scholarly journals Inhibition of ERK 1/2 kinases prevents tendon matrix breakdown

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ulrich Blache ◽  
Stefania L. Wunderli ◽  
Amro A. Hussien ◽  
Tino Stauber ◽  
Gabriel Flückiger ◽  
...  
Keyword(s):  
Collagen Type ◽  
Dependent Manner ◽  
Catabolic Gene ◽  
Extracellular Signal Regulated Kinase ◽  
Tissue Explants ◽  
Mechanical Unloading ◽  
Extracellular Signal ◽  
Tissue Degradation ◽  
Type 3 ◽  
Interleukin 11

AbstractTendon extracellular matrix (ECM) mechanical unloading results in tissue degradation and breakdown, with niche-dependent cellular stress directing proteolytic degradation of tendon. Here, we show that the extracellular-signal regulated kinase (ERK) pathway is central in tendon degradation of load-deprived tissue explants. We show that ERK 1/2 are highly phosphorylated in mechanically unloaded tendon fascicles in a vascular niche-dependent manner. Pharmacological inhibition of ERK 1/2 abolishes the induction of ECM catabolic gene expression (MMPs) and fully prevents loss of mechanical properties. Moreover, ERK 1/2 inhibition in unloaded tendon fascicles suppresses features of pathological tissue remodeling such as collagen type 3 matrix switch and the induction of the pro-fibrotic cytokine interleukin 11. This work demonstrates ERK signaling as a central checkpoint to trigger tendon matrix degradation and remodeling using load-deprived tissue explants.

scholarly journals Polycystin-1 Regulates Extracellular Signal-Regulated Kinase-Dependent Phosphorylation of Tuberin To Control Cell Size through mTOR and Its Downstream Effectors S6K and 4EBP1

2009 ◽  
Vol 29 (9) ◽  
pp. 2359-2371 ◽  
Author(s):  
Gianfranco Distefano ◽  
Manila Boca ◽  
Isaline Rowe ◽  
Claas Wodarczyk ◽  
Li Ma ◽  
...  
Keyword(s):  
Cell Size ◽  
Control Cell ◽  
Cyst Formation ◽  
Mtor Pathway ◽  
Orphan Receptor ◽  
Dependent Manner ◽  
Independent Manner ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Autosomal Dominant Polycystic Kidney

ABSTRACT Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disease characterized by bilateral renal cyst formation. Both hyperproliferation and hypertrophy have been previously observed in ADPKD kidneys. Polycystin-1 (PC-1), a large orphan receptor encoded by the PKD1 gene and mutated in 85% of all cases, is able to inhibit proliferation and apoptosis. Here we show that overexpression of PC-1 in renal epithelial cells inhibits cell growth (size) in a cell cycle-independent manner due to the downregulation of mTOR, S6K1, and 4EBP1. Upregulation of the same pathway leads to increased cell size, as found in mouse embryonic fibroblasts derived from Pkd1 − / − mice. We show that PC-1 controls the mTOR pathway in a Tsc2-dependent manner, by inhibiting the extracellular signal-regulated kinase (ERK)-mediated phosphorylation of tuberin in Ser664. We provide a detailed molecular mechanism by which PC-1 can inhibit the mTOR pathway and regulate cell size.

Involvement of the extracellular signal-regulated kinase 1/2 signaling pathway in amylin's eating inhibitory effect

2012 ◽  
Vol 302 (3) ◽  
pp. R340-R351 ◽  
Author(s):  
Catarina Soares Potes ◽  
Christina Neuner Boyle ◽  
Peter John Wookey ◽  
Thomas Riediger ◽  
Thomas Alexander Lutz
Keyword(s):  
Area Postrema ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Neuronal Responses ◽  
Extracellular Signal Regulated Kinase ◽  
Erk Phosphorylation ◽  
Extracellular Signal ◽  
Anorectic Effect ◽  
Feeding Trials ◽  
Dose Dependent

Peripheral amylin inhibits eating via the area postrema (AP). Because amylin activates the extracellular-signal regulated kinase 1/2 (ERK) pathway in some tissues, and because ERK1/2 phosphorylation (pERK) leads to acute neuronal responses, we postulated that it may be involved in amylin's eating inhibitory effect. Amylin-induced ERK phosphorylation (pERK) was investigated by immunohistochemistry in brain sections containing the AP. pERK-positive AP neurons were double-stained for the calcitonin 1a/b receptor, which is part of the functional amylin-receptor. AP sections were also phenotyped using dopamine-β-hydroxylase (DBH) as a marker of noradrenergic neurons. The effect of fourth ventricular administration of the ERK cascade blocker U0126 on amylin's eating inhibitory action was tested in feeding trials. The number of pERK-positive neurons in the AP was highest ∼10–15 min after amylin treatment; the effect appeared to be dose-dependent (5–20 μg/kg amylin). A portion of pERK-positive neurons in the AP carried the amylin-receptor and 22% of the pERK-positive neurons were noradrenergic. Pretreatment of rats with U0126 decreased the number of pERK-positive neurons in the AP after amylin injection. U0126 also attenuated the ability of amylin to reduce eating, at least when the animals had been fasted 24 h prior to the feeding trial. Overall, our results suggest that amylin directly stimulates pERK in AP neurons in a time- and dose-dependent manner. Part of the AP neurons displaying pERK were noradrenergic. At least under fasting conditions, pERK was shown to be a necessary part in the signaling cascade mediating amylin's anorectic effect.

scholarly journals The Corepressor mSin3A Regulates Phosphorylation-Induced Activation, Intranuclear Location, and Stability of AML1

2004 ◽  
Vol 24 (3) ◽  
pp. 1033-1043 ◽  
Author(s):  
Yoichi Imai ◽  
Mineo Kurokawa ◽  
Yuko Yamaguchi ◽  
Koji Izutsu ◽  
Eriko Nitta ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Protein Modification ◽  
Transcriptional Activity ◽  
Regulatory Mechanism ◽  
Dna Binding Protein ◽  
Time Dependent ◽  
Myeloid Differentiation ◽  
Dependent Manner ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal

ABSTRACT The AML1 (RUNX1) gene, one of the most frequent targets of translocations associated with human leukemias, encodes a DNA-binding protein that plays pivotal roles in myeloid differentiation through transcriptional regulation of various genes. Previously, we reported that AML1 is phosphorylated on two serine residues with dependence on activation of extracellular signal-regulated kinase, which positively regulates the transcriptional activity of AML1. Here, we demonstrate that the interaction between AML1 and the corepressor mSin3A is regulated by phosphorylation of AML1 and that release of AML1 from mSin3A induced by phosphorylation activates its transcriptional activity. Furthermore, phosphorylation of AML1 regulates its intranuclear location and disrupts colocalization of AML1 with mSin3A in the nuclear matrix. PEBP2β/CBFβ, a heterodimeric partner of AML1, was shown to play a role in protecting AML1 from proteasome-mediated degradation. We show that mSin3A also protects AML1 from proteasome-mediated degradation and that phosphorylation-induced release of AML1 from mSin3A results in degradation of AML1 in a time-dependent manner. This study provides a novel regulatory mechanism for the function of transcription factors mediated by protein modification and interaction with cofactors.

scholarly journals Interferon α Induces Nucleus-independent Apoptosis by Activating Extracellular Signal-regulated Kinase 1/2 and c-Jun NH2-Terminal Kinase Downstream of Phosphatidylinositol 3-Kinase and Mammalian Target of Rapamycin

2008 ◽  
Vol 19 (1) ◽  
pp. 41-50 ◽  
Author(s):  
Theocharis Panaretakis ◽  
Linn Hjortsberg ◽  
Katja Pokrovskaja Tamm ◽  
Ann-Charlotte Björklund ◽  
Bertrand Joseph ◽  
...  
Keyword(s):  
Apoptotic Cell ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Interferon Α ◽  
Dependent Manner ◽  
Phosphatidylinositol 3 Kinase ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Induced Apoptosis ◽  
Phosphatidylinositol 3

Interferon (IFN)α induces apoptosis via Bak and Bax and the mitochondrial pathway. Here, we investigated the role of known IFNα-induced signaling cascades upstream of Bak activation. By pharmacological and genetic inhibition of the kinases protein kinase C (PKC)δ, extracellular signal-regulated kinase (ERK), and c-Jun NH2-terminal kinase (JNK) in U266-1984 and RHEK-1 cells, we could demonstrate that all three enzymes are critical for the apoptosis-associated mitochondrial events and apoptotic cell death induced by IFNα, at a step downstream of phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR). Furthermore, the activation of JNK was found to occur in a PKCδ/ERK-dependent manner. Inhibition of these kinases did not affect the canonical IFNα-stimulated Janus tyrosine kinase-signal transducer and activator of transcription signaling or expression of IFN-responsive genes. Therefore, enucleated cells (cytoplasts) were examined for IFNα-induced apoptosis, to test directly whether this process depends on gene transcription. Cytoplasts were found to undergo apoptosis after IFNα treatment, as analyzed by several apoptosis markers by using flow cytometry, live cell imaging, and biochemical analysis of flow-sorted cytoplasts. Furthermore, inhibition of mTOR, ERK, and JNK blocked IFNα-induced apoptosis in cytoplasts. In conclusion, IFNα-induced apoptosis requires activation of ERK1/2, PKCδ, and JNK downstream of PI3K and mTOR, and it can occur in a nucleus-independent manner, thus demonstrating for the first time that IFNα induces apoptosis in the absence of de novo transcription.

scholarly journals Tropisetron Protects Against Acetaminophen-Induced Liver Injury via Suppressing Hepatic Oxidative Stress and Modulating the Activation of JNK/ERK MAPK Pathways

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Fu-Chao Liu ◽  
Hung-Chen Lee ◽  
Chia-Chih Liao ◽  
Allen H. Li ◽  
Huang-Ping Yu
Keyword(s):  
Liver Injury ◽  
Map Kinases ◽  
Dependent Manner ◽  
Protective Effects ◽  
Mice Model ◽  
Terminal Protein ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Hepatic Lipid Peroxidation ◽  
Dose Dependent

Objectives. To investigate the protective effects of tropisetron on acetaminophen- (APAP-) induced liver injury in a mice model.Methods. C57BL/6 male mice were given tropisetron (0.3 to 10 mg/kg) 30 minutes before a hepatotoxic dose of acetaminophen (300 mg/kg) intraperitoneally. Twenty hours after APAP intoxication, sera alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, hepatic myeloperoxidase (MPO), malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD) activities, and liver histopathological changes were examined. The MAP kinases were also detected by western blotting.Results. Our results showed that tropisetron pretreatment significantly attenuated the acute elevations of the liver enzyme ALT level, hepatic MPO activity, and hepatocytes necrosis in a dose-dependent manner (0.3–10 mg/kg) in APAP-induced hepatotoxicity mice. Tropisetron (1 and 3 mg/kg) suppressed APAP-induced hepatic lipid peroxidation expression and alleviated GSH and SOD depletion. Administration of tropisetron also attenuated the phosphorylation of c-Jun-NH2-terminal protein kinase (JNK) and extracellular signal-regulated kinase (ERK) caused by APAP.Conclusion. Our data demonstrated that tropisetron’s hepatoprotective effect was in part correlated with the antioxidant, which were mediated via JNK and ERK pathways on acetaminophen-induced liver injury in mice.

scholarly journals Almost nontoxic tetrodotoxin analog, 5,6,11-trideoxytetrodotoxin, as an olfactory chemoattractant for the grass puffer

2021 ◽  
Author(s):  
Yasuhisa Noguchi ◽  
Takehisa Suzuki ◽  
Keigo Matsutani ◽  
Ryota Nakahigashi ◽  
Yoshiki Satake ◽  
...  
Keyword(s):  
Sensory Neurons ◽  
Olfactory Sensory Neurons ◽  
Dependent Manner ◽  
Behavioral Experiments ◽  
Extracellular Signal Regulated Kinase ◽  
Behavioral Studies ◽  
Defense Substance ◽  
Extracellular Signal ◽  
Dose Dependent ◽  
Fluorescent Dextran

Toxic puffers contain the potent neurotoxin, tetrodotoxin (TTX). Although TTX is considered to serve as a defense substance, previous behavioral studies have demonstrated that TTX (extracted from the ovary) acts as an attractive pheromone for some toxic puffers. To determine the putative pheromonal action of TTX, we examined whether grass puffers (Takifugu alboplumbeus) can detect TTX using electrophysiological, morphological, and behavioral experiments. Electroolfactogram results suggest that the olfactory epithelium of grass puffers responded in a dose-dependent manner to a type of TTX analog (5,6,11-trideoxyTTX), although it did not respond to TTX. We also examined the attractive action of 5,6,11-trideoxyTTX on grass puffers by recording their swimming behavior under dark conditions. Grass puffers preferred to stay on the side of the aquarium where 5,6,11-trideoxyTTX was administered, and their swimming speed decreased. Additionally, odorant-induced labeling of olfactory sensory neurons using a fluorescent dextran conjugate or immunohistochemistry against phosphorylated extracellular signal regulated kinase (pERK) revealed that labeled olfactory sensory neurons were localized in the region surrounding "islets" where there was abundant cilia on the olfactory lamella. 5,6,11-trideoxyTTX has been known to accumulate in grass puffers, but its toxicity is much lower (almost nontoxic) than TTX. Our results suggest that grass puffers can detect 5,6,11-trideoxyTTX using their nose and may positively use this functionally unknown TTX analog as an olfactory chemoattractant.

scholarly journals Pref-1 (Preadipocyte Factor 1) Activates the MEK/Extracellular Signal-Regulated Kinase Pathway To Inhibit Adipocyte Differentiation

2006 ◽  
Vol 27 (6) ◽  
pp. 2294-2308 ◽  
Author(s):  
Kyung-Ah Kim ◽  
Jung-Hyun Kim ◽  
Yuhui Wang ◽  
Hei Sook Sul
Keyword(s):  
Adipocyte Differentiation ◽  
Transmembrane Protein ◽  
Biologically Active ◽  
Soluble Form ◽  
Null Mouse ◽  
Dependent Manner ◽  
Wild Type ◽  
Extracellular Signal Regulated Kinase ◽  
Erk Phosphorylation ◽  
Extracellular Signal

ABSTRACT Preadipocyte factor 1 (Pref-1) is found in preadipocytes but is absent in adipocytes. Pref-1 is made as a transmembrane protein but is cleaved to generate a biologically active soluble form. Although Pref-1 inhibition of adipogenesis has been well studied in vitro and in vivo, the signaling pathway for Pref-1 is not known. Here, by using purified soluble Pref-1 in Pref-1 null mouse embryo fibroblasts (MEF), we show that Pref-1 increases MEK/extracellular signal-regulated kinase (ERK) phosphorylation in a time- and dose-dependent manner. Compared to wild-type MEF, differentiation of Pref-1 null MEF into adipocytes is enhanced, as judged by lipid accumulation and adipocyte marker expression. Both wild-type and Pref-1 null MEF show a transient burst of ERK phosphorylation upon addition of adipogenic agents. Wild-type MEF show a significant, albeit lower, second increase in ERK phosphorylation peaking at day 2. This ERK phosphorylation, corresponding to Pref-1 abundance, is absent during differentiation of Pref-1 null MEF. Prevention of this second increase in ERK1/2 phosphorylation in wild-type MEF by the MEK inhibitor PD98059 or by transient depletion of ERK1/2 via small interfering RNA-enhanced adipocyte differentiation. Furthermore, treatment of Pref-1 null MEF with Pref-1 restores this ERK phosphorylation, resulting in inhibition of adipocyte differentiation primarily by preventing peroxisome proliferator-activated receptor γ2 induction. However, in the presence of PD98059 or depletion of ERK1/2, exogenous Pref-1 cannot inhibit adipocyte differentiation in Pref-1 null MEF. We conclude that Pref-1 activates MEK/ERK signaling, which is required for Pref-1 inhibition of adipogenesis.

scholarly journals Inhibitory Effect of Arctigenin from Fructus Arctii Extract on Melanin Synthesis via Repression of Tyrosinase Expression

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Hwayong Park ◽  
Kwang Hoon Song ◽  
Pil Mun Jung ◽  
Ji-Eun Kim ◽  
Hyunju Ro ◽  
...  
Keyword(s):  
Active Compound ◽  
Gene Promoter ◽  
Inhibitory Effect ◽  
Tyrosinase Activity ◽  
Dependent Manner ◽  
Melanin Content ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal

To identify the active compound arctigenin in Fructus Arctii (dried seed of medicinal plantArctium lappa) and to elucidate the inhibitory mechanism in melanogenesis, we analyzed melanin content and tyrosinase activity on B16BL6 murine melanoma and melan-A cell cultures. Water extracts of Fructus Arctii were shown to inhibit tyrosinase activity in vitro and melanin content inα-melanocyte stimulating hormone-stimulated cells to similar levels as the well-known kojic acid and arbutin, respectively. The active compound arctigenin of Fructus Arctii displayed little or no cytotoxicity at all concentrations examined and decreased the relative melanin content and tyrosinase activity in a dose-dependent manner. Melanogenic inhibitory activity was also identified in vivo with zebrafish embryo. To determine the mechanism of inhibition, the effects of arctigenin on tyrosinase gene expression and tyrosinase promoter activity were examined. Also in addition, in the signaling cascade, arctigenin dose dependently decreased the cAMP level and promoted the phosphorylation of extracellular signal-regulated kinase. This result suggests that arctigenin downregulates cAMP and the tyrosinase enzyme through its gene promoter and subsequently upregulates extracellular signal-regulated kinase activity by increasing phosphorylation in the melanogenesis signaling pathway, which leads to a lower melanin content.

Sign in / Sign up

Export Citation Format

Share Document