scholarly journals Constitutive intestinal NF-κB does not trigger destructive inflammation unless accompanied by MAPK activation

2011 ◽  
Vol 208 (9) ◽  
pp. 1889-1900 ◽  
Author(s):  
Monica Guma ◽  
Dariusz Stepniak ◽  
Helena Shaked ◽  
Martina E. Spehlmann ◽  
Steve Shenouda ◽  
...  
Keyword(s):  
Tissue Damage ◽  
Inflammatory Diseases ◽  
Active Form ◽  
Intestinal Barrier ◽  
Tissue Destruction ◽  
Iκb Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Inflammatory Chemokines ◽  
Destructive Inflammation

Nuclear factor (NF)-κB, activated by IκB kinase (IKK), is a key regulator of inflammation, innate immunity, and tissue integrity. NF-κB and one of its main activators and transcriptional targets, tumor necrosis factor (TNF), are up-regulated in many inflammatory diseases that are accompanied by tissue destruction. The etiology of many inflammatory diseases is poorly understood, but often depends on genetic factors and environmental triggers that affect NF-κB and related pathways. It is unknown, however, whether persistent NF-κB activation is sufficient for driving symptomatic chronic inflammation and tissue damage. To address this question, we generated IKKβ(EE)IEC mice, which express a constitutively active form of IKKβ in intestinal epithelial cell (IECs). IKKβ(EE)IEC mice exhibit NF-κB activation in IECs and express copious amounts of inflammatory chemokines, but only small amounts of TNF. Although IKKβ(EE)IEC mice exhibit inflammatory cell infiltration in the lamina propria (LP) of their small intestine, they do not manifest tissue damage. Yet, upon challenge with relatively mild immune and microbial stimuli, IKKβ(EE)IEC mice succumb to destructive acute inflammation accompanied by enterocyte apoptosis, intestinal barrier disruption, and bacterial translocation. Inflammation is driven by massive TNF production, which requires additional activation of p38 and extracellular-signal–regulated kinase mitogen-activated protein kinases (MAPKs).

scholarly journals Modelling of active forms of protein kinases: p38--a case study.

1997 ◽  
Vol 44 (3) ◽  
pp. 557-564
Author(s):  
K Ginalski ◽  
B Lesyng ◽  
J Sowadski ◽  
M Wojciechowski
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
General Scheme ◽  
Active Form ◽  
Binding Mode ◽  
Extracellular Signal Regulated Kinase ◽  
Inactive Form ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

An active form of p38 protein kinase, belonging to the mitogen-activated protein kinases subfamily, has been designed based on crystallographically known structures of two other kinases, an active form of protein kinase A (PKA) and an inactive form of extracellular signal-regulated kinase 2 (ERK2). The modelling procedure is described. Its general scheme can also be applied to other kinases. The structure of the active forms of p38 and PKA is very similar in the region which binds the substrate. The ATP-binding mode is very similar in the active forms of all the three studied kinases. Models of the active forms allow for further studies on transphosphorylation processes at the molecular level, and modelling of inhibitors competitive with ATP and/or substrates.

Inhibition of neutrophil apoptosis by acrolein: a mechanism of tobacco-related lung disease?

2001 ◽  
Vol 281 (3) ◽  
pp. L732-L739 ◽  
Author(s):  
Erik I. Finkelstein ◽  
Mirella Nardini ◽  
Albert van der Vliet
Keyword(s):  
P38 Mapk ◽  
Inflammatory Diseases ◽  
Neutrophil Function ◽  
Human Neutrophils ◽  
Neutrophil Apoptosis ◽  
Membrane Asymmetry ◽  
Extracellular Signal ◽  
Dependent Inhibition ◽  
Mitogen Activated Protein ◽  
Inflammatory Processes

Cigarette smoking is known to contribute to inflammatory diseases of the respiratory tract by promoting recruitment of inflammatory-immune cells such as neutrophils and perhaps by altering neutrophil functional properties. We investigated whether acrolein, a toxic unsaturated aldehyde found in cigarette smoke, could directly affect neutrophil function. Exposure of freshly isolated human neutrophils to acrolein markedly inhibited spontaneous neutrophil apoptosis as indicated by loss of membrane asymmetry and DNA fragmentation and induced increased neutrophil production of the chemokine interleukin-8 (IL-8). Acrolein (1–50 μM) was found to induce marked activation of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinases (MAPKs), and inhibition of p38 MAPK activation by SB-203580 prevented acrolein-induced IL-8 release. However, inhibition of either ERK or p38 MAPK did not affect acrolein-dependent inhibition of apoptosis. Acrolein exposure prevented the activation of caspase-3, a crucial step in the execution of neutrophil apoptosis, presumably by direct inhibition of the enzyme. Our results indicate that acrolein may contribute to smoke-induced inflammatory processes in the lung by increasing neutrophil recruitment and reducing neutrophil clearance by apoptosis.

scholarly journals Repurposing protein degradation for optogenetic modulation of protein activities

2019 ◽  
Author(s):  
Payel Mondal ◽  
Vishnu V. Krishnamurthy ◽  
Savanna R. Sharum ◽  
Neeka Haack ◽  
Kai Zhang
Keyword(s):  
Active Form ◽  
Specific Protein ◽  
Protein Stabilization ◽  
Negative Regulator ◽  
Mitogen Activated Protein Kinase ◽  
Live Cells ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Photoactivatable Proteins

AbstractNon-neuronal optogenetic approaches empower precise regulation of protein dynamics in live cells but often require target-specific protein engineering. To address this challenge, we developed a generalizable light modulated protein stabilization system (GLIMPSe) to control intracellular protein level independent of its functionality. We applied GLIMPSe to control two distinct classes of proteins: mitogen-activated protein kinase phosphatase 3 (MKP3), a negative regulator of the extracellular signal-regulated kinase (ERK) pathway, as well as a constitutively active form of MEK (CA MEK), a positive regulator of the same pathway. Kinetics study showed that light-induced protein stabilization could be achieved within 1 minute of blue light stimulation. GLIMPSe enables target-independent optogenetic control of protein activities and therefore minimizes the systematic variation embedded within different photoactivatable proteins. Overall, GLIMPSe promises to achieve light-mediated post-translational stabilization of a wide array of target proteins in live cells.

scholarly journals ATM and the Catalytic Subunit of DNA-Dependent Protein Kinase Activate NF-κB through a Common MEK/Extracellular Signal-Regulated Kinase/p90rsk Signaling Pathway in Response to Distinct Forms of DNA Damage

2004 ◽  
Vol 24 (5) ◽  
pp. 1823-1835 ◽  
Author(s):  
Ganesh R. Panta ◽  
Swayamjot Kaur ◽  
Lakita G. Cavin ◽  
Maria L. Cortés ◽  
Frank Mercurio ◽  
...  
Keyword(s):  
Dna Damage ◽  
Protein Kinase ◽  
Nuclear Factor Κb ◽  
Catalytic Subunit ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Protein Kinase ◽  
Iκb Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Dependent Protein

ABSTRACT We have identified a novel pathway of ataxia telangiectasia mutated (ATM) and DNA-dependent protein kinase (DNA-PK) signaling that results in nuclear factor κB (NF-κB) activation and chemoresistance in response to DNA damage. We show that the anthracycline doxorubicin (DOX) and its congener N-benzyladriamycin (AD 288) selectively activate ATM and DNA-PK, respectively. Both ATM and DNA-PK promote sequential activation of the mitogen-activated protein kinase (MAPK)/p90 rsk signaling cascade in a p53-independent fashion. In turn, p90 rsk interacts with the IκB kinase 2 (IKK-2) catalytic subunit of IKK, thereby inducing NF-κB activity and cell survival. Collectively, our findings suggest that distinct members of the phosphatidylinositol kinase family activate a common prosurvival MAPK/IKK/NF-κB pathway that opposes the apoptotic response following DNA damage.

scholarly journals Pyropia yezoensis Extract Suppresses IFN-Gamma- and TNF-Alpha-Induced Proinflammatory Chemokine Production in HaCaT Cells via the Down-Regulation of NF-κB

Nutrients ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1238 ◽  
Author(s):  
Yuna Ha ◽  
Won-Hwi Lee ◽  
JaeWoo Jeong ◽  
Mira Park ◽  
Ju-Young Ko ◽  
...  
Keyword(s):  
Pyropia Yezoensis ◽  
Hacat Cells ◽  
Chemokine Production ◽  
Protein Levels ◽  
Extracellular Signal ◽  
Tnf Α ◽  
Mitogen Activated Protein ◽  
Inflammatory Chemokines ◽  
Medicinal Properties ◽  
Hacat Keratinocyte

Pyropia yezoensis, a red alga, is popular and harvested a lot in East Asia and is famous for its medicinal properties attributable to its bioactive compounds including amino acids (porphyra-334 and shinorine, etc.), polysaccharides, phytosterols, and pigments, but its anti-inflammatory effect and mechanism of anti-atopic dermatitis (AD) have not been elucidated. In this study, we investigate the anti-AD effect of P. yezoensis extract (PYE) on mRNA and protein levels of the pro-inflammatory chemokines, thymus, and activation-regulated chemokine (TARC/CCL17) and macrophage-derived chemokine (MDC/CCL22), in human HaCaT keratinocyte cells treated to interferon (IFN)-γ or tumor necrosis factor (TNF)-α (10 ng/mL each). The effect of the PYE on extracellular signal-regulated kinase (ERK) and other mitogen-activated protein kinases (MAPKs) was related to its suppression of TARC and MDC production by blocking NF-κB activation in HaCaT cells. Furthermore, astaxanthin and xanthophyll from P. yezoensis were identified as anti-AD candidate compounds. These results suggest that the PYE may improve AD and contained two carotenoids by regulating pro-inflammatory chemokines.

scholarly journals Identification of 23-(S)-2-Amino-3-Phenylpropanoyl-Silybin as an Antiviral Agent for Influenza A Virus InfectionIn VitroandIn Vivo

2013 ◽  
Vol 57 (9) ◽  
pp. 4433-4443 ◽  
Author(s):  
Jian-Ping Dai ◽  
Li-Qi Wu ◽  
Rui Li ◽  
Xiang-Feng Zhao ◽  
Qian-Ying Wan ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Antiviral Agent ◽  
Screening Strategy ◽  
Mitogen Activated Protein Kinase ◽  
Content Type ◽  
Iκb Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Important Regulator

ABSTRACTIt has been reported that autophagy is involved in the replication of many viruses. In this study, we screened 89 medicinal plants, using an assay based on the inhibition of the formation of the Atg12-Atg5/Atg16 heterotrimer, an important regulator of autophagy, and selectedSilybum marianumL. for further study. An antiviral assay indicated that silybin (S0), the major active compound ofS. marianumL., can inhibit influenza A virus (IAV) infection. We later synthesized 5 silybin derivatives (S1 through S5) and found that 23-(S)-2-amino-3-phenylpropanoyl-silybin (S3) had the best activity. When we compared the polarities of the substituent groups, we found that the hydrophobicity of the substituent groups was positively correlated with their activities. We further studied the mechanisms of action of these compounds and determined that S0 and S3 also inhibited both the formation of the Atg12-Atg5/Atg16 heterotrimer and the elevated autophagy induced by IAV infection. In addition, we found that S0 and S3 could inhibit several components induced by IAV infection, including oxidative stress, the activation of extracellular signal-regulated kinase (ERK)/p38 mitogen-activated protein kinase (MAPK) and IκB kinase (IKK) pathways, and the expression of autophagic genes, especially Atg7 and Atg3. All of these components have been reported to be related to the formation of the Atg12-Atg5/Atg16 heterotrimer, which might validate our screening strategy. Finally, we demonstrated that S3 can significantly reduce influenza virus replication and the associated mortality in infected mice. In conclusion, we identified 23-(S)-2-amino-3-phenylpropanoyl-silybin as a promising inhibitor of IAV infection.

scholarly journals Melanogenesis Inhibitor(s) fromPhyla nodifloraExtract

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Feng-Lin Yen ◽  
Moo-Chin Wang ◽  
Chan-Jung Liang ◽  
Horng-Huey Ko ◽  
Chiang-Wen Lee
Keyword(s):  
Inflammatory Diseases ◽  
Folk Medicine ◽  
Camp Response Element Binding ◽  
Dependent Manner ◽  
Melanin Content ◽  
Camp Response Element ◽  
Alternative Medicines ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Element Binding Protein

Overexpression of tyrosinase can cause excessive production of melanin and lead to hyperpigmentation disorders, including melasma and freckles. Recently, agents obtained from plants are being used as alternative medicines to downregulate tyrosinase synthesis and decrease melanin production.Phyla nodifloraGreene (Verbenaceae) is used as a folk medicine in Taiwanese for treating and preventing inflammatory diseases such as hepatitis and dermatitis. However, the antimelanogenesis activity and molecular biological mechanism underlying the activity of the methanolic extract ofP. nodiflora(PNM) have not been investigated to date. Our results showed that PNM treatment was not cytotoxic and significantly reduced the cellular melanin content and tyrosinase activity in a dose-dependent manner (P<0.05). Further, PNM exhibited a significant antimelanogenesis effect (P<0.05) by reducing the levels of phospho-cAMP response element-binding protein and microphthalmia-associated transcription factor (MITF), inhibiting the synthesis of tyrosinase, tyrosinase-related protein-1 (TRP-1), and TRP-2, and decreasing the cellular melanin content. Moreover, PNM significantly activated the phosphorylation of mitogen-activated protein kinases, including phospho-extracellular signal-regulated kinase, c-Jun N-terminal kinase, and phospho-p38, and inhibited the synthesis of MITF, thus decreasing melanogenesis. These properties suggest that PNM could be used as a clinical and cosmetic skin-whitening agent to cure and/or prevent hyperpigmentation.

scholarly journals PPARγand MEK Interactions in Cancer

PPAR Research ◽  
2008 ◽  
Vol 2008 ◽  
pp. 1-16 ◽  
Author(s):  
Elke Burgermeister ◽  
Rony Seger
Keyword(s):  
Cell Fate ◽  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Mitogen Activated Protein Kinase ◽  
Peroxisome Proliferator ◽  
Signaling Crosstalk ◽  
Peroxisome Proliferator Activated Receptor ◽  
Mapk Cascades ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

Peroxisome proliferator-activated receptor-gamma (PPARγ) exerts multiple functions in determination of cell fate, tissue metabolism, and host immunity. Two synthetic PPARγligands (rosiglitazone and pioglitazone) were approved for the therapy of type-2 diabetes mellitus and are expected to serve as novel cures for inflammatory diseases and cancer. However, PPARγand its ligands exhibit a janus-face behaviour as tumor modulators in various systems, resulting in either tumor suppression or tumor promotion. This may be in part due to signaling crosstalk to the mitogen-activated protein kinase (MAPK) cascades. The genomic activity of PPARγis modulated, in addition to ligand binding, by phosphorylation of a serine residue by MAPKs, such as extracellular signal-regulated protein kinases-1/2 (ERK-1/2), or by nucleocytoplasmic compartmentalization through the ERK activators MAPK kinases-1/2 (MEK-1/2). PPARγligands themselves activate the ERK cascade through nongenomic and often PPARγ-independent signaling. In the current review, we discuss the molecular mechanisms and physiological implications of the crosstalk of PPARγwith MEK-ERK signaling and its potential as a novel drug target for cancer therapy in patients.

scholarly journals A mutation in Irak2c identifies IRAK-2 as a central component of the TLR regulatory network of wild-derived mice

2009 ◽  
Vol 206 (7) ◽  
pp. 1615-1631 ◽  
Author(s):  
James R. Conner ◽  
Irina I. Smirnova ◽  
Alexander Poltorak
Keyword(s):  
Late Phase ◽  
Model Organism ◽  
Nuclear Factor Κb ◽  
Mitogen Activated Protein Kinase ◽  
Model Organisms ◽  
Central Component ◽  
Iκb Kinase ◽  
Extracellular Signal ◽  
Phenotypic Screen ◽  
Mitogen Activated Protein

In a phenotypic screen of the wild-derived mouse strain MOLF/Ei, we describe an earlier and more potent toll-like receptor (TLR)–mediated induction of IL-6 transcription compared with the classical inbred strain C57BL/6J. The phenotype correlated with increased activity of the IκB kinase axis as well as p38, but not extracellular signal-regulated kinase or c-Jun N-terminal kinase, mitogen-activated protein kinase (MAPK) phosphorylation. The trait was mapped to the Why1 locus, which contains Irak2, a gene previously implicated as sustaining the late phase of TLR responses. In the MOLF/Ei TLR signaling network, IRAK-2 promotes early nuclear factor κB (NF-κB) activity and is essential for the activation of p38 MAPK. We identify a deletion in the MOLF/Ei promoter of the inhibitory Irak2c gene, leading to an increased ratio of pro- to antiinflammatory IRAK-2 isoforms. These findings demonstrate that IRAK-2 is an essential component of the early TLR response in MOLF/Ei mice and show a distinct pathway of p38 and NF-κB activation in this model organism. In addition, they demonstrate that studies in evolutionarily divergent model organisms are essential to complete dissection of signal transduction pathways.

scholarly journals Dephosphorylation of specific sites in the kinase-specificity sequence domain leads to ubiquitin-mediated degradation of the tyrosine phosphatase STEP

2011 ◽  
Vol 440 (1) ◽  
pp. 115-125 ◽  
Author(s):  
Saibal Mukherjee ◽  
Ranjana Poddar ◽  
Ishani Deb ◽  
Surojit Paul
Keyword(s):  
Tyrosine Phosphatase ◽  
Critical Role ◽  
Active Form ◽  
Proteasome Inhibitors ◽  
Neuronal Cell ◽  
Inactive Form ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
The Central Nervous System ◽  
Kinase Specificity

STEP (striatal-enriched phosphatase) is a non-receptor tyrosine phosphatase that is specifically expressed in the neurons of the central nervous system. STEP regulates the activity of several effector molecules involved in synaptic plasticity and neuronal cell survival, including MAPKs (mitogen-activated protein kinases), Src family kinases and NMDA (N-methyl-D-aspartic acid) receptors. The critical role of STEP in regulating these effectors requires that its activity be tightly regulated. Previous studies have demonstrated that the activity of STEP is regulated through reversible phosphorylation of a serine residue within the KIM (kinase-interacting motif), by cAMP-dependent PKA (protein kinase A). In the present paper we show that STEP is endogenously phosphorylated at two additional sites located within the KISs (kinase-specificity sequences). The basal activity of ERK (extracellular-signal-regulated kinase) and p38 MAPKs plays an important role in the phosphorylation of these two sites. Dephosphorylation of these two sites leads to polyubiquitination and proteolytic degradation of STEP. Conversely, the proteasome inhibitors MG-132 and epoxomicin can stabilize STEP. The active form of STEP is more susceptible to degradation than the inactive form. Taken together the results of the present paper establish that ubiquitin-dependent proteolysis could be a novel mechanism for irreversibly terminating the activity of STEP.

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