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.

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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]

The tumor suppressor p53 plays a pivotal role in suppressing tumorigenesis by inducing genomic stability, cell cycle arrest or apoptosis. AIF is a mitochondrial protein, which, upon translocation to the nucleus, can participate in apoptosis, primarily in a caspase-independent contexts. We now report that AIF gene expression is subject to positive transcriptional regulation by p53. Interestingly, unlike most known p53 target genes, the AIF gene is regulated by basal levels of p53, and activation of p53 by genotoxic stress does not result in a substantial further increase in AIF expression. The AIF gene harbors a p53 responsive element, which is bound by p53 within cells. p53 drives efficient induction of large-scale DNA fragmentation, a hallmark of AIF activity. Importantly, caspase-independent death is compromised in cells lacking functional p53, in line with the known role of AIF in this process. Thus, in addition to its documented effects on caspase-dependent apoptosis, p53 may also sensitize cells to caspase-independent death through positive regulation of AIF expression. Moreover, in the absence of overt apoptotic signals, the constitutive induction of AIF by p53 may underpin a cytoprotective maintenance role, based on the role of AIF in ensuring proper mitochondrial function.

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