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53, Is a Regulator of NF-Κb Repression by the Glucocorticoid Receptor

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53, Is a Regulator of NF-Κb Repression by the Glucocorticoid Receptor Tumor suppressor protein (p)53, is a regulator of NF-κB repression by the glucocorticoid receptor Samantha H. Murphya,b, Kotaro Suzukia,1, Michael Downesc, Genevieve L. Welchd, Paul De Jesusd,2, Loren J. Miragliad, Anthony P. Orthd, Sumit K. Chandad,2, Ronald M. Evansc, and Inder M. Vermaa,3 aLaboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA 92037; bGraduate Program, Division of Biology, University of California, San Diego, CA 92093; cGene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037; and dGenomics Institute of the Novartis Research Foundation, San Diego, CA 92121 Contributed by Inder M. Verma, September 6, 2011 (sent for review August 8, 2011) Glucocorticoids can inhibit inflammation by abrogating the activ- Dexamethasone (Dex), a synthetic glucocorticoid that activates ity of NF-κB, a family of transcription factors that regulates the GR upon binding, is a commonly prescribed antiinflammatory production of proinflammatory cytokines. To understand the mo- drug used to provide relief from inflammation, infection, and lecular mechanism of repression of NF-κB activity by glucocorti- immune diseases associated with NF-κB up-regulation (16–20). coids, we performed a high-throughput siRNA oligo screen to Although the precise molecular details of how glucocorticoids identify novel genes involved in this process. Here, we report that repress NF-κB activity are not fully elucidated, a number of loss of p53, a tumor suppressor protein, impaired repression of NF- mechanisms have been proposed which include (i) increased ex- κB target gene transcription by glucocorticoids. Additionally, loss pression of IκBα by GR, which increases the sequestration of p65/ of p53 also impaired transcription of glucocorticoid receptor (GR) p50 heterodimers in the cytoplasm and limits NF-κB translocation target genes, whereas upstream NF-κB and glucocorticoid receptor to the nucleus and subsequent activation of its target genes (21, signaling cascades remained intact. We further demonstrate that 22); (ii) GR binding as a monomer to the promoter regions of NF- p53 loss severely impaired glucocorticoid rescue of death in κB target genes, thus inhibiting NF-κB binding and transcriptional a mouse model of LPS shock. Our findings unveil a new role for activation; (iii) GR and NF-κB competition for Creb-binding p53 in the repression of NF-κB by glucocorticoids and suggest im- protein and p300, members of the transcriptional activation ma- portant implications for treatment of the proinflammatory micro- chinery; (iv) GR recruitment of histone deacetylase complexes to environments found in tumors with aberrant p53 activity. the promoter regions of NF-κB target genes; and (v)GRandNF- κB interaction in the nucleus, where GR tethers NF-κB, thereby uclear factor kappa B (NF-κB) is a family of transcription inhibiting transcriptional activation of its target genes (23–27). factors that have an essential regulatory function in in- Some of the proposed mechanisms of repression are likely to be N fi fi flammation, the immune response, cell proliferation, and apo- cell-type speci c or context speci c, and a universal mechanism of ptosis (1). Constitutive activation of the NF-κB pathway is often repression has yet to be clearly established. Discovery of novel genes κ associated with cancer and chronic inflammatory diseases such as involved in NF- B repression by GR, elucidation of their mecha- fl nisms, and identification of universal mechanisms, will be critical for multiple sclerosis, in ammatory bowel disease, rheumatoid ar- κ thritis (RA), and asthma. NF-κB family members include p50 a more comprehensive understanding of how GR inhibits NF- B. To address these issues, we used a RNAi-based screening approach (NF-κB1), p52 (NF-κB2), p65 (RELA), RELB, and c-REL, and to identify novel genes that regulate GR repression of NF-κBand,in these subunits bind to form homo- and heterodimerized com- κ κ follow-up experiments, validate p53 as a novel regulator of NF- B plexes (2, 3). In the classical NF- B signaling pathway, the p65 and repression by GR both in vitro and in vivo. p50 subunits heterodimerize and are sequestered in an inactive complex in the cytoplasm bound to IκBα (2, 4, 5). Upon activation Results fl by proin ammatory stimuli such as tumor necrosis factor-alpha p53 Is Required for Repression of NF-κB Activity. We developed and (TNFα) or lipopolysaccharide (LPS), the IκB kinase (IKK) com- optimized a high-throughput luciferase assay using four siRNA plex phosphorylates IκBα (6), targeting it for ubiquitination and oligo library collections to search for potential genes that play a role proteasomal degradation (7), allowing the p65/50 complex to in NF-κB repression by the glucocorticoid receptor. The number of translocate to the nucleus where p65 can bind to the promoter genes represented and characteristics of two kinase libraries and regions of its target genes. p65 phosphorylation by protein kinase two druggable genome libraries used for screening are summarized A (PKA) or mitogen- and stress-activated protein kinase-1 (MSK- in Table S1. siRNA oligos from each of the libraries were pre- 1) at serine (Ser)276 (8, 9) and also by ζPKC at serine 311 (10) arrayed into 384-well plates and reverse transfected for 48 h into then aids in the recruitment of transcriptional activation machin- 293T cells stably transfected with a NF-κB luciferase reporter (Fig. MEDICAL SCIENCES ery, leading to transcription of NF-κBtargetgenes. 1A). Cells were then treated for 24 h with 10 ng/mL TNF ± 1 μM The glucocorticoid receptor (GR) is a member of the nuclear Dex in duplicate and assayed for luciferase activity (Fig. 1A). hormone receptor superfamily and plays a critical role in meta- The efficacy of the screen was determined by luciferase anal- bolism, development, reproduction, and homeostasis. Intracell- ysis of siGR, sip65, si luciferase, and mock controls added to ular GR resides in the cytoplasm in an inactive state, bound to a low molecular weight protein (p23), immunophilin FKBP51, and a variety of heat shock proteins (hsps), including hsp90, hsp70, Author contributions: S.H.M., K.S., M.D., S.K.C., R.M.E., and I.M.V. designed research; S.H.M., K.S., and G.L.W. performed research; P.D.J., L.J.M., A.P.O., and S.K.C. contributed new hsp56, and hsp40 (11, 12). Upon passive diffusion and subse- reagents/analytic tools; S.H.M., K.S., and L.J.M. analyzed data; and S.H.M., M.D., R.M.E., quent binding by glucocorticoids, GR can dissociate from its and I.M.V. wrote the paper. inhibitory complex and translocate to the nucleus via active The authors declare no conflict of interest. transport by dynein (13). In the nucleus, GR homodimers bind to 1Present address: Chiba University Graduate School of Medicine, Chiba 260-8670, Japan. glucocorticoid response elements (GREs) in the promoter re- 2Present address: Sanford-Burnham Medical Research Institute, La Jolla, CA 92037. gions of GR target genes to activate their transcription. GR can 3To whom correspondence should be addressed. E-mail: [email protected]. also bind as a monomer to negative (n)GREs in promoter This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. regions of genes to inhibit their transcription (14, 15). 1073/pnas.1114420108/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1114420108 PNAS | October 11, 2011 | vol. 108 | no. 41 | 17117–17122 Downloaded by guest on October 1, 2021 3x-NF B-Luc homeostasis, developmental, and metabolic processes, as well as A TNF + puromycin Luciferase Assay apoptotic, cell cycle, and kinase activity categories were among the selection 384 well plates list of overrepresented pathways (Fig. S3A). KEGG pathway analysis showed enrichment for 29 pathways with P values <0.05, TNF + Dex including MAPK signaling (a pathway with known p53 and GR 293T Cells 293T-NF B-Luc cells pre-coated with interactions), apoptosis, cell cycle, and 13 cancer-related pathways siRNA oligos Lipofectamine 2000 (Fig. 1B). We also performed Reactome analysis to determine Timeline: 48hr Transfection 24hr Treatment which pathways were overrepresented in our list of 290 genes and 72 hours Day 1 Day 3 Day 4 to confirm results from KEGG pathway analysis. A total of 181 genes, of the 290 analyzed, were not represented in the database, Cell cycle 14 Invitrogen Kinase Library suggesting that a number of uncharacterized and/or unstudied B Apoptosis C Renal cell carcinoma 12 genes may play a role in GR repression of NF-κB. Reactome Acute myeloid leukemia 10 < Pathways in cancer 88 analysis revealed that 109 events with P values 0.05 were over- Colorectal cancer 66 Pancreatic cancer represented, including a number of events related to metabolism Melanoma 44 κ Glioma 22 and MAPK signaling, as well as NF- B related signaling events of TNF Condition Thyroid cancer 00 (Fig. S3B), confirming results obtained by KEGG pathway analysis Chronic myeloid leukemia 14121086420 Avg. Normalized Raw Value Avg. 0246810 Prostate cancer Avg. Normalized Raw Value (Fig. 1B). Through the STRING database, we analyzed protein– Bladder cancer of TNF + Dex Condition Non-small cell lung cancer protein interactions for genes overrepresented in the MAPK and Endometrial cancer MAPK signaling cancer pathways by KEGG analysis (Fig. S4). We included GR in 01234567 each STRING analysis to map known interactions with GR and -log P-value the genes of interest shown in each pathway. p53, shown in red, was found in both the MAPK signaling pathway (Fig. S4, Upper) and ** 293Ts ** the cancer pathways (Fig. S4, Lower). D 4040 3535 Untreated Sixteen wells containing a siRNA oligo targeting p53 were 3030 TNF included as a control in the Invitrogen kinase library collection. Fold Change 1 2525 TNF + Dex When siRNAs were rank ordered according to fold change be- 2020 1515 tween the TNF and TNF + Dex conditions, 14 of the 16 wells Fold Change 10 Fold Change 1010 were near or at the top of the list.
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