: (804) 827-1427. E-mail: sdeb{at}hsc.vcu.edu.

Molecular and Cellular Biology, November 2005, p. 10097-10110, Vol. 25, No. 22
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.22.10097-10110.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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