scholarly journals Alcohol Activates TGF-Beta but Inhibits BMP Receptor-Mediated Smad Signaling and Smad4 Binding to Hepcidin Promoter in the Liver

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Lisa Nicole Gerjevic ◽  
Na Liu ◽  
Sizhao Lu ◽  
Duygu Dee Harrison-Findik
Keyword(s):  
Bone Morphogenetic Proteins ◽  
Iron Metabolism ◽  
Binding Activity ◽  
Bmp Signaling ◽  
Tgf Beta ◽  
Smad Signaling ◽  
Bmp Receptor ◽  
Dna Binding Activity ◽  
Smad2 Phosphorylation ◽  
Smad Signaling Pathway

Hepcidin, a key regulator of iron metabolism, is activated by bone morphogenetic proteins (BMPs). Mice pair-fed with regular and ethanol-containing L. De Carli diets were employed to study the effect of alcohol on BMP signaling and hepcidin transcription in the liver. Alcohol induced steatosis and TGF-beta expression. Liver BMP2, but not BMP4 or BMP6, expression was significantly elevated. Despite increased BMP expression, the BMP receptor, and transcription factors, Smad1 and Smad5, were not activated. In contrast, alcohol stimulated Smad2 phosphorylation. However, Smad4 DNA-binding activity and the binding of Smad4 to hepcidin promoter were attenuated. In summary, alcohol stimulates TGF-beta and BMP2 expression, and Smad2 phosphorylation but inhibits BMP receptor, and Smad1 and Smad5 activation. Smad signaling pathway in the liver may therefore be involved in the regulation of hepcidin transcription and iron metabolism by alcohol. These findings may help to further understand the mechanisms of alcohol and iron-induced liver injury.

scholarly journals SKLB023 as an iNOS inhibitor alleviated liver fibrosis by inhibiting the TGF-beta/Smad signaling pathway

RSC Advances ◽  
2018 ◽  
Vol 8 (54) ◽  
pp. 30919-30924
Author(s):  
Jinhang Zhang ◽  
Yanping Li ◽  
Qinhui Liu ◽  
Rui Li ◽  
Shiyun Pu ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Signaling Pathway ◽  
Inos Expression ◽  
Tgf Beta ◽  
Hepatocellular Injury ◽  
Smad Signaling ◽  
Smad Signaling Pathway ◽  
Inos Inhibitor

NASH is characterized by hepatocellular injury accompanied by steatosis, inflammation and fibrosis. SKLB023 as a potent iNOS inhibitor, suppressed the activation of TGF-β/Smad signaling pathway by blocking iNOS expression to attenuate liver fibrosis in MCD diet-induced mice.

scholarly journals CCAAT/Enhancer-Binding Protein Homologous Protein (CHOP) Regulates Osteoblast Differentiation

2006 ◽  
Vol 26 (16) ◽  
pp. 6105-6116 ◽  
Author(s):  
Ken Shirakawa ◽  
Shingo Maeda ◽  
Tomomi Gotoh ◽  
Makoto Hayashi ◽  
Kenichi Shinomiya ◽  
...  
Keyword(s):  
Osteoblast Differentiation ◽  
Binding Activity ◽  
Bmp Signaling ◽  
Dominant Negative ◽  
Dependent Manner ◽  
Mesenchymal Progenitors ◽  
Homologous Protein ◽  
Dna Binding Activity ◽  
Dominant Negative Inhibitor ◽  
Primary Osteoblasts

ABSTRACT Differentiation of committed osteoblasts is controlled by complex activities involving signal transduction and gene expression, and Runx2 and Osterix function as master regulators for this process. Recently, CCAAT/enhancer-binding proteins (C/EBPs) have been reported to regulate osteogenesis in addition to adipogenesis. However, the roles of C/EBP transcription factors in the control of osteoblast differentiation have yet to be fully elucidated. Here we show that C/EBP homologous protein (CHOP; also known as C/EBPζ) is expressed in bone as well as in mesenchymal progenitors and primary osteoblasts. Overexpression of CHOP reduces alkaline phosphatase activity in primary osteoblasts and suppresses the formation of calcified bone nodules. CHOP-deficient osteoblasts differentiate more strongly than their wild-type counterparts, suggesting that endogenous CHOP plays an important role in the inhibition of osteoblast differentiation. Furthermore, endogenous CHOP induces differentiation of calvarial osteoblasts upon bone morphogenetic protein (BMP) treatment. CHOP forms heterodimers with C/EBPβ and inhibits the DNA-binding activity as well as Runx2-binding activity of C/EBPβ, leading to inhibition of osteocalcin gene transcription. These findings indicate that CHOP acts as a dominant-negative inhibitor of C/EBPβ and prevents osteoblast differentiation but promotes BMP signaling in a cell-type-dependent manner. Thus, endogenous CHOP may have dual roles in regulating osteoblast differentiation and bone formation.

Positive and negative regulation of TGF-beta signaling

2000 ◽  
Vol 113 (7) ◽  
pp. 1101-1109 ◽  
Author(s):  
K. Miyazono
Keyword(s):  
Bone Morphogenetic Proteins ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Growth Inhibitor ◽  
Cell Types ◽  
Negative Regulation ◽  
Bmp Signaling ◽  
Tgf Beta ◽  
Transcription Complexes ◽  
Nuclear Levels

Cytokines of the transforming growth factor beta (TGF-beta) superfamily, including TGF-betas, activins and bone morphogenetic proteins (BMPs), bind to specific serine/threonine kinase receptors and transmit intracellular signals through Smad proteins. Upon ligand stimulation, Smads move into the nucleus and function as components of transcription complexes. TGF-beta and BMP signaling is regulated positively and negatively through various mechanisms. Positive regulation amplifies signals to a level sufficient for biological activity. Negative regulation occurs at the extracellular, membrane, cytoplasmic and nuclear levels. TGF-beta and BMP signaling is often regulated through negative feedback mechanisms, which limit the magnitude of signals and terminate signaling. Negative regulation is also important for formation of gradients of morphogens, which is crucial in developmental processes. In addition, other signaling pathways regulate TGF-beta and BMP signaling through cross-talk. Nearly 20 BMP isoforms have been identified, and their activities are regulated by various extracellular antagonists. Regulation of TGF-beta signaling might be tightly linked to tumor progression, since TGF-beta is a potent growth inhibitor in most cell types.

The unique activity of bone morphogenetic proteins in bone: a critical role of the Smad signaling pathway

2013 ◽  
Vol 394 (6) ◽  
pp. 703-714 ◽  
Author(s):  
Takenobu Katagiri ◽  
Sho Tsukamoto
Keyword(s):  
Skeletal Muscle ◽  
Transcription Factors ◽  
Bone Formation ◽  
Bone Morphogenetic Proteins ◽  
Fibrodysplasia Ossificans Progressiva ◽  
Type I ◽  
Heterotopic Bone ◽  
Heterotopic Bone Formation ◽  
Smad Signaling ◽  
Smad Signaling Pathway

Abstract Bone morphogenetic proteins (BMPs) are multifunctional cytokines that belong to the transforming growth factor-β family. BMPs were originally identified based on their unique activity, inducing heterotopic bone formation in skeletal muscle. This unique BMP activity is transduced by specific type I and type II transmembrane kinase receptors. Among the downstream pathways activated by these receptors, the Smad1/5/8 transcription factors appear to play critical roles in BMP activity. Smad1/5/8 transcription factors are phosphorylated at the C-terminal SVS motif by BMP type I receptors and then induce the transcription of early BMP-responsive genes by binding to conserved sequences in their enhancer regions. The linker regions of Smad1/5/8 contain multiple kinase phosphorylation sites, and phosphorylation and dephosphorylation of these sites regulate the transcriptional activity of Smad proteins. Gain-of-function mutations in one BMP type I receptor have been identified in patients with fibrodysplasia ossificans progressiva, a rare genetic disorder that is characterized by progressive heterotopic bone formation in the skeletal muscle. The mutant receptors activate the Smad signaling pathway even in the absence of BMPs, therefore novel inhibitors for the BMP receptor – Smad axis are being developed to prevent heterotopic bone formation in fibrodysplasia ossificans progressiva. Taken together, the data in the literature show that the BMP type I receptor – Smad signaling axis is the critical pathway for the unique activity of BMPs and is a potential therapeutic target for pathological conditions caused by inappropriate BMP activity.

BMP signaling in rats with TNBS-induced colitis following BMP7 therapy

2012 ◽  
Vol 302 (10) ◽  
pp. G1151-G1162 ◽  
Author(s):  
Ivana Maric ◽  
Natalia Kucic ◽  
Tamara Turk Wensveen ◽  
Ivana Smoljan ◽  
Blazenka Grahovac ◽  
...  
Keyword(s):  
Bone Morphogenetic Proteins ◽  
Chronic Phase ◽  
Acute Stage ◽  
Tissue Growth ◽  
Bmp Signaling ◽  
Rat Colon ◽  
Trinitrobenzene Sulfonic Acid ◽  
Opposite Pattern ◽  
Bmp Receptor ◽  
Experimental Inflammatory Bowel Disease

Beyond stimulating bone formation, bone morphogenetic proteins (BMPs) are important in development, inflammation, and malignancy of the gut. We have previously shown that BMP7 has a regenerative, anti-inflammatory, and antiproliferative effect on experimental inflammatory bowel disease (IBD) in rats. To further investigate the BMP signaling pathway we monitored the effect of BMP7 therapy on the BMP signaling components in the rat colon during different stages of experimentally induced colitis by 2,4,6-trinitrobenzene sulfonic acid (TNBS). The results showed a significantly decreased BMP7 expression in the acute phase, followed by a significantly increased BMP2 and decreased BMP6 expression during the chronic phase of colitis. BMP7 therapy influenced the expression of several BMPs with the most prominent effect on downregulation of BMP2 and upregulation of BMP4 in the chronic phase of colitis. Importantly, connective tissue growth factor and noggin expression were elevated in the acute stage and significantly decreased upon BMP7 therapy. BMP receptor I expression was unchanged, whereas BMP receptor II was decreased at day 2 and increased at days 14 and 30 of TNBS inflammation. However, an opposite pattern of expression following BMP7 therapy has been observed. BMP7 increased the expression of BR-Smad including Smad3 and Smad4. Inhibitory Smads were increased in colitis and significantly decreased following BMP7 therapy at later stages of the disease. We suggest that BMP signaling was altered during TNBS-induced colitis and was recovered with BMP7 administration, suggesting that IBD is a reversible process.

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