Oncotarget

Research Papers:

Ligand dependent restoration of human TLR3 signaling and death in p53 mutant cells

Daniel Menendez _, Julie M. Lowe, Joyce Snipe and Michael A. Resnick

PDF  |  HTML  |  Supplementary Files  |  How to cite

Oncotarget. 2016; 7:61630-61642. https://doi.org/10.18632/oncotarget.11210

Metrics: PDF 2273 views  |   HTML 3075 views  |   ?  


Abstract

Daniel Menendez1, Julie M. Lowe1,2, Joyce Snipe1, Michael A. Resnick1

1Genome Integrity & Structural Biology Laboratory, Inflammation Disease Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA

2Immunity, Inflammation Disease Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA

Correspondence to:

Daniel Menendez, email: [email protected]

Michael A. Resnick, email: [email protected]

Keywords: apoptosis, poly (I:C), innate immunity, mutant p53, cancer therapy

Received: May 30, 2016    Accepted: July 19, 2016    Published: August 11, 2016

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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.
PII: 11210