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Proc Natl Acad Sci U S A. 2011 Oct 11;108(41):17117-22. doi: 10.1073/pnas.1114420108. Epub 2011 Sep 26.

Tumor suppressor protein (p)53, is a regulator of NF-kappaB repression by the glucocorticoid receptor.

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  • 1Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA 92037, USA

Abstract

Glucocorticoids can inhibit inflammation by abrogating the activity of NF-κB, a family of transcription factors that regulates the production of proinflammatory cytokines. To understand the molecular mechanism of repression of NF-κB activity by glucocorticoids, we performed a high-throughput siRNA oligo screen to identify novel genes involved in this process. Here, we report that loss of p53, a tumor suppressor protein, impaired repression of NF-κB target gene transcription by glucocorticoids. Additionally, loss of p53 also impaired transcription of glucocorticoid receptor (GR) target genes, whereas upstream NF-κB and glucocorticoid receptor signaling cascades remained intact. We further demonstrate that p53 loss severely impaired glucocorticoid rescue of death in a mouse model of LPS shock. Our findings unveil a new role for p53 in the repression of NF-κB by glucocorticoids and suggest important implications for treatment of the proinflammatory microenvironments found in tumors with aberrant p53 activity.

PMID:
21949408
[PubMed - indexed for MEDLINE]
PMCID:
PMC3193198
Free PMC Article
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