scholarly journals Two BMP responsive elements, STAT, and bZIP/HNF4/COUP motifs of the hepcidin promoter are critical for BMP, SMAD1, and HJV responsiveness

Blood ◽  
2009 ◽  
Vol 113 (3) ◽  
pp. 688-695 ◽  
Author(s):  
Jaroslav Truksa ◽  
Pauline Lee ◽  
Ernest Beutler
Keyword(s):  
Transcription Factors ◽  
Signaling Pathway ◽  
Bone Morphogenetic Proteins ◽  
Binding Sites ◽  
Iron Homeostasis ◽  
Bmp Signaling ◽  
Physical Association ◽  
Maximal Activation ◽  
Bmp Pathway ◽  
Responsive Element

Abstract Hepcidin plays a major role in the regulation of iron homeostasis. Several bone morphogenetic proteins (BMPs) are strong inducers of hepcidin (Hamp1, HAMP) expression. Hemojuvelin, a protein critical for maintaining appropriate levels of hepcidin, acts as a coreceptor for BMP2 and BMP4, thereby providing a link between iron homeostasis and the BMP-signaling pathway. We show that a robust BMP, hemojuvelin, and SMAD1 response by murine Hamp1 is dependent on a distal BMP responsive element (BMP-RE2), the adjacent bZIP, HNF4α/COUP binding sites, and plus or minus 50 bp of the flanking area within −1.6 to −1.7 kb of the Hamp1 promoter. Furthermore, the STAT site and the BMP responsive element (BMP-RE1) located in the proximal 260-bp region of the Hamp1 promoter are also indispensable for maximal activation of hepcidin transcription. The homologous motifs in the distal and proximal regions of the human HAMP promoter act in a manner similar to the murine Hamp1 promoter. Therefore, we propose that the regulation of hepcidin by the BMP pathway involves the formation of a complex of liver-specific and response-specific transcription factors bound to the distal BMP-RE2 /bZIP/HNF4α/COUP region and to the proximal BMP-RE1/STAT region possibly by physical association of the 2 regions.

Inhibition of Hamp1 Expression by TMPRSS6, GDF15, PIAS4 and SMAD6 Utilize Several Target Sites in the Hamp1 Promoter

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3838-3838
Author(s):  
Jaroslav Truksa ◽  
Pauline Lee ◽  
Ernest Beutler
Keyword(s):  
Transcription Factors ◽  
Bone Morphogenetic Proteins ◽  
Iron Homeostasis ◽  
Negative Regulator ◽  
Luciferase Reporter ◽  
Reporter Expression ◽  
Hepcidin Expression ◽  
Double Deletion ◽  
Bmp Pathway ◽  
Transmembrane Serine Protease

Abstract Hepcidin, the key regulator of iron homeostasis, is up-regulated by iron excess, bone morphogenetic proteins (BMPs) and inflammatory cytokines and down-regulated by hypoxia and anemia. Known positive regulators at the level of transcription factors include SMAD1/4, STAT3 and CEBPα. In this study, we focused on negative regulators of hepcidin regulation: Matriptase II/TMPRSS6 (Transmembrane serine protease 6, a recently identified negative regulator in which disruption leads to anemia in mice as well in humans); Protein inhibitor of activated STATs no. 4 (PIAS4); Growth and differentiation factor 15 (GDF15, a potential erythroid negative regulator); and SMAD6 (Mothers against decapentaplegic homolog 6, an inhibitory SMAD blocking the SMAD/BMP pathway). All tested inhibitors significantly decreased expression of the luciferase reporter under the control of 2.5 Kb murine Hamp1 promoter with GDF15 and PIAS4 Hamp1 specific since none of the inhibitors were able to reduce expression of the luciferase reporter under the control of the murine Hamp2 promoter. Inhibition of the luciferase reporter under the control of the 2.5 Kb murine Hamp1 promoter by SMAD6, unlike TMPRSS6, PIAS4 and GDF15, did not require liver specific transcription factors since the inhibition could also be observed in transfected HEK293T cells. GDF15, PIAS4, TMPRSS6 and SMAD6 all reduced basal level expression of the luciferase reporter under the control of the 2.5 Kb murine Hamp1 promoter as well as the total level of reporter expression induced by IL-6 and BMP-4. Nevertheless, GDF15 did not affect responsiveness (fold induction) to IL-6 and BMP-4. PIAS4 and TMPRSS6 inhibited responsiveness to IL-6 but had little effect on responsiveness to BMP-4. In contrast, SMAD6 did not affect responsiveness to IL-6 but reduced responsiveness to BMP-4. Deletion of the −140 bp −260 bp region of the murine Hamp1 or double deletion of the BMP-RE1 and BMP-RE2 motifs severely reduced the ability of all inhibitors to reduce reporter expression. Deletion of the STAT site abrogated PIAS4 inhibition while deletion of either BMP-RE1 or BMP-RE2 motifs alone partially reduced inhibition by TMPRSS6 and SMAD6. We conclude that there are several independent pathways that inhibit hepcidin expression.

scholarly journals The Role of BMP Signaling in Osteoclast Regulation

2021 ◽  
Vol 9 (3) ◽  
pp. 24
Author(s):  
Brian Heubel ◽  
Anja Nohe
Keyword(s):  
Bone Formation ◽  
Bone Morphogenetic Proteins ◽  
Bone Diseases ◽  
Bmp Signaling ◽  
Bone Homeostasis ◽  
Direct Stimulation ◽  
Federal Drug Administration ◽  
Bmp Pathway ◽  
Stimulation Of

The osteogenic effects of Bone Morphogenetic Proteins (BMPs) were delineated in 1965 when Urist et al. showed that BMPs could induce ectopic bone formation. In subsequent decades, the effects of BMPs on bone formation and maintenance were established. BMPs induce proliferation in osteoprogenitor cells and increase mineralization activity in osteoblasts. The role of BMPs in bone homeostasis and repair led to the approval of BMP2 by the Federal Drug Administration (FDA) for anterior lumbar interbody fusion (ALIF) to increase the bone formation in the treated area. However, the use of BMP2 for treatment of degenerative bone diseases such as osteoporosis is still uncertain as patients treated with BMP2 results in the stimulation of not only osteoblast mineralization, but also osteoclast absorption, leading to early bone graft subsidence. The increase in absorption activity is the result of direct stimulation of osteoclasts by BMP2 working synergistically with the RANK signaling pathway. The dual effect of BMPs on bone resorption and mineralization highlights the essential role of BMP-signaling in bone homeostasis, making it a putative therapeutic target for diseases like osteoporosis. Before the BMP pathway can be utilized in the treatment of osteoporosis a better understanding of how BMP-signaling regulates osteoclasts must be established.

scholarly journals A Survey of Strategies to Modulate the Bone Morphogenetic Protein Signaling Pathway: Current and Future Perspectives

2016 ◽  
Vol 2016 ◽  
pp. 1-15 ◽  
Author(s):  
Jonathan W. Lowery ◽  
Brice Brookshire ◽  
Vicki Rosen
Keyword(s):  
Bone Morphogenetic Proteins ◽  
Bmp Signaling ◽  
Protein Signaling ◽  
Bone Morphogenetic Protein Signaling ◽  
Human Organ ◽  
Morphogenetic Protein ◽  
Organ Systems ◽  
Bmp Pathway ◽  
Wide Perspective ◽  
The Relationship

Bone morphogenetic proteins (BMPs) constitute the largest subdivision of the TGF-βfamily of ligands and are unequivocally involved in regulating stem cell behavior. Appropriate regulation of canonical BMP signaling is critical for the development and homeostasis of numerous human organ systems, as aberrations in the BMP pathway or its regulation are increasingly associated with diverse human pathologies. In this review, we provide a wide-perspective on strategies that increase or decrease BMP signaling. We briefly outline the current FDA-approved approaches, highlight emerging next-generation technologies, and postulate prospective avenues for future investigation. We also detail how activating other pathways may indirectly modulate BMP signaling, with a particular emphasis on the relationship between the BMP and Activin/TGF-βpathways.

scholarly journals Identification of hydatidosis-related modules and key regulatory genes

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e9280
Author(s):  
Jijun Song ◽  
Mingxin Song
Keyword(s):  
Transcription Factors ◽  
Signaling Pathway ◽  
Target Genes ◽  
Expression Profiles ◽  
Differential Expression Analysis ◽  
Interaction Network ◽  
Enrichment Analysis ◽  
Bmp Signaling ◽  
Differentially Expressed ◽  
Regulatory Effects

Background Echinococcosis caused by larval of Echinococcus is prevalent all over the world. Although clinical experience showed that the presence of tapeworms could not be found in liver lesions, the repeated infection and aggravation of lesions still occur in the host. Here, this study constructed a multifactor-driven disease-related dysfunction network to explore the potential molecular pathogenesis mechanism in different hosts after E.multilocularis infection. Method First, iTRAQ sequencing was performed on human liver infected with E.multilocularis. Second, obtained microRNAs(miRNAs) expression profiles of humans and canine infected with Echinococcus from the GEO database. In addition, we also performed differential expression analysis, protein interaction network analysis, enrichment analysis, and crosstalk analysis to obtain genes and modules related to E.multilocularis infection. Pivot analysis is used to calculate the potential regulatory effects of multiple factors on the module and identify related non-coding RNAs(ncRNAs) and transcription factors(TFs). Finally, we screened the target genes of miRNAs of Echinococcus to further explore its infection mechanism. Results A total of 267 differentially expressed proteins from humans and 3,635 differentially expressed genes from canine were obtained. They participated in 16 human-related dysfunction modules and five canine-related dysfunction modules, respectively. Both human and canine dysfunction modules are significantly involved in BMP signaling pathway and TGF-beta signaling pathway. In addition, pivot analysis found that 1,129 ncRNAs and 110 TFs significantly regulated human dysfunction modules, 158 ncRNAs and nine TFs significantly regulated canine dysfunction modules. Surprisingly, the Echinococcus miR-184 plays a role in the pathogenicity regulation by targeting nine TFs and one ncRNA in humans. Similarly, miR-184 can also cause physiological dysfunction by regulating two transcription factors in canine. Conclusion The results show that the miRNA-184 of Echinococcus can regulate the pathogenic process through various biological functions and pathways. The results laid a solid theoretical foundation for biologists to further explore the pathogenic mechanism of Echinococcosis.

Hepcidin Regulation by the BMP Pathway.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. SCI-25-SCI-25
Author(s):  
Jodie L. Babitt
Keyword(s):  
Signaling Pathway ◽  
Serum Iron ◽  
Iron Homeostasis ◽  
Iron Absorption ◽  
Bmp Signaling ◽  
Smad Pathway ◽  
Hepcidin Expression ◽  
Iron Administration ◽  
Smad Proteins

Abstract Abstract SCI-25 Systemic iron balance is regulated by the key iron regulatory hormone hepcidin. Secreted by the liver, hepcidin inhibits iron absorption from the diet and iron mobilization from body stores by decreasing cell surface expression of the iron export protein ferroportin. Iron administration increases hepcidin expression, thereby providing a feedback mechanism to limit further iron absorption, while anemia and hypoxia inhibit hepcidin expression, thereby increasing iron availability for erythropoiesis. Hepcidin excess is thought to have a role in the anemia of inflammation, while hepcidin deficiency is thought to be the common pathogenic mechanism underlying the iron overload disorder hereditary hemochromatosis, due to mutations in the genes encoding hepcidin itself (HAMP), HFE, transferrin receptor 2 (TFR2), or hemojuvelin (HFE2). Notably the precise molecular mechanisms by which iron levels are “sensed” and how this iron “signal” is transduced to modulate hepcidin expression have remained elusive. We have recently discovered that hemojuvelin is a co-receptor for the bone morphogenetic protein (BMP) signaling pathway, and that hemojuvelin-mediated BMP signals increase hepcidin expression at the transcriptional level. In addition to patients with HFE2 mutations and Hfe2 knockout mice, other genetic mouse models associated with impaired hepatic BMP signaling through a global knockout of the ligand Bmp6, or selective hepatic knockout of an intracellular mediator of BMP signaling, Smad4, also cause inappropriately low hepcidin expression and iron overload. Exogenous BMP6 administration in mice increases hepatic hepcidin expression and reduces serum iron, while BMP6 antagonists inhibit hepatic hepcidin expression, mobilize reticuloendothelial cell iron stores and increase serum iron. Not only does the BMP6-hemojuvelin-SMAD pathway regulate hepcidin expression and thereby systemic iron homeostasis, but also the BMP6-SMAD pathway itself is regulated by iron. Acute iron administration in mice increases phosphorylation of Smad proteins in the liver, and chronic changes in dietary iron modulate hepatic Bmp6 mRNA expression and phosphorylation of Smad proteins concordantly with Hamp mRNA expression. Together, these data support the paramount role of the BMP6-hemojuvelin-SMAD signaling pathway in the iron-mediated regulation of hepcidin expression and systemic iron homeostasis, and suggest that modulators of this pathway may be an alternative therapeutic strategy for treating disorders of iron homeostasis. Recent work elucidating the role of the BMP signaling pathway in hepcidin regulation and systemic iron homeostasis will be presented. Disclosures Babitt: Ferrumax Pharmaceuticals, Inc.: Equity Ownership.

scholarly journals Calcium-dependent Nr4a1 expression in mouse Leydig cells requires distinct AP1/CRE and MEF2 elements

2016 ◽  
Vol 56 (3) ◽  
pp. 151-161 ◽  
Author(s):  
Houssein S Abdou ◽  
Nicholas M Robert ◽  
Jacques J Tremblay
Keyword(s):  
Gene Expression ◽  
Endoplasmic Reticulum ◽  
Transcription Factors ◽  
Signaling Pathway ◽  
Binding Sites ◽  
Leydig Cells ◽  
Sex Differentiation ◽  
Calcium Dependent ◽  
Male Sex ◽  
Camp Levels

The nuclear receptor NR4A1 is expressed in steroidogenic Leydig cells where it plays pivotal roles by regulating the expression of several genes involved in steroidogenesis and male sex differentiation including Star, HSD3B2, and Insl3. Activation of the cAMP and Ca2+ signaling pathways in response to LH stimulation leads to a rapid and robust activation of Nr4a1 gene expression that requires the Ca2+/CAMKI pathway. However, the downstream transcription factor(s) have yet to be characterized. To identify potential Ca2+/CaM effectors responsible for hormone-induced Nr4a1 expression, MA-10 Leydig cells were treated with forskolin to increase endogenous cAMP levels, dantrolene to inhibit endoplasmic reticulum Ca2+ release, and W7 to inhibit CaM activity. We identified Ca2+-responsive elements located in the discrete regions of the Nr4a1 promoter, which contain binding sites for several transcription factors such as AP1, CREB, and MEF2. We found that one of the three AP1/CRE sites located at –255 bp is the most responsive to the Ca2+ signaling pathway as are the two MEF2 binding sites at –315 and –285 bp. Furthermore, we found that the hormone-induced recruitment of phospho-CREB and of the co-activator p300 to the Nr4a1 promoter requires the Ca2+ pathway. Lastly, siRNA-mediated knockdown of CREB impaired NR4A1 expression and steroidogenesis. Together, our data indicate that the Ca2+ signaling pathway increases Nr4a1 expression in MA-10 Leydig cells, at least in part, by enhancing the recruitment of coactivator most likely through the MEF2, AP1, and CREB transcription factors thus demonstrating an important interplay between the Ca2+ and cAMP pathways in regulating Nr4a1 expression.

Furin-mediated release of soluble hemojuvelin: a new link between hypoxia and iron homeostasis

Blood ◽  
2008 ◽  
Vol 111 (2) ◽  
pp. 924-931 ◽  
Author(s):  
Laura Silvestri ◽  
Alessia Pagani ◽  
Clara Camaschella
Keyword(s):  
Iron Deficiency ◽  
Bone Morphogenetic Proteins ◽  
Skeletal Muscles ◽  
Iron Homeostasis ◽  
Bmp Signaling ◽  
Specific Mechanism ◽  
Furin Cleavage ◽  
In Cells

The liver peptide hepcidin regulates iron absorption and recycling. Hemojuvelin (HJV) has a key role in hepcidin regulation, and its inactivation causes severe iron overload both in humans and in mice. Membrane HJV (m-HJV) acts as a coreceptor for bone morphogenetic proteins (BMPs), whereas soluble HJV (s-HJV) may down-regulate hepcidin in a competitive way interfering with BMP signaling. s-HJV is decreased by iron in vitro and increased by iron deficiency in vivo. However, the mechanisms regulating the 2 HJV isoforms remain unclear. Here we show that s-HJV originates from a furin cleavage at position 332–335. s-HJV is reduced in the cleavage mutant R335Q as well as in cells treated with a furin inhibitor, and increased in cells overexpressing exogenous furin, but not in cells overexpressing an inactive furin variant. Furin is up-regulated by iron deficiency and hypoxia in association with the stabilization of HIF-1α. Increased s-HJV in response to HIF-1α occurs during differentiation of murine muscle cells expressing endogenous Hjv. Our data are relevant to the mechanisms that relate iron metabolism to the hypoxic response. The release of s-HJV might be a tissue-specific mechanism, signaling the local iron requests of hypoxic skeletal muscles independently of the oxygen status of the liver.

scholarly journals The BMP Pathway in Blood Vessel and Lymphatic Vessel Biology

2021 ◽  
Vol 22 (12) ◽  
pp. 6364
Author(s):  
Ljuba C. Ponomarev ◽  
Jakub Ksiazkiewicz ◽  
Michael W. Staring ◽  
Aernout Luttun ◽  
An Zwijsen
Keyword(s):  
Endothelial Cells ◽  
Bone Morphogenetic Proteins ◽  
Lymphatic Vessel ◽  
Lymphatic Vessels ◽  
Vascular Diseases ◽  
Bmp Signaling ◽  
Molecular Heterogeneity ◽  
Active Components ◽  
Surrounding Matrix ◽  
Bmp Pathway

Bone morphogenetic proteins (BMPs) were originally identified as the active components in bone extracts that can induce ectopic bone formation. In recent decades, their key role has broadly expanded beyond bone physiology and pathology. Nowadays, the BMP pathway is considered an important player in vascular signaling. Indeed, mutations in genes encoding different components of the BMP pathway cause various severe vascular diseases. Their signaling contributes to the morphological, functional and molecular heterogeneity among endothelial cells in different vessel types such as arteries, veins, lymphatic vessels and capillaries within different organs. The BMP pathway is a remarkably fine-tuned pathway. As a result, its signaling output in the vessel wall critically depends on the cellular context, which includes flow hemodynamics, interplay with other vascular signaling cascades and the interaction of endothelial cells with peri-endothelial cells and the surrounding matrix. In this review, the emerging role of BMP signaling in lymphatic vessel biology will be highlighted within the framework of BMP signaling in the circulatory vasculature.

scholarly journals Neural stem/precursor cells dynamically change their epigenetic landscape to differentially respond to BMP signaling for fate switching during brain development

2021 ◽  
Author(s):  
Sayako Katada ◽  
Jun Takouda ◽  
Takumi Nakagawa ◽  
Mizuki Honda ◽  
Katsuhide Igarashi ◽  
...  
Keyword(s):  
Bone Morphogenetic Proteins ◽  
Binding Sites ◽  
Precursor Cells ◽  
Bmp Signaling ◽  
Specific Gene ◽  
Brain Functions ◽  
Histone H3k27 ◽  
Astrocytic Differentiation ◽  
Target Binding ◽  
Underlying Mechanisms

During neocortical development, tight regulation of neurogenesis-to-astrogenesis switching of neural precursor cells (NPCs) is critical to generate a balanced number of each neural cell type for proper brain functions. Accumulating evidence indicates that a complex array of epigenetic modifications and the availability of extracellular factors control the timing of neuronal and astrocytic differentiation. However, our understanding of NPC fate regulation is still far from complete. Bone morphogenetic proteins (BMPs) are renowned as cytokines that induce astrogenesis of gliogenic late-gestational NPCs. They also promote neurogenesis of mid-gestational NPCs, although the underlying mechanisms remain elusive. By performing multiple genome-wide analyses, we demonstrate that Smads, transcription factors that act downstream from BMP signaling, target dramatically different genomic regions in neurogenic and gliogenic NPCs. We found that histone H3K27 trimethylation and DNA methylation around Smad-binding sites change rapidly as gestation proceeds, strongly associated with the alteration of accessibility of Smads to their target binding sites. Furthermore, we identified two lineage-specific Smad-interacting partners—Sox11 for neurogenic and Sox8 for astrocytic differentiation—that further ensure Smad-regulated fate-specific gene induction. Our findings illuminate an exquisite regulation of NPC property change mediated by the interplay between cell-extrinsic cues and -intrinsic epigenetic programs during cortical development.

Genome-Wide Computational Screen for Blood Stem Cell Enhancers Integrates RUNX1 and the BMP Signaling Pathway into the SCL Transcriptional Network.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4196-4196
Author(s):  
John E. Pimanda ◽  
Ian J. Donaldson ◽  
Marella F. Bruijn ◽  
Sarah J. Kinston ◽  
Kathy Knezevic ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Stem Cell ◽  
Transcription Factors ◽  
Signaling Pathway ◽  
Bmp Signaling ◽  
Hematopoietic Stem ◽  
Genome Wide ◽  
A Genome ◽  
Smad Signaling Pathway ◽  
Runx1 Expression

Abstract Hematopoietic stem cell (HSC) development is regulated by several signaling pathways and a number of key transcription factors, which include Scl/Tal1, Runx1 and members of the Smad family. However, it remains unclear how these various determinants interact. Using a genome-wide computational screen based on the well-characterized Scl +19 HSC enhancer, we have identified a related Smad6 enhancer that also targets expression to blood and endothelial cells in transgenic mice. We show that at E10.5, Smad6 and Bmp4 transcripts are concentrated along the ventral pole of the dorsal aorta and resemble Runx1 expression in the aorta-gonad-mesonephros (AGM) region where HSCs originate. Moreover, Smad6 binds and inhibits Runx1 activity whereas Smad1, a mediator of Bmp4 signaling, transactivates the Runx1 promoter. Taken together, our results integrate three key determinants of HSC development; the Scl network, Runx1 activity and the Bmp4/Smad signaling pathway.

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