Summary
Concomitant expression of mutant p53 and oncogenic Ras, leading to cellular transformation, is well documented. However, the mechanisms by which the various mutant p53 categories cooperate with Ras remain largely obscure. From this study we suggest that different mutant p53 categories cooperate with H-Ras in different ways to induce a unique expression pattern of a cancer-related gene signature (CGS). The DNA-contact p53 mutants (p53R248Q and p53R273H) exhibited the highest level of CGS expression by cooperating with NFκB. Furthermore, the Zn+2 region conformational p53 mutants (p53R175H and p53H179R) induced the CGS by elevating H-Ras activity. This elevation in H-Ras activity stemmed from a perturbed function of the p53 transcription target gene, BTG2. By contrast, the L3 loop region conformational mutant (p53G245S) did not affect CGS expression. Our findings were further corroborated in human tumor-derived cell lines expressing Ras and the aforementioned mutated p53 proteins. These data might assist in future tailor-made therapy targeting the mutant p53–Ras axis in cancer.
Footnotes
Funding
This research was supported by a Center of Excellence grant from Flight Attendant Medical Research Institute, Yad Abraham Center for Cancer Diagnosis and Therapy [grant number 7034640901]; and the European Community EC FP7-INFLACARE [number 223151, grant number 7104370402]. This publication reflects the authors' views and not necessarily those of the European Community. The EC is not liable for any use that may be made of the information contained herein. V. R. is the incumbent of the Norman and Helen Asher Professorial Chair Cancer Research at the Weizmann Institute.
Supplementary material available online at http://jcs.biologists.org/lookup/suppl/doi:10.1242/jcs.099663/-/DC1
- Accepted February 13, 2012.
- © 2012. Published by The Company of Biologists Ltd
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