ERK1/2 MAPKs and Wnt Signaling Pathways are Independently Involved in Adipocytokine-Mediated Aldosterone Secretion

2011 ◽  
Vol 119 (10) ◽  
pp. 644-648 ◽  
Author(s):  
K. Vleugels ◽  
S. Schinner ◽  
D. Krause ◽  
H. Morawietz ◽  
S. Bornstein ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Signaling Pathways ◽  
Regulatory Protein ◽  
Wnt Signaling Pathway ◽  
Fat Cell ◽  
Aldosterone Secretion ◽  
Cellular Mechanisms ◽  
Adrenocortical Cells ◽  
Star Activity ◽  
Adrenal Steroidogenesis

AbstractObesity is one major risk factor for the development of arterial hypertension, and the development of obesity-related hypertension has been associated with increased plasma aldosterone levels. Our previous work shows a direct stimulatory effect of adipokines on aldosterone secretion from human adrenocortical cells, mediated via ERK1/2-dependent upregulation of steroid acute regulatory protein (StAR) activity. Recent evidence also indicates the involvement of the Wnt-signaling pathway in fat cell-mediated aldosterone secretion. Wnt-signaling molecules are secreted by adipocytes and regulate the activity of SF-1, a key transcription factor in adrenal steroidogenesis. The goal of this study was to investigate the cellular mechanisms of adipocyte-induced aldosterone secretion in detail, and to evaluate effects and possible interactions of the ERK1/2 MAPK- and the Wnt-signaling pathways on adipocyte-induced adreno­cortical aldosterone secretion. Our results show that, similar to adipocyte-conditioned medium (ACM), β-catenin, which is an intracellular mediator of canonical Wnt-signaling, induced StAR promotor activity in human NCI-H295R adrenocortical cells, and ACM-induced StAR promotor activity depended on intact SF-1 binding sites. Wnt antagonist sFRP-1 inhibited adipokine-mediated StAR activity, but did not affect ERK1/2 MAPK activation. Accordingly, Wnt did not stimulate ERK1/2 phosphorylation in adrenocortical cells, indicating that ERK1/2 MAPK and Wnt signaling pathways are independently involved in adipocyte-mediated aldosterone secretion.

scholarly journals Genetic Polymorphism in Extracellular Regulators of Wnt Signaling Pathway

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Garima Sharma ◽  
Ashish Ranjan Sharma ◽  
Eun-Min Seo ◽  
Ju-Suk Nam
Keyword(s):  
Genetic Polymorphism ◽  
Wnt Signaling ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Wnt Signaling Pathway ◽  
The Other ◽  
Present Review ◽  
Receptor Complex ◽  
Related Proteins ◽  
Related Association

The Wnt signaling pathway is mediated by a family of secreted glycoproteins through canonical and noncanonical mechanism. The signaling pathways are regulated by various modulators, which are classified into two classes on the basis of their interaction with either Wnt or its receptors. Secreted frizzled-related proteins (sFRPs) are the member of class that binds to Wnt protein and antagonizes Wnt signaling pathway. The other class consists of Dickkopf (DKK) proteins family that binds to Wnt receptor complex. The present review discusses the disease related association of various polymorphisms in Wnt signaling modulators. Furthermore, this review also highlights that some of the sFRPs and DKKs are unable to act as an antagonist for Wnt signaling pathway and thus their function needs to be explored more extensively.

scholarly journals Modulation of Calretinin Expression in Human Mesothelioma Cells Reveals the Implication of the FAK and Wnt Signaling Pathways in Conferring Chemoresistance towards Cisplatin

2019 ◽  
Vol 20 (21) ◽  
pp. 5391 ◽  
Author(s):  
Wörthmüller ◽  
Salicio ◽  
Oberson ◽  
Blum ◽  
Schwaller
Keyword(s):  
Wnt Signaling ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Expression System ◽  
Single Agent ◽  
Wnt Signaling Pathway ◽  
Tumor Formation ◽  
Mesenchymal Transition

Malignant mesothelioma (MM) is an aggressive asbestos-linked neoplasm, characterized by dysregulation of signaling pathways. Due to intrinsic or acquired chemoresistance, MM treatment options remain limited. Calretinin is a Ca2+-binding protein expressed during MM tumorigenesis that activates the FAK signaling pathway, promoting invasion and epithelial-to-mesenchymal transition. Constitutive calretinin downregulation decreases MM cells’ growth and survival, and impairs tumor formation in vivo. In order to evaluate early molecular events occurring during calretinin downregulation, we generated a tightly controlled IPTG-inducible expression system to modulate calretinin levels in vitro. Calretinin downregulation significantly reduced viability and proliferation of MM cells, attenuated FAK signaling and reduced the invasive phenotype of surviving cells. Importantly, surviving cells showed a higher resistance to cisplatin due to increased Wnt signaling. This resistance was abrogated by the Wnt signaling pathway inhibitor 3289-8625. In various MM cell lines and regardless of calretinin expression levels, blocking of FAK signaling activated the Wnt signaling pathway and vice versa. Thus, blocking both pathways had the strongest impact on MM cell proliferation and survival. Chemoresistance mechanisms in MM cells have resulted in a failure of single-agent therapies. Targeting of multiple components of key signaling pathways, including Wnt signaling, might be the future method-of-choice to treat MM.

scholarly journals Misregulation of Wnt Signaling Pathways at the Plasma Membrane in Brain and Metabolic Diseases

Membranes ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 844
Author(s):  
Mustafa Karabicici ◽  
Yagmur Azbazdar ◽  
Evin Iscan ◽  
Gunes Ozhan
Keyword(s):  
Plasma Membrane ◽  
Wnt Signaling ◽  
Signaling Pathways ◽  
Metabolic Diseases ◽  
Wnt Signaling Pathway ◽  
Membrane Domains ◽  
Physiological Processes ◽  
Pathway Activation ◽  
Wnt Pathways ◽  
Membrane Components

Wnt signaling pathways constitute a group of signal transduction pathways that direct many physiological processes, such as development, growth, and differentiation. Dysregulation of these pathways is thus associated with many pathological processes, including neurodegenerative diseases, metabolic disorders, and cancer. At the same time, alterations are observed in plasma membrane compositions, lipid organizations, and ordered membrane domains in brain and metabolic diseases that are associated with Wnt signaling pathway activation. Here, we discuss the relationships between plasma membrane components—specifically ligands, (co) receptors, and extracellular or membrane-associated modulators—to activate Wnt pathways in several brain and metabolic diseases. Thus, the Wnt–receptor complex can be targeted based on the composition and organization of the plasma membrane, in order to develop effective targeted therapy drugs.

scholarly journals Autophagy Is Required for Hepatic Differentiation of Hepatic Progenitor Cells via Wnt Signaling Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Jianxing Zeng ◽  
Yingying Jing ◽  
Qionglan Wu ◽  
Jinhua Zeng ◽  
Lixin Wei ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Signaling Pathways ◽  
Progenitor Cells ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Wnt Signaling Pathway ◽  
Hepatic Progenitor Cells ◽  
Hepatic Differentiation ◽  
Development And Differentiation ◽  
Progenitor Cell Line

The molecular mechanisms regulating differentiation of hepatic progenitor cells (HPCs), which play pivotal roles in liver regeneration and development, remain obscure. Autophagy and Wnt signaling pathways regulate the development and differentiation of stem cells in various organs. However, the roles of autophagy and Wnt signaling pathways in hepatic differentiation of HPCs are not well understood. Here, we describe the effects of autophagy and Wnt signaling pathways during hepatic differentiation of HPCs. We used a well-established rat hepatic progenitor cell line called WB-F344, which was treated with differentiation medium to promote differentiation of WB-F344 cells along the hepatic phenotype. Firstly, autophagy was highly activated in HPCs and gradually decreased during hepatic differentiation of HPCs. Induction of autophagy by rapamycin or starvation suppressed hepatic differentiation of HPCs. Secondly, Wnt3a signaling pathway was downregulated, and Wnt5a signaling pathway was upregulated in hepatic differentiation of HPCs. At last, Wnt3a signaling pathway was enhanced, and Wnt5a signaling pathway was inhibited by activation of autophagy during hepatic differentiation of HPCs. In summary, these results demonstrate that autophagy regulates hepatic differentiation of hepatic progenitor cells through Wnt signaling pathway.

scholarly journals Regulation of Wnt Signaling Pathways at the Plasma Membrane and Their Misregulation in Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Yagmur Azbazdar ◽  
Mustafa Karabicici ◽  
Esra Erdal ◽  
Gunes Ozhan
Keyword(s):  
Plasma Membrane ◽  
Wnt Signaling ◽  
Signaling Pathways ◽  
Cancer Progression ◽  
Malignant Tumors ◽  
Wnt Signaling Pathway ◽  
Receptor Complex ◽  
Breast Cancers ◽  
Membrane Composition ◽  
Membrane Components

Wnt signaling is one of the key signaling pathways that govern numerous physiological activities such as growth, differentiation and migration during development and homeostasis. As pathway misregulation has been extensively linked to pathological processes including malignant tumors, a thorough understanding of pathway regulation is essential for development of effective therapeutic approaches. A prominent feature of cancer cells is that they significantly differ from healthy cells with respect to their plasma membrane composition and lipid organization. Here, we review the key role of membrane composition and lipid order in activation of Wnt signaling pathway by tightly regulating formation and interactions of the Wnt-receptor complex. We also discuss in detail how plasma membrane components, in particular the ligands, (co)receptors and extracellular or membrane-bound modulators, of Wnt pathways are affected in lung, colorectal, liver and breast cancers that have been associated with abnormal activation of Wnt signaling. Wnt-receptor complex components and their modulators are frequently misexpressed in these cancers and this appears to correlate with metastasis and cancer progression. Thus, composition and organization of the plasma membrane can be exploited to develop new anticancer drugs that are targeted in a highly specific manner to the Wnt-receptor complex, rendering a more effective therapeutic outcome possible.

scholarly journals Leukemia inhibitory factor as a regulator of steroidogenesis in human NCI-H295R adrenocortical cells

2008 ◽  
Vol 199 (3) ◽  
pp. 435-444 ◽  
Author(s):  
Irina V Mikhaylova ◽  
Tiina Jääskeläinen ◽  
Jarmo Jääskeläinen ◽  
Jorma J Palvimo ◽  
Raimo Voutilainen
Keyword(s):  
Leukemia Inhibitory Factor ◽  
Regulatory Protein ◽  
Culture Conditions ◽  
Inhibitory Factor ◽  
Adrenocortical Cells ◽  
Mrna Accumulation ◽  
Adrenal Steroidogenesis ◽  
Aldosterone Production ◽  
Steroidogenic Acute Regulatory

Leukemia inhibitory factor (LIF) is a multiple function cytokine regulating the hypothalamic–pituitary–adrenal axis at the pituitary level. LIF and its receptor are expressed in the adrenal glands, suggesting their potential regulatory role also at the adrenal level. Our aim was to clarify the effects of LIF on adrenal steroidogenesis using cell culture conditions. NCI-H295R human adrenocortical cells were treated with LIF (0.01–100 ng/ml) for 3–48 h with or without 8-bromo-cAMP (8-Br-cAMP; 1 mM). LIF treatment augmented cortisol, dehydroepiandrosterone (DHEA), DHEA sulfate, androstenedione, and aldosterone production (up to 224, 211, 149, 229, and 170% of control respectively, P<0.05 for all). It increased basal steroidogenic acute regulatory protein (STAR) and 17α-hydroxylase/17,20-lyase (CYP17A1) mRNAs (up to 142 and 170% of control respectively, P<0.05) and the respective proteins, but decreased 3β-hydroxysteroid dehydrogenase type 2 (HSD3B2) mRNA (down to 72% of control, P<0.05), and protein. LIF also increased 8-Br-cAMP-induced cortisol and DHEA production and STAR mRNA accumulation, while it attenuated 8-Br-cAMP-induced HSD3B2 expression and androstenedione production. It had an additive effect on tumour necrosis factor-induced cortisol production. LIF had no effect on apoptosis, but it increased slightly the number of metabolically active cells (up to 120% of control, P<0.05). These findings indicate that LIF is a potential physiological and/or pathophysiological regulator of steroidogenesis at the adrenal level.

Human Recombinant Activin-A Modulates the Steroidogenesis of Cultured Bovine Adrenocortical Cells

1992 ◽  
Vol 132 (3) ◽  
pp. R1-R4 ◽  
Author(s):  
Y. Nishi ◽  
M. Haji ◽  
S. Tanaka ◽  
T. Yanase ◽  
R. Takayanagi ◽  
...  
Keyword(s):  
Inhibitory Effect ◽  
Activin A ◽  
Dependent Manner ◽  
Cortisol Secretion ◽  
Inhibitory Effects ◽  
Aldosterone Secretion ◽  
Adrenocortical Cells ◽  
Adrenal Steroidogenesis ◽  
Direct Inhibitory Effect ◽  
Dose Dependent

ABSTRACT The effect of human recombinant activin-A on adrenal steroidogenesis was studied in cultured bovine adrenocortical cells. Activin-A significantly reduced cortisol output from ACTH (10nmol/l)-stimulated adrenocortical cells incubated for 24 hours in a dose-dependent manner (10, 100 and 500ng activin-A /ml suppressed cortisol secretion by 19, 33 and 40%), although no significant effect was observed in the case of 3 h incubation. Dehydroepiandrosterone (DHEA) secretion from ACTH-stimulated adrenocortical cells incubated for 24 h was also decreased by the addition of activin-A in a dose-dependent manner. (10, 100 and 500ng activin-A /ml suppressed DHEA secretion by 22, 56 and 58%). These inhibitory effects of activin-A (100ng/ml) on cortisol and DHEA secretion were partially blocked by the addition of follistatin / FSH-Suppressing Protein (200ng/ml). In contrast, activin-A treatment resulted in no significant decrease in aldosterone secretion. There were no significant effects of activin-A on basal secretions of cortisol, DHEA or aldosterone from adrenocortical cells. These results suggest that activin-A has a direct inhibitory effect on ACTH-stimulated bovine adrenocortical steroidogenesis.

scholarly journals Wnt-Signaling Regulated by Glucocorticoid-Induced miRNAs

2021 ◽  
Vol 22 (21) ◽  
pp. 11778
Author(s):  
Henriett Butz ◽  
Katalin Mészáros ◽  
István Likó ◽  
Attila Patocs
Keyword(s):  
Wnt Signaling ◽  
Signaling Pathways ◽  
Expression Profile ◽  
Mirna Expression ◽  
Wnt Signaling Pathway ◽  
Fine Tuning ◽  
Target Tissue ◽  
Adrenocortical Adenoma ◽  
Glucocorticoid Treatment ◽  
Signaling Mechanism

Glucocorticoids (GCs) are pleiotropic hormones which regulate innumerable physiological processes. Their comprehensive effects are due to the diversity of signaling mechanism networks. MiRNAs, small, non-coding RNAs contribute to the fine tuning of signaling pathways and reciprocal regulation between GCs and miRNAs has been suggested. Our aim was to investigate the expressional change and potential function of GC mediated miRNAs. The miRNA expression profile was measured in three models: human adrenocortical adenoma vs. normal tissue, steroid-producing H295R cells and in hormonally inactive HeLa cells before and after dexamethasone treatment. The gene expression profile in 82 control and 57 GC-affected samples was evaluated in GC producing and six different GC target tissue types. Tissue-specific target prediction (TSTP) was applied to identify the most relevant miRNA−mRNA interactions. Glucocorticoid treatment resulted in cell type-dependent miRNA expression changes. However, 19.5% of the influenced signaling pathways were common in all three experiments, of which the Wnt-signaling pathway seemed to be the most affected. Transcriptome data and TSTP showed similar results, as the Wnt pathway was significantly altered in both the GC-producing adrenal gland and all investigated GC target tissue types. In different cell types, different miRNAs led to the regulation of similar pathways. Wnt signaling may be one of the most important signaling pathways affected by hypercortisolism. It is, at least in part, regulated by miRNAs that mediate the glucocorticoid effect. Our findings on GC producing and GC target tissues suggest that the alteration of Wnt signaling (together with other pathways) may be responsible for the leading symptoms observed in Cushing’s syndrome.

scholarly journals Novel newt regeneration genes regulate Wingless signaling to restore patterning in Drosophila eye

2021 ◽  
Author(s):  
Abijeet Singh Mehta ◽  
Prajakta Deshpande ◽  
Anuradha Venkatakrishnan Chimata ◽  
Panagiotis A. Tsonis ◽  
Amit Singh
Keyword(s):  
Wnt Signaling ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Ectopic Expression ◽  
Wnt Signaling Pathway ◽  
Protein S ◽  
Photoreceptor Cells ◽  
Body Parts ◽  
Regeneration Potential ◽  
Regeneration Capability

AbstractA fundamental process of regeneration, which varies among animals, recruits conserved signaling pathways to restore missing parts. Only a few animals like newts can repeatedly regenerate lost body parts throughout their lifespan that can be attributed to strategic regulation of conserved signaling pathways by newt’s regeneration tool-kit genes. Here we report the use of a genetically tractable Drosophila eye model to demonstrate the regeneration potential of a group of unique protein(s) from newt (Notophthalmus viridescens), which when ectopically expressed can significantly rescue missing photoreceptor cells in a Drosophila eye mutant. These newt proteins with signal peptides motifs exhibit non-cell-autonomous rescue properties and their regeneration potential even extends into later stages of fly development. Ectopic expression of these newt genes can rescue eye mutant phenotype by promoting cell proliferation and blocking cell death. These novel newt genes downregulate the evolutionarily conserved Wingless (Wg)/Wnt signaling pathway to promote rescue. Modulation of Wg/Wnt signaling levels by using antagonists or agonists of Wg/Wnt signaling pathway in eye mutant background where newt gene(s) is ectopically expressed suggests that Wg signaling acts downstream of newt genes. Our data highlights the regeneration potential of novel newt proteins that regulate conserved pathways to trigger a robust regeneration response in Drosophila model with weak regeneration capability.

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