p53 cooperates with MAP kinase and NFkB signal transduction pathways to potentiate human immune/inflammatory response

Wednesday, October 10, 2012 — Poster Session II
Noon – 2:00 p.m	Natcher Conference Center, Building 45	NIEHS	SIG-5

* FARE Award Winner

Authors

• M. Shatz
• D. Menendez
• M. A. Resnick

Abstract

The p53 tumor suppressor regulates transcription of genes associated with cellular functions including apoptosis, growth arrest, DNA repair, differentiation and glycolysis. Recently, we extended this list to include Toll-like receptor (TLR) human innate immunity genes. TLRs recognize chemically distinct pathogen-associated molecular patterns. Upon stimulation, TLRs lead to activation of NFκB, interferon responsive factors and MAP-kinases resulting in distinct patterns of gene expression essential to immune/inflammatory responses. MCF7 cells with wild type levels of p53 or MCF7 cells stably-transfected with p53 shRNA were treated to induce p53 and subsequent induction of TLR receptors and then exposed to TLR5 ligand flagellin. Gene expression analysis revealed over 200 genes that were synergistically increased by a combination of flagellin and p53 induction. Genes associated with Gene Ontology terms such as immune, defense and inflammatory response and have NFkB binding sites in their promoters were significantly (p-value <0.0001) over represented. The p53-dependent increase in transcriptional response to flagellin was accompanied by enhanced phosphorylation of p38 MAP kinase and was partially reversed by p38 inhibitor SB203580. Additionally, Nutlin-3 increased cytokine expression in response to TNFalpha that similarly utilize MAP kinase and NFkB pathways demonstrating that p53 broadly interacts with these signaling pathways to promote immune/inflammatory response.

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