scholarly journals Identification of a distal RXFP1 gene enhancer with differential activity in fibrotic lung fibroblasts involving AP-1

PLoS ONE ◽  
2021 ◽  
Vol 16 (12) ◽  
pp. e0254466
Author(s):  
Ting-Yun Chen ◽  
Xiaoyun Li ◽  
Gillian C. Goobie ◽  
Ching-Hsia Hung ◽  
Tin-Kan Hung ◽  
...  
Keyword(s):  
Complex Formation ◽  
Binding Sites ◽  
Regulatory Region ◽  
Regulatory Elements ◽  
Site Directed Mutagenesis ◽  
Lung Fibroblasts ◽  
Luciferase Reporter ◽  
Distal Enhancer ◽  
Reporter System ◽  
Reduced Activity

Relaxin/insulin-like family peptide receptor 1 (RXFP1) mediates relaxin’s antifibrotic effects and has reduced expression in the lung and skin of patients with fibrotic interstitial lung disease (fILD) including idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc). This may explain the failure of relaxin-based anti-fibrotic treatments in SSc, but the regulatory mechanisms controlling RXFP1 expression remain largely unknown. This study aimed to identify regulatory elements of RXFP1 that may function differentially in fibrotic fibroblasts. We identified and evaluated a distal regulatory region of RXFP1 in lung fibroblasts using a luciferase reporter system. Using serial deletions, an enhancer upregulating pGL3-promoter activity was localized to the distal region between -584 to -242bp from the distal transcription start site (TSS). This enhancer exhibited reduced activity in IPF and SSc lung fibroblasts. Bioinformatic analysis identified two clusters of activator protein 1 (AP-1) transcription factor binding sites within the enhancer. Site-directed mutagenesis of the binding sites confirmed that only one cluster reduced activity (-358 to -353 relative to distal TSS). Co-expression of FOS in lung fibroblasts further increased enhancer activity. In vitro complex formation with a labeled probe spanning the functional AP-1 site using nuclear proteins isolated from lung fibroblasts confirmed a specific DNA/protein complex formation. Application of antibodies against JUN and FOS resulted in the complex alteration, while antibodies to JUNB and FOSL1 did not. Analysis of AP-1 binding in 5 pairs of control and IPF lung fibroblasts detected positive binding more frequently in control fibroblasts. Expression of JUN and FOS was reduced and correlated positively with RXFP1 expression in IPF lungs. In conclusion, we identified a distal enhancer of RXFP1 with differential activity in fibrotic lung fibroblasts involving AP-1 transcription factors. Our study provides insight into RXFP1 downregulation in fILD and may support efforts to reevaluate relaxin-based therapeutics alongside upregulation of RXFP1 transcription.

scholarly journals Identification of a distal RXFP1 gene enhancer with differential activity in fibrotic lung fibroblasts involving AP-1

2021 ◽  
Author(s):  
Ting-Yun Chen ◽  
Xiaoyun Li ◽  
Gillian C Goobie ◽  
Ching-Hsia Hung ◽  
Hyle hamilton ◽  
...  
Keyword(s):  
Complex Formation ◽  
Binding Sites ◽  
Regulatory Region ◽  
Regulatory Elements ◽  
Site Directed Mutagenesis ◽  
Lung Fibroblasts ◽  
Luciferase Reporter ◽  
Distal Enhancer ◽  
Reporter System ◽  
Reduced Activity

Relaxin/insulin-like family peptide receptor 1 (RXFP1) mediates relaxin’s antifibrotic effects and has reduced expression in the lung and skin of patients with fibrotic interstitial lung disease (fILD) including idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc). This may explain the failure of relaxin-based anti-fibrotic treatments in SSc, but the regulatory mechanisms controlling RXFP1 expression remain largely unknown. This study aimed to identify regulatory elements of RXFP1 that may function differentially in fibrotic fibroblasts. We identified and evaluated a distal regulatory region of RXFP1 in lung fibroblasts using a luciferase reporter system. Using serial deletions, an enhancer upregulating pGL3-promoter activity was localized to the distal region between -584 to -242bp from the distal transcription start site (TSS). This enhancer exhibited reduced activity in IPF and SSc lung fibroblasts. Bioinformatic analysis identified two clusters of activator protein 1 (AP-1) transcription factor binding sites within the enhancer. Site-directed mutagenesis of the binding sites confirmed that only one cluster reduced activity (-358 to -353 relative to distal TSS). Co-expression of FOS in lung fibroblasts further increased enhancer activity. In vitro complex formation with a labeled probe spanning the functional AP-1 site using nuclear proteins isolated from lung fibroblasts confirmed a specific DNA/protein complex formation. Application of antibodies against JUN and FOS resulted in the complex alteration, while antibodies to JUNB and FOSL1 did not. Analysis of AP-1 binding in 5 pairs of control and IPF lung fibroblasts detected positive binding more frequently in control fibroblasts. Expression of JUN and FOS was reduced and correlated positively with RXFP1 expression in IPF lungs. In conclusion, we identified a distal enhancer of RXFP1 with differential activity in fibrotic lung fibroblasts involving AP-1 transcription factors. Our study provides insight into RXFP1 downregulation in fILD and may support efforts to reevaluate relaxin-based therapeutics alongside upregulation of RXFP1 transcription.

scholarly journals A Retroviral Promoter and a Cellular Enhancer Define a Bipartite Element Which Controls env ERVWE1 Placental Expression

2004 ◽  
Vol 78 (22) ◽  
pp. 12157-12168 ◽  
Author(s):  
Sarah Prudhomme ◽  
Guy Oriol ◽  
François Mallet
Keyword(s):  
Binding Sites ◽  
Regulatory Element ◽  
Regulatory Region ◽  
Cell Types ◽  
Regulatory Elements ◽  
Site Directed Mutagenesis ◽  
Basic Activity ◽  
Flanking Sequences ◽  
High Level ◽  
Functional Analyses

ABSTRACT The HERV-W family contains hundreds of loci diversely expressed in several physiological and pathological contexts. A unique locus termed ERVWE1 encodes an envelope glycoprotein (syncytin) involved in hominoid placental physiology. Here we show that syncytin expression is regulated by a bipartite element consisting of a cyclic AMP (cAMP)-inducible long terminal repeat (LTR) retroviral promoter adjacent to a cellular enhancer conferring a high level of expression and placental tropism. Deletion mutant analysis showed that the ERVWE1 5′ LTR contains binding sites essential for basal placental activity in the region from positions +1 to +125. The region from positions +125 to +310 represents a cAMP-responsive core HERV-W promoter active in all cell types. Site-directed mutagenesis analysis highlighted the complexity of U3 regulation. ERVWE1 placenta-specific positive (e.g., T240) and negative (e.g., G71) regulatory sites were identified, as were essential sites required for basic activity (e.g., A247). The flanking sequences of the ERVWE1 provirus contain several putative regulatory elements. The upstream HERV-H and HERV-P LTRs were found to be inactive. Conversely, the 436-bp region located between the HERV-P LTR and ERVWE1 was shown to be an upstream regulatory element (URE) which is significantly active in placenta cells. This URE acts as a tissue-specific enhancer. Genetic and functional analyses of hominoid UREs revealed large differences between UREs of members of the Hominidae and the Hylobatidae. These data allowed the identification of a positive regulatory region from positions −436 to −128, a mammalian apparent LTR retrotransposon negative regulatory region from positions −128 to −67, and a trophoblast-specific enhancer (TSE) from positions −67 to −35. Putative AP-2, Sp-1, and GCMa binding sites are essential constituents of the 33-bp TSE.

scholarly journals Gamma-Globin Gene Promoter Elements Required for Interaction With Globin Enhancers

Blood ◽  
1998 ◽  
Vol 91 (1) ◽  
pp. 309-318 ◽  
Author(s):  
Scott D. Langdon ◽  
Russel E. Kaufman
Keyword(s):  
Binding Sites ◽  
Globin Gene ◽  
Gene Promoter ◽  
Regulatory Elements ◽  
Site Directed Mutagenesis ◽  
Luciferase Reporter ◽  
Promoter Strength ◽  
Gene Promoters ◽  
Wild Type ◽  
Luciferase Reporter Gene

Abstract Normal expression of the human β-globin domain genes is dependent on at least three types of regulatory elements located within the β-globin domain: the locus control region (LCR), globin enhancer elements (3′β and 3′Aγ), and the individual globin gene promoter and upstream regions. It has been postulated that regulation occurs through physical interactions between factors bound to these elements, which are located at considerable distances from each other. To identify the elements required for promoter-enhancer interactions from a distance, we have investigated the expression of the wild-type, truncated, and mutated γ-globin promoters linked to the 5′HS2 enhancer. We show that in K562 cells, 5′HS2 increases activity approximately 20-fold from both a wild-type and truncated (-135 → +25) γ promoter and that truncation or site-directed mutagenesis of the tandem CCAAT boxes eliminated the enhancement by 5′HS2. Mutation of the γ-globin gene promoter GATA-1 binding sites did not decrease either promoter strength or enhancement of activity by 5′HS2. To determine if enhanced expression of γ-globin gene promoters carrying mutations associated with hereditary persistence of fetal hemoglobin (HPFH) was due to greater interactions with enhancers, we linked these HPFH γ-globin gene promoters to 5′HS2 and demonstrated a twofold to threefold higher expression than the corresponding wild-type promoter plus enhancer in MEL cells. Addition of the Aγ-globin gene 3′ enhancer to a plasmid containing the γ-globin gene promoter and 5′HS2 did not further enhance promoter strength. Furthermore, we have demonstrated that the previously identified core 5′HS2 enhancer (46-bp tandem AP-1/NF-E2 sites) increased expression only when located 5′, but not 3′, to the γ-globin-luciferase reporter gene, suggesting that its enhancer effect is not by DNA looping. Our results suggest that CCAAT boxes, but not GATA or CACCC binding sites, are required for interaction between the γ-globin promoter and the LCR/5′HS2 and that regulatory elements in addition to the core enhancer may be required for the enhancer to act from a distance.

scholarly journals Gamma-Globin Gene Promoter Elements Required for Interaction With Globin Enhancers

Blood ◽  
1998 ◽  
Vol 91 (1) ◽  
pp. 309-318
Author(s):  
Scott D. Langdon ◽  
Russel E. Kaufman
Keyword(s):  
Binding Sites ◽  
Globin Gene ◽  
Gene Promoter ◽  
Regulatory Elements ◽  
Site Directed Mutagenesis ◽  
Luciferase Reporter ◽  
Promoter Strength ◽  
Gene Promoters ◽  
Wild Type ◽  
Luciferase Reporter Gene

Normal expression of the human β-globin domain genes is dependent on at least three types of regulatory elements located within the β-globin domain: the locus control region (LCR), globin enhancer elements (3′β and 3′Aγ), and the individual globin gene promoter and upstream regions. It has been postulated that regulation occurs through physical interactions between factors bound to these elements, which are located at considerable distances from each other. To identify the elements required for promoter-enhancer interactions from a distance, we have investigated the expression of the wild-type, truncated, and mutated γ-globin promoters linked to the 5′HS2 enhancer. We show that in K562 cells, 5′HS2 increases activity approximately 20-fold from both a wild-type and truncated (-135 → +25) γ promoter and that truncation or site-directed mutagenesis of the tandem CCAAT boxes eliminated the enhancement by 5′HS2. Mutation of the γ-globin gene promoter GATA-1 binding sites did not decrease either promoter strength or enhancement of activity by 5′HS2. To determine if enhanced expression of γ-globin gene promoters carrying mutations associated with hereditary persistence of fetal hemoglobin (HPFH) was due to greater interactions with enhancers, we linked these HPFH γ-globin gene promoters to 5′HS2 and demonstrated a twofold to threefold higher expression than the corresponding wild-type promoter plus enhancer in MEL cells. Addition of the Aγ-globin gene 3′ enhancer to a plasmid containing the γ-globin gene promoter and 5′HS2 did not further enhance promoter strength. Furthermore, we have demonstrated that the previously identified core 5′HS2 enhancer (46-bp tandem AP-1/NF-E2 sites) increased expression only when located 5′, but not 3′, to the γ-globin-luciferase reporter gene, suggesting that its enhancer effect is not by DNA looping. Our results suggest that CCAAT boxes, but not GATA or CACCC binding sites, are required for interaction between the γ-globin promoter and the LCR/5′HS2 and that regulatory elements in addition to the core enhancer may be required for the enhancer to act from a distance.

Identification of ATF2 as a transcriptional regulator of renin gene

2012 ◽  
Vol 393 (1-2) ◽  
pp. 93-100 ◽  
Author(s):  
Michael Desch ◽  
Gerit Hackmayer ◽  
Vladimir T. Todorov
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Transcriptional Control ◽  
Regulatory Region ◽  
Inhibitory Effect ◽  
Luciferase Reporter ◽  
Distal Enhancer ◽  
Reporter System ◽  
Renin Gene ◽  
Factor Α

Abstract The cAMP response element (enhCRE) in the distal enhancer regulatory region of renin gene is believed to play a major role in the control of renin transcription. enhCRE binds the CRE-binding protein (CREB), which is the main transcription factor target of cAMP signaling. Using the mouse renin-producing cell line As4.1 we found that activating transcription factor-2 (ATF2) also binds to enhCRE. N-terminal phosphorylation of ATF2, which controls its transactivation, is associated with downregulation of renin gene expression by the cytokine tumor necrosis factor-α (TNFα). The ubiquitin proteasome inhibitor MG132 also phosphorylates ATF2 and inhibits renin expression. Knockdown of ATF2 attenuated the suppression of renin gene expression by MG132, thus demonstrating that ATF2 mediates the inhibitory effect of MG132. In addition, MG132 increased the DNA-binding of ATF2 as well as the ratio of bound ATF2 to CREB. Using ATF2- and CREB-Gal4 fusion protein constructs coupled with luciferase reporter system we showed that ATF2 has a weaker transactivating capacity than CREB. These data suggest that ATF2 represses renin expression by drifting the transcriptional control of renin gene away from CREB. Accordingly, TNFα completely abrogated the cAMP-dependent stimulation of renin gene expression.

Differentiation-dependent mechanisms of transcriptional regulation of the catalytic subunit of phosphorylase kinase

2002 ◽  
Vol 362 (2) ◽  
pp. 199-211
Author(s):  
Alison M. O'MAHONY ◽  
Donal A. WALSH
Keyword(s):  
Transcriptional Regulation ◽  
Core Promoter ◽  
Regulatory Element ◽  
Regulatory Region ◽  
Regulatory Elements ◽  
Catalytic Subunit ◽  
Luciferase Reporter ◽  
Phosphorylase Kinase ◽  
Subunit Gene ◽  
Reporter System

The amount of phosphorylase kinase in skeletal muscle is exquisitely sensitive to developmental signals such as differentiation and innervation, and is clearly regulated in such a manner so as to always maintain the γ catalytic subunit under the control of its regulatory α, β and γ subunits. To identify how the transcription of the γ subunit is regulated, we have analysed 3.8kb of the upstream regulatory region using a luciferase reporter system. A complex sequence of interdependent regulations is evident. The γ catalytic subunit gene contains two inhibitory controls with very dominant features. Also evident are an array of multiple positive regulatory elements, prominent amongst which are four E-boxes, of which two are downstream, one is upstream and one is in the middle of the CAAT-TATA core promoter. Differentiation-dependent positive regulation arises as a consequence of both E-box regulation and the activation of at least one other regulatory element. The primary mode of transcriptional regulation of the γ catalytic subunit gene appears to occur by the relief of regulation of an otherwise default inhibitory status. It is noteworthy that such a mode of regulation mirrors the regulation of the enzymic activity of many protein kinases, including phosphorylase kinase. With phosphorylase kinase, both its transcriptional regulation as well as the regulation of the protein itself, are primed to maintain the γ catalytic subunit either unexpressed or inactivate respectively, until a positive signal occurs to override an otherwise dominant default inhibitory condition.

scholarly journals Two different negative regulatory elements control the transcription of T-cell activation gene 3 in activated mast cells

1997 ◽  
Vol 323 (2) ◽  
pp. 511-519 ◽  
Author(s):  
Chad K. OH ◽  
Markus NEURATH ◽  
Jeong-Je CHO ◽  
Tekli SEMERE ◽  
Dean D. METCALFE
Keyword(s):  
Protein Synthesis ◽  
T Cell ◽  
Mast Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Regulatory Region ◽  
Regulatory Elements ◽  
Site Directed Mutagenesis ◽  
Mobility Shift ◽  
Integrin Gene

T-cell activation gene 3 (TCA3) encodes a β-chemokine that is transcriptionally regulated in mast cells; the gene has a functional NF-κB element at positions -194 to -185. The 5´-flanking region of this gene is also known to have a negative regulatory region between -2057 and -1342. To characterize the negative regulatory elements (NREs), this region was sequenced and then digested by HindIII enzyme into two fragments, NRE-1 (-2057 to -1493) and NRE-2 (-1492 to -1342). Both NRE-1 and NRE-2 in the 5´–3´ orientation inhibited chloramphenicol acetyltransferase (CAT)-protein synthesis by a TCA3–CAT construct transfected into mast cells that were then activated. Only NRE-1 inhibited CAT-protein synthesis in the 3´–5´ orientation. Further deletion of the 5´ region of NRE-1 partially abolished the inhibitory activity. Both NRE-1 and NRE-2 inhibited the activity of a CD20–CAT construct independent of cell activation. Electrophoretic mobility shift assays showed DNA–protein complex formation with subsequences (CCCCCATTCT) of NRE-1 (NRE-1a) and (CCATGA) of NRE-2 (NRE-2b). NRE-1a appears to be novel. NRE-2b is identical with a putative silencer motif in the αIIb integrin gene. Site-directed mutagenesis demonstrated that both NRE-1a and NRE-2b are important in the negative regulation of TCA3 promoter activity. In vivo ligation-mediated PCR footprinting of the NRE-2 region revealed protection between -1372 and -1354, which contains NRE-2b. The data thus demonstrate identity of a silencer motif, here termed NRE-2b, in both the αIIb integrin gene and the TCA3, and that this silencer region in mast cells is functional both in vivoand in vitro. Further, evidence is presented that the promoter for TCA3 contains a novel silencer motif, termed NRE-1a, characterized by a CT-rich sequence.

scholarly journals BTG4 is A Novel p53 Target Gene That Inhibits Cell Growth and Induces Apoptosis

Genes ◽  
2020 ◽  
Vol 11 (2) ◽  
pp. 217 ◽  
Author(s):  
Na Zhang ◽  
Tinghui Jiang ◽  
Yitao Wang ◽  
Lanyue Hu ◽  
Youquan Bu
Keyword(s):  
Transcription Factor ◽  
Cell Growth ◽  
Binding Sites ◽  
Transcription Initiation ◽  
Core Promoter ◽  
Site Directed Mutagenesis ◽  
Luciferase Assay ◽  
Luciferase Reporter ◽  
Colorectal Cancers ◽  
P53 Overexpression

BTG4 is the last cloned and poorly studied member of BTG/Tob family. Studies have suggested that BTG4 is critical for the degradation of maternal mRNAs in mice during the process of maternal-to-zygotic transition, and downregulated in cancers, such as gastric cancer. However, the regulatory mechanism of BTG4 and its function in cancers remain elusive. In this study, we have for the first time identified the promoter region of the human BTG4 gene. Serial luciferase reporter assay demonstrated that the core promoter of BTG4 is mainly located within the 388 bp region near its transcription initiation site. Transcription factor binding site analysis revealed that the BTG4 promoter contains binding sites for canonical transcription factors, such as Sp1, whereas its first intron contains two overlapped consensus p53 binding sites. However, overexpression of Sp1 has negligible effects on BTG4 promoter activity, and site-directed mutagenesis assay further suggested that Sp1 is not a critical transcription factor for the transcriptional regulation of BTG4. Of note, luciferase assay revealed that one of the intronic p53 binding sites is highly responsive to p53. Both exogenous p53 overexpression and adriamycin-mediated endogenous p53 activation result in the transcriptional upregulation of BTG4. In addition, BTG4 is downregulated in lung and colorectal cancers, and overexpression of BTG4 inhibits cell growth and induces apoptosis in cancer cells. Taken together, our results strongly suggest that BTG4 is a novel p53-regulated gene and probably functions as a tumor suppressor in lung and colorectal cancers.

Analysis of the human CD10/neutral endopeptidase 24.11 promoter region: two separate regulatory elements

Blood ◽  
1995 ◽  
Vol 85 (11) ◽  
pp. 3199-3207 ◽  
Author(s):  
F Ishimaru ◽  
MA Shipp
Keyword(s):  
Binding Sites ◽  
Lymphoblastic Leukemia ◽  
Regulatory Region ◽  
Neutral Endopeptidase ◽  
Regulatory Elements ◽  
Control Element ◽  
Regulatory Regions ◽  
Endopeptidase 24.11

The cell surface zinc metalloproteinase CD10/neutral endopeptidase 24.11 (NEP) is expressed on normal and malignant lymphoid progenitors, granulocytes, and a variety of epithelial cells. To further define the tissue-specific and developmentally related expression of CD10/NEP, we have characterized two separate regulatory regions that control the transcription of 5′ alternatively spliced CD10/NEP transcripts. These type 1 and 2 CD10/NEP regulatory regions are both characterized by the presence of multiple transcription initiation sites and the absence of classic TATA boxes and consensus initiator elements. The purine-rich type 1 regulatory region, which includes 5′ UTR exon 1 sequence, is characterized by multiple putative PU.1 binding sites and consensus ets-binding motifs. In marked contrast, the GC-rich type 2 regulatory region contains multiple putative Sp1 binding sites, a potential consensus retinoblastoma control element (RCE), and an inverted CCAAT box. In the majority of tissues examined to date, type 2 CD10/NEP transcripts were more abundant; the abundance of type 1 transcripts was more variable, with the highest type 1 levels in fetal thymus and certain lymphoblastic leukemia cell lines.

Characterization of Hepcidin-Inducing Cytokines in Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2001-2001
Author(s):  
Ken Maes ◽  
Alissa Huston ◽  
David Roodman ◽  
Seth Rivera ◽  
Elizabeta Nemeth ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Promoter Activity ◽  
Site Directed Mutagenesis ◽  
Luciferase Reporter ◽  
Reporter System ◽  
Advisory Committees ◽  
Hepcidin Expression ◽  
Equity Ownership

Abstract Abstract 2001 Poster Board I-1023 Introduction: Hepcidin, the principal iron-regulatory hormone, plays an important role in the development of anemia of inflammation and other iron-restricted anemias. Patients with multiple myeloma (MM) frequently present with anemia not attributable to a known mechanism. We previously found that hepcidin is increased in MM and thus could cause or contribute to the anemia of MM. The BMP and IL-6 pathways are the two known major transcriptional regulators of hepcidin. Methods: To identify cytokines that increase hepcidin in MM patients, we screened patient sera with an in vitro cellular reporter system, consisting of human hepatoma 7 cell line (HuH7) and the hepcidin promoter-firefly luciferase reporter. Using site-directed mutagenesis, the promoter was mutated at the STAT3-binding site (STAT3-BS) and/or two BMP responsive elements (BREs), sequences known to be involved in the regulation of hepcidin expression by IL-6 and BMPs, respectively. Results: As expected, recombinant IL-6 and BMP-4, -6 and -9 activated wild-type hepcidin promoter activity several fold. Of note, IL-6 and BMP-9 interacted synergistically at low doses, at the level of the promoter. Mutations in STAT3-BS abrogated the response to IL-6. Mutations in either BRE site by itself did not abolish the response to BMPs, but concurrent mutagenesis of both sites resulted in a complete loss of hepcidin response. Importantly, STAT3-BS and BREs affected hepcidin promoter response independently from each other. Using the in vitro system, we compared sera from six MM patients with previously measured serum hepcidin levels to sera from healthy controls. Sera of four patients with high hepcidin and one with low hepcidin significantly induced hepcidin promoter activity, while serum of another patient with low hepcidin did not. Mutations in STAT3-BS only abrogated the response to two patient sera, both of which had high hepcidin. Mutations in two BREs abrogated the response in all six sera as did the triple mutation involving STAT3-BS and both BREs. Conclusions: We could separately interrogate the signaling pathways by which IL-6 and BMPs induce hepcidin transcription, allowing us to discriminate between the effects of IL-6-like or BMP-like cytokines in each patient serum. BMP-like cytokines were involved in the upregulation of hepcidin in all tested MM patients, and in some patients IL-6 or related cytokines contributed as well, either independently or through a synergistic interaction. No residual activation of hepcidin promoter by other factors was noted. Antibody neutralization may identify the specific myeloma-associated cytokines that stimulate hepcidin production through the two canonical pathways. Disclosures: Roodman: Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy; Acceleron: Consultancy. Nemeth:Intrinsic LifeSciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Ganz:Intrinsic LifeSciences: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Xenon Pharmaceuticals: Consultancy, Equity Ownership.

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