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Epidermal Growth Factor Receptor (EGFR) and Nuclear Factor kappa B (NF- κ B) both play key roles in promoting tumorigenesis in a variety of cancers but their connection is not yet well understood. We have used Western assays, transcription analysis of known NF- κ B target genes, and chromatin immunopreciptiation (ChIP) assays to show that EGF activates NF- κ B-dependent signaling robustly, through I kappa B (I κ B) and I κ B kinase (IKK) phosphorylation. We then studied how NF- κ B-dependent transcription is regulated differentially by EGFR, compared to the Interleukin-1 receptor (IL-1R), a classical NF- κ B activator. Our preliminary global analysis of NF- κ B promoter enrichment of EGF- and IL-1-activated genes leads us to propose that EGF induces distinct NF- κ B targets that are not induced by IL-1. We are currently testing this hypothesis by global ChIP-seq and RNA-seq analyses, to identify target genes that are differentially activated by the two signals and have identified a novel set of NF- κ B-dependent genes that are induced by EGF but not by IL-1. We will investigate the underlying mechanisms of differential NF- κ B gene regulation by analyzing post-translational modifications of NF- κ B and induction of specific transcriptional co-regulators that are activated differentially by the two signals. We expect that this work will lead to a better understanding of how EGF-dependent pathways contribute to NF- κ B-dependent gene expression in normal and cancer cells, and we hope that it leads to improved treatment of EGFR-driven cancers, in which NF- κ B is known to play a key role in mediating resistance to therapy.