Abstract
Diversity within the p53 transcriptional network can arise from a matrix of changes that include target response element sequences and p53 expression level variations. We previously found that wild type p53 (WT p53) can regulate expression of most innate immune-related Toll-like-receptor genes (TLRs) in human cells, thereby affecting immune responses. Since many tumor-associated p53 mutants exhibit change-of-spectrum transactivation from various p53 targets, we examined the ability of twenty-five p53 mutants to activate endogenous expression of the TLR gene family in p53 null human cancer cell lines following transfection with p53 mutant expression vectors. While many mutants retained the ability to drive TLR expression at WT levels, others exhibited null, limited, or change-of-spectrum transactivation of TLR genes. Using TLR3 signaling as a model, we show that some cancer-associated p53 mutants amplify cytokine, chemokine and apoptotic responses after stimulation by the cognate ligand poly(I:C). Furthermore, restoration of WT p53 activity for loss-of-function p53 mutants by the p53 reactivating drug RITA restored p53 regulation of TLR3 gene expression and enhanced DNA damage-induced apoptosis via TLR3 signaling. Overall, our findings have many implications for understanding the impact of WT and mutant p53 in immunological responses and cancer therapy.
Highlights
The tumor suppressor p53 is a sequence-dependent transcription factor that is critical for several signaling events in response to a variety of stress signals
We previously found that wild type p53 (WT p53) can regulate expression of most innate immune-related Toll-like-receptor genes (TLRs) in human cells, thereby affecting immune responses
Since many tumor-associated p53 mutants exhibit change-of-spectrum transactivation from various p53 targets, we examined the ability of twenty-five p53 mutants to activate endogenous expression of the TLR gene family in p53 null human cancer cell lines following transfection with p53 mutant expression vectors
Summary
The tumor suppressor p53 is a sequence-dependent transcription factor that is critical for several signaling events in response to a variety of stress signals. Among the different mutations that have been associated with cancer, approximately one-third retain transactivation capability [4,5,6,7] Many of these can result in a change-of-spectrum transactivation of various p53 targets, thereby altering subsequent cellular responses such as DNA repair, genome stability and programmed cell death that facilitates tumorigenesis [4, 6, 8]. TLRs orchestrate downstream signaling pathways involving adaptor proteins, protein kinases and effector transcription factors that induce expression of pro-inflammatory mediators including cytokines, chemokines and interferons [19, 20]. We demonstrate that the functional recovery of p53 activity with the reactivating drug RITA can restore p53 responsiveness of TLR3 gene expression including enhanced DNA damage-induced apoptosis via TLR3 poly(I:C) signaling
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