scholarly journals Role of SMAD proteins in colitis-associated cancer: from known to the unknown

Oncogene ◽  
2017 ◽  
Vol 37 (1) ◽  
pp. 1-7 ◽  
Author(s):  
P Chandrasinghe ◽  
B Cereser ◽  
M Moorghen ◽  
I Al Bakir ◽  
N Tabassum ◽  
...  
Keyword(s):  
Smad Proteins

scholarly journals Role of Smad Proteins in Resistance to BMP-Induced Growth Inhibition in B-Cell Lymphoma

PLoS ONE ◽  
2012 ◽  
Vol 7 (10) ◽  
pp. e46117 ◽  
Author(s):  
Kanutte Huse ◽  
Maren Bakkebø ◽  
Sébastien Wälchli ◽  
Morten P. Oksvold ◽  
Vera I. Hilden ◽  
...  
Keyword(s):  
Growth Inhibition ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Smad Proteins

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 220 The role of TGF-ß and Smad proteins in steatosis of liver disease in cystic fibrosis

2012 ◽  
Vol 11 ◽  
pp. S113
Author(s):  
F. Sotiriadou ◽  
M. Fotoulaki ◽  
N. Argentou ◽  
S. Nousia-Arvanitakis ◽  
P. Chitiroglou ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Liver Disease ◽  
Smad Proteins

Role of TGF-β1, its receptor TGFβRII, and Smad proteins in the progression of colorectal cancer

2010 ◽  
Vol 25 (5) ◽  
pp. 591-599 ◽  
Author(s):  
Maya Gulubova ◽  
Irena Manolova ◽  
Julian Ananiev ◽  
Alexander Julianov ◽  
Yovcho Yovchev ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Smad Proteins ◽  
Tgf Β1

scholarly journals Roles of Binding Elements, FOXL2 Domains, and Interactions With cJUN and SMADs in Regulation of FSHβ

2014 ◽  
Vol 28 (10) ◽  
pp. 1640-1655 ◽  
Author(s):  
Lacey L. Roybal ◽  
Arpi Hambarchyan ◽  
Jason D. Meadows ◽  
Nermeen H. Barakat ◽  
Patricia A. Pepa ◽  
...  
Keyword(s):  
Binding Sites ◽  
Pituitary Hormones ◽  
Order Complex ◽  
Wild Type ◽  
Smad Proteins ◽  
Forkhead Domain ◽  
Synergistic Induction ◽  
Smad Binding Element ◽  
Multiple Promoter

We previously identified FOXL2 as a critical component in FSHβ gene transcription. Here, we show that mice deficient in FOXL2 have lower levels of gonadotropin gene expression and fewer LH- and FSH-containing cells, but the same level of other pituitary hormones compared to wild-type littermates, highlighting a role of FOXL2 in the pituitary gonadotrope. Further, we investigate the function of FOXL2 in the gonadotrope cell and determine which domains of the FOXL2 protein are necessary for induction of FSHβ transcription. There is a stronger induction of FSHβ reporter transcription by truncated FOXL2 proteins, but no induction with the mutant lacking the forkhead domain. Specifically, FOXL2 plays a role in activin induction of FSHβ, functioning in concert with activin-induced SMAD proteins. Activin acts through multiple promoter elements to induce FSHβ expression, some of which bind FOXL2. Each of these FOXL2-binding sites is either juxtaposed or overlapping with a SMAD-binding element. We determined that FOXL2 and SMAD4 proteins form a higher order complex on the most proximal FOXL2 site. Surprisingly, two other sites important for activin induction bind neither SMADs nor FOXL2, suggesting additional factors at work. Furthermore, we show that FOXL2 plays a role in synergistic induction of FSHβ by GnRH and activin through interactions with the cJUN component of the AP1 complex that is necessary for GnRH responsiveness. Collectively, our results demonstrate the necessity of FOXL2 for proper FSH production in mice and implicate FOXL2 in integration of transcription factors at the level of the FSHβ promoter.

scholarly journals The Newly Synthetized Chalcone L1 Is Involved in the Cell Growth Inhibition, Induction of Apoptosis and Suppression of Epithelial-to-Mesenchymal Transition of HeLa Cells

Molecules ◽  
2021 ◽  
Vol 26 (5) ◽  
pp. 1356
Author(s):  
Tomas Kuruc ◽  
Martin Kello ◽  
Klaudia Petrova ◽  
Zuzana Kudlickova ◽  
Peter Kubatka ◽  
...  
Keyword(s):  
Hela Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Biological Activities ◽  
Tumour Microenvironment ◽  
Transforming Growth Factor Β1 ◽  
M Cell ◽  
Mesenchymal Transition ◽  
Smad Proteins

Over the past decades, natural products have emerged as promising agents with multiple biological activities. Many studies suggest the antioxidant, antiangiogenic, antiproliferative and anticancer effects of chalcones and their derivatives. Based on these findings, we decided to evaluate the effects of the newly synthetized chalcone L1 in a human cervical carcinoma cell (HeLa) model. Presented results were obtained by western blot and flow cytometric analyses, live cell imaging and antimigratory potential of L1 in HeLa cells was demonstrated by scratch assay. In the present study, we proved the role of L1 as an effective agent with antiproliferative activity supported by G2/M cell cycle arrest and apoptosis. Moreover, we proved that L1 is involved in modulating Transforming Growth Factor-β1 (TGF-β) signal transduction through Smad proteins and it also modulates other signalling pathways including Akt, JNK, p38 MAPK, and Erk1/2. The involvement of L1 in epithelial-to-mesenchymal transition was demonstrated by the regulation of N-cadherin, E-cadherin, and MMP-9 levels. Here, we also evaluated the effect of conditioned medium from BJ-5ta human foreskin fibroblasts in HeLa cell cultures with subsequent L1 treatment. Taken together, these data suggest the potential role of newly synthesized chalcone L1 as an anticancer-tumour microenvironment modulating agent.

scholarly journals Dengue virus non-structural protein 1 disrupts the TGF-β/Smad signaling 

2020 ◽  
Author(s):  
Anismrita Lahon ◽  
Ravi Arya ◽  
Vivek Kumar ◽  
Ritu Mishra ◽  
Akhil Banerjea
Keyword(s):  
Nuclear Translocation ◽  
Denv Infection ◽  
Structural Protein ◽  
Cellular Functions ◽  
E3 Ligases ◽  
Smad Signaling ◽  
Smad Proteins ◽  
Significant Impairment ◽  
Viral Factor

Abstract TGF-β signaling is tightly regulated to ensure cellular functions. Role of DENV on the TGF-β/Smad signaling has not been well established. Therefore, we aimed to study the association between DENV infection and TGF-β/Smad signaling. We observed significant impairment in the expression of Smad2, Smad3, Smad4, Smad6 and Smad7 during DENV replication, which are the key players in TGF-β signaling. Significant reduction in the expression of phosphorylated Smad3 was also documented. Overexpression of Smad2/3/4/6 provided the evidence of slight inhibition on DENV replication indicating these Smads may work against the establishment of DENV replication. DENV non-structural protein 1 (NS1) was noted as crucial viral factor that impaired the expression of Smad2, Smad3 and Smad4 and also physically interacts with these proteins as confirmed by co-immunoprecipitation assay. Additionally, we observed NS1 is also capable of blocking the nuclear translocation of Smad3 and thus further ensuring inhibition of Smad signaling. To figure out degradation mechanisms, we studied the role of two distinct E3 ligases, CHIP and Smurf2, which are essential for the degradation of Smad proteins. Co-expression of Smad2/3/4 and NS1 with Smurf2, Smurf2mut, CHIP or use of CHIP-/- cells suggests that only Smurf2 has significant role in the degradation of Smad proteins during DENV infection. NS1 may acts as a co-factor with Smurf2 to escalate the proteasome and lysosome mediated degradation of Smad3 and Smad4 proteins respectively. Therefore, our results confirm that NS1 interacts with Smad proteins and reduces their expression by utilizing E3 ligase and disrupt the TGF-β/Smad signaling.

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