Summary The p53 gene is mutated in many human tumors. Cells of such tumors often contain abundant mutant p53 (mutp53) protein, which may contribute actively to tumor progression via a gain of function (GOF) mechanism. We applied ChIP-on-chip analysis and identified the VDR (vitamin D receptor) response element as over-represented in promoter sequences bound by mutp53. We report that mutp53 can interact functionally and physically with VDR. Mutp53 is recruited to VDR-regulated genes and modulates their expression, augmenting the transactivation of some genes and relieving the repression of others. Furthermore, mutp53 increases the nuclear accumulation of VDR. Importantly, mutp53 converts vitamin D into an antiapoptotic agent. Thus, p53 status can determine the biological impact of vitamin D on tumor cells.

Mutations in the p53 tumor suppressor are very frequent in human cancer. Often, such mutations lead to the constitutive overproduction of mutant p53 proteins, which may exert a cancer-promoting gain of function. We now report that cancer-associated mutant p53 can augment the induction of nuclear factor KB (NFKB) transcriptional activity in response to the cytokine tumor necrosis factor A (TNFA). Conversely, down-regulation of endogenous mutant p53 sensitizes cancer cells to the apoptotic effects of TNFA. Analysis of human head and neck tumors and lung tumors reveals a close correlation between the presence of abundant mutant p53 proteins and the constitutive activation of NFKB. Together, these findings suggest that p53 mutations may promote cancer progression by augmenting NFKB activation in the context of chronic inflammation. [Cancer Res 2007;67(6):2396-401]

Mutant p53 proteins are thought to have acquired a "gain of function" (GOF) activity that mainly contributes to tumor aggressiveness. Previously we reported that constitutive downregulation of mutant p53 by RNA interference reduces the tumorigenicity of cancer cells in an animal model; however, effects of adaptation to long-term mutant p53 inhibition could not be excluded. To address this point, mimicking more physiological conditions, we now describe the establishment of a lentiviral-based system for conditional interference with mutant p53 expression. In vivo studies assessed the efficacy of conditional RNA interference in inhibiting gain of function activity of mutant p53 proteins by reducing tumor growth ability. Moreover by using this system, microarray data were validated in vitro and in vivo and putative mutant p53 target genes that may contribute to its gain of function effects in cancer were identified. Results are confirmatory that depletion of mutant p53 protein impacts on tumor malignancy and validated the inducible lentiviral-based system as an efficient tool to study the gain of function activity of human tumor derived p53 mutants.

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Supplementary Figures 1-7 from Mutant p53 Enhances Nuclear Factor κB Activation by Tumor Necrosis Factor α in Cancer Cells