title: Tumor suppressor protein (p)53, is a regulator of NF-kappaB repression by the glucocorticoid receptor.
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.
authors.affiliation: Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
authors.forename: Samantha H
authors.initials: SH
authors.lastname: Murphy
authors.forename: Kotaro
authors.initials: K
authors.lastname: Suzuki
authors.forename: Michael
authors.initials: M
authors.lastname: Downes
authors.forename: Genevieve L
authors.initials: GL
authors.lastname: Welch
authors.forename: Paul
authors.initials: P
authors.lastname: De Jesus
authors.forename: Loren J
authors.initials: LJ
authors.lastname: Miraglia
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Orth
authors.forename: Sumit K
authors.initials: SK
authors.lastname: Chanda
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Evans
authors.forename: Inder M
authors.initials: IM
authors.lastname: Verma
mesh_terms: D000818:Animals; D003907:Dexamethasone / Q000494:pharmacology; D057166:High-Throughput Screening Assays; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D060066:Protein Interaction Maps; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D012772:Shock, Septic / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; D016328:NF-kappa B; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011965:Receptors, Glucocorticoid; D016159:Tumor Suppressor Protein p53; D003907:Dexamethasone