scholarly journals Targeting MAPK Signaling in Cancer: Mechanisms of Drug Resistance and Sensitivity

2020 ◽  
Vol 21 (3) ◽  
pp. 1102 ◽  
Author(s):  
Shannon Lee ◽  
Jens Rauch ◽  
Walter Kolch
Keyword(s):  
Drug Sensitivity ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Signal Transduction Pathways ◽  
Erk Pathway ◽  
Mapk Pathways ◽  
Extracellular Signaling ◽  
New Findings ◽  
Mitogen Activated Protein

Mitogen-activated protein kinase (MAPK) pathways represent ubiquitous signal transduction pathways that regulate all aspects of life and are frequently altered in disease. Here, we focus on the role of MAPK pathways in modulating drug sensitivity and resistance in cancer. We briefly discuss new findings in the extracellular signaling-regulated kinase (ERK) pathway, but mainly focus on the mechanisms how stress activated MAPK pathways, such as p38 MAPK and the Jun N-terminal kinases (JNK), impact the response of cancer cells to chemotherapies and targeted therapies. In this context, we also discuss the role of metabolic and epigenetic aberrations and new therapeutic opportunities arising from these changes.

scholarly journals Role of Surface-Exposed Loops of Haemophilus influenzae Protein P2 in the Mitogen-Activated Protein Kinase Cascade

2003 ◽  
Vol 71 (5) ◽  
pp. 2798-2809 ◽  
Author(s):  
Stefania Galdiero ◽  
Domenica Capasso ◽  
Mariateresa Vitiello ◽  
Marina D'Isanto ◽  
Carlo Pedone ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Protein Kinase ◽  
Haemophilus Influenzae ◽  
Outer Membrane ◽  
Synthetic Peptides ◽  
Mitogen Activated Protein Kinase ◽  
Signal Transduction Pathways ◽  
Mapk Pathways ◽  
Mitogen Activated Protein

ABSTRACT The outer membrane of gram-negative bacteria contains several proteins, and some of these proteins, the porins, have numerous biological functions in the interaction with the host; porins are involved in the activation of signal transduction pathways and, in particular, in the activation of the Raf/MEK1-MEK2/mitogen-activated protein kinase (MAPK) cascade. The P2 porin is the most abundant outer membrane protein of Haemophilus influenzae type b. A three-dimensional structural model for P2 was constructed based on the crystal structures of Klebsiella pneumoniae OmpK36 and Escherichia coli PhoE and OmpF. The protein was readily assembled into the β-barrel fold characteristic of porins, despite the low sequence identity with the template proteins. The model provides information on the structural features of P2 and insights relevant for prediction of domains corresponding to surface-exposed loops, which could be involved in the activation of signal transduction pathways. To identify the role of surface-exposed loops, a set of synthetic peptides were synthesized according to the proposed model and were assayed for MEK1-MEK2/MAPK pathway activation. Our results show that synthetic peptides corresponding to surface loops of protein P2 are able to activate the MEK1-MEK2/MAPK pathways like the entire protein, while peptides modeled on internal β strands are unable to induce significant phosphorylation of the MEK1-MEK2/MAPK pathways. In particular, the peptides corresponding to loops L5 (Lys206 to Gly219), L6B (Ser239 to Lys253), and L7 (Thr280 to Lys287) activate, as the whole protein, essentially JNK and p38.

scholarly journals Topical Spilanthol Inhibits MAPK Signaling and Ameliorates Allergic Inflammation in DNCB-Induced Atopic Dermatitis in Mice

2019 ◽  
Vol 20 (10) ◽  
pp. 2490 ◽  
Author(s):  
Wen-Chung Huang ◽  
Chun-Hsun Huang ◽  
Sindy Hu ◽  
Hui-Ling Peng ◽  
Shu-Ju Wu
Keyword(s):  
Atopic Dermatitis ◽  
Mast Cells ◽  
Protein Kinase ◽  
Allergic Inflammation ◽  
Skin Lesions ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Mapk Pathways ◽  
Mitogen Activated Protein ◽  
Cox 2

Atopic dermatitis (AD) is a recurrent allergic skin disease caused by genetic and environmental factors. Patients with AD may experience immune imbalance, increased levels of mast cells, immunoglobulin (Ig) E and pro-inflammatory factors (Cyclooxygenase, COX-2 and inducible NO synthase, iNOS). While spilanthol (SP) has anti-inflammatory and analgesic activities, its effect on AD remains to be explored. To develop a new means of SP, inflammation-related symptoms of AD were alleviated, and 2,4-dinitrochlorobenzene (DNCB) was used to induce AD-like skin lesions in BALB/c mice. Histopathological analysis was used to examine mast cells and eosinophils infiltration in AD-like skin lesions. The levels of IgE, IgG1 and IgG2a were measured by enzyme-linked immunosorbent assay (ELISA) kits. Western blot was used for analysis of the mitogen-activated protein kinase (MAPK) pathways and COX-2 and iNOS protein expression. Topical SP treatment reduced serum IgE and IgG2a levels and suppressed COX-2 and iNOS expression via blocked mitogen-activated protein kinase (MAPK) pathways in DNCB-induced AD-like lesions. Histopathological examination revealed that SP reduced epidermal thickness and collagen accumulation and inhibited mast cells and eosinophils infiltration into the AD-like lesions skin. These results indicate that SP may protect against AD skin lesions through inhibited MAPK signaling pathways and may diminish the infiltration of inflammatory cells to block allergic inflammation.

scholarly journals JCPyV-Induced MAPK Signaling Activates Transcription Factors during Infection

2019 ◽  
Vol 20 (19) ◽  
pp. 4779 ◽  
Author(s):  
Jeanne K. DuShane ◽  
Colleen L. Mayberry ◽  
Michael P. Wilczek ◽  
Sarah L. Nichols ◽  
Melissa S. Maginnis
Keyword(s):  
Transcription Factors ◽  
Mapk Signaling ◽  
Mapk Cascade ◽  
Mitogen Activated Protein Kinase ◽  
Erk Pathway ◽  
Downstream Signaling ◽  
Dual Specificity ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Underlying Mechanisms

JC polyomavirus (JCPyV), a ubiquitous human pathogen, is the etiological agent of the fatal neurodegenerative disease progressive multifocal leukoencephalopathy (PML). Like most viruses, JCPyV infection requires the activation of host-cell signaling pathways in order to promote viral replication processes. Previous works have established the necessity of the extracellular signal-regulated kinase (ERK), the terminal core kinase of the mitogen-activated protein kinase (MAPK) cascade (MAPK-ERK) for facilitating transcription of the JCPyV genome. However, the underlying mechanisms by which the MAPK-ERK pathway becomes activated and induces viral transcription are poorly understood. Treatment of cells with siRNAs specific for Raf and MAP kinase kinase (MEK) targets proteins in the MAPK-ERK cascade, significantly reducing JCPyV infection. MEK, the dual-specificity kinase responsible for the phosphorylation of ERK, is phosphorylated at times congruent with early events in the virus infectious cycle. Moreover, a MAPK-specific signaling array revealed that transcription factors downstream of the MAPK cascade, including cMyc and SMAD4, are upregulated within infected cells. Confocal microscopy analysis demonstrated that cMyc and SMAD4 shuttle to the nucleus during infection, and nuclear localization is reduced when ERK is inhibited. These findings suggest that JCPyV induction of the MAPK-ERK pathway is mediated by Raf and MEK and leads to the activation of downstream transcription factors during infection. This study further defines the role of the MAPK cascade during JCPyV infection and the downstream signaling consequences, illuminating kinases as potential therapeutic targets for viral infection.

scholarly journals Role of Muramyl Dipeptide in Lipopolysaccharide-Mediated Biological Activity and Osteoclast Activity

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Hideki Kitaura ◽  
Masahiko Ishida ◽  
Keisuke Kimura ◽  
Haruki Sugisawa ◽  
Akiko Kishikawa ◽  
...  
Keyword(s):  
Biological Activities ◽  
Muramyl Dipeptide ◽  
Mapk Signaling ◽  
Osteoclast Formation ◽  
Mitogen Activated Protein Kinase ◽  
Immunological Activity ◽  
Mitogen Activated Protein

Lipopolysaccharide (LPS) is an endotoxin and bacterial cell wall component that is capable of inducing inflammation and immunological activity. Muramyl dipeptide (MDP), the minimal essential structural unit responsible for the immunological activity of peptidoglycans, is another inflammation-inducing molecule that is ubiquitously expressed by bacteria. Several studies have shown that inflammation-related biological activities were synergistically induced by interactions between LPS and MDP. MDP synergistically enhances production of proinflammatory cytokines that are induced by LPS exposure. Injection of MDP induces lethal shock in mice challenged with LPS. LPS also induces osteoclast formation and pathological bone resorption; MDP enhances LPS induction of both processes. Furthermore, MDP enhances the LPS-induced receptor activator of NF-κB ligand (RANKL) expression and toll-like receptor 4 (TLR4) expression bothin vivoandin vitro. Additionally, MDP enhances LPS-induced mitogen-activated protein kinase (MAPK) signaling in stromal cells. Taken together, these findings suggest that MDP plays an important role in LPS-induced biological activities. This review discusses the role of MDP in LPS-mediated biological activities, primarily in relation to osteoclastogenesis.

scholarly journals Mitogen-activated protein kinase phosphatase 2, MKP-2, regulates early inflammation in acute lung injury

2012 ◽  
Vol 303 (3) ◽  
pp. L251-L258 ◽  
Author(s):  
Timothy T. Cornell ◽  
Andrew Fleszar ◽  
Walker McHugh ◽  
Neal B. Blatt ◽  
Ann Marie Le Vine ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Protein Kinase ◽  
Lung Injury ◽  
Neutrophil Infiltration ◽  
Mitogen Activated Protein Kinase ◽  
Molecular Response ◽  
Proinflammatory Response ◽  
Mapk Pathways ◽  
Mitogen Activated Protein

Acute lung injury (ALI) is mediated by an early proinflammatory response resulting from either a direct or indirect insult to the lung mediating neutrophil infiltration and consequent disruption of the alveolar capillary membrane ultimately leading to refractory hypoxemia. The mitogen-activated protein kinase (MAPK) pathways are a key component of the molecular response activated by those insults triggering the proinflammatory response in ALI. The MAPK pathways are counterbalanced by a set of dual-specific phosphatases (DUSP) that deactivate the kinases by removing phosphate groups from tyrosine or threonine residues. We have previously shown that one DUSP, MKP-2, regulates the MAPK pathway in a model of sepsis-induced inflammation; however, the role of MKP-2 in modulating the inflammatory response in ALI has not been previously investigated. We utilized both MKP-2-null (MKP-2−/−) mice and MKP-2 knockdown in a murine macrophage cell line to elucidate the role of MKP-2 in regulating inflammation during ALI. Our data demonstrated attenuated proinflammatory cytokine production as well as decreased neutrophil infiltration in the lungs of MKP-2−/− mice following direct, intratracheal LPS. Importantly, when challenged with a viable pathogen, this decrease in neutrophil infiltration did not impact the ability of MKP-2−/− mice to clear either gram-positive or gram-negative bacteria. Furthermore, MKP-2 knockdown led to an attenuated proinflammatory response and was associated with an increase in phosphorylation of ERK and induction of a related DUSP, MKP-1. These data suggest that altering MKP-2 activity may have therapeutic potential to reduce lung inflammation in ALI without impacting pathogen clearance.

scholarly journals Interaction between Connexin50 and Mitogen-activated Protein Kinase Signaling in Lens Homeostasis

2009 ◽  
Vol 20 (10) ◽  
pp. 2582-2592 ◽  
Author(s):  
Teresa I. Shakespeare ◽  
Caterina Sellitto ◽  
Leping Li ◽  
Clio Rubinos ◽  
Xiaohua Gong ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Signal Transduction Pathways ◽  
Gap Junctional Communication ◽  
Junctional Communication ◽  
Mitogen Activated Protein ◽  
Gap Junctional

Both connexins and signal transduction pathways have been independently shown to play critical roles in lens homeostasis, but little is known about potential cooperation between these two intercellular communication systems. To investigate whether growth factor signaling and gap junctional communication interact during the development of lens homeostasis, we examined the effect of mitogen-activated protein kinase (MAPK) signaling on coupling mediated by specific lens connexins by using a combination of in vitro and in vivo assays. Activation of MAPK signaling pathways significantly increased coupling provided by Cx50, but not Cx46, in paired Xenopus laevis oocytes in vitro, as well as between freshly isolated lens cells in vivo. Constitutively active MAPK signaling caused macrophthalmia, cataract, glucose accumulation, vacuole formation in differentiating fibers, and lens rupture in vivo. The specific removal or replacement of Cx50, but not Cx46, ameliorated all five pathological conditions in transgenic mice. These results indicate that MAPK signaling specifically modulates coupling mediated by Cx50 and that gap junctional communication and signal transduction pathways may interact in osmotic regulation during postnatal fiber development.

scholarly journals Bark tissue transcriptome analyses of inverted Populus yunnanensis cuttings reveal the crucial role of plant hormones in response to inversion

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e7740 ◽  
Author(s):  
An-Pei Zhou ◽  
Pei-Hua Gan ◽  
Dan Zong ◽  
Xuan Fei ◽  
Yuan-Yuan Zhong ◽  
...  
Keyword(s):  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Receptor Kinase ◽  
Ethylene Response ◽  
Mitogen Activated Protein ◽  
Bark Tissue ◽  
Plant Pathogen Interaction ◽  
Transcriptomic Changes ◽  
Stem Position

Inverted cuttings of Populus yunnanensis exhibit an interesting growth response to inversion. This response is characterized by enlargement of the stem above the shoot site, while the upright stem shows obvious outward growth below the shoot site. In this study, we examined transcriptome changes in bark tissue at four positions on upright and inverted cuttings of P. yunnanensis: position B, the upper portion of the stem; position C, the lower portion of the stem; position D, the bottom of new growth; and position E, the top of new growth. The results revealed major transcriptomic changes in the stem, especially at position B, but little alteration was observed in the bark tissue of the new shoot. The differentially expressed genes (DEGs) were mainly assigned to four pathways: plant hormone signal transduction, plant-pathogen interaction, mitogen-activated protein kinase (MAPK) signaling pathway-plant, and adenosine triphosphate-binding cassette (ABC) transporters. Most of these DEGs were involved in at least two pathways. The levels of many hormones, such as auxin (IAA), cytokinin (CTK), gibberellins (GAs), ethylene (ET), and brassinosteroids (BRs), underwent large changes in the inverted cuttings. A coexpression network showed that the top 20 hub unigenes at position B in the upright and inverted cutting groups were associated mainly with the BR and ET signaling pathways, respectively. Furthermore, brassinosteroid insensitive 1-associated receptor kinase 1 (BAK1) in the BR pathway and both ethylene response (ETR) and constitutive triple response 1 (CTR1) in the ET pathway were important hubs that interfaced with multiple pathways.

scholarly journals Results of TETimaX Trial of Langerhans Cell Histiocytosis Treatment and Perspectives on the Role of Imatinib Mesylate in the Era of MAPK Signaling

Biomedicines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1759
Author(s):  
Liliana Montella ◽  
Margaret Ottaviano ◽  
Vittorio Riccio ◽  
Fernanda Picozzi ◽  
Gaetano Facchini ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Langerhans Cell Histiocytosis ◽  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Mapk Signaling ◽  
Langerhans Cell ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein

Langerhans cell histiocytosis (LCH) is a rare disease that has a variable clinical presentation and unpredictable behavior. Until recently, therapeutic options were limited. Insights into the role of mitogen-activated protein kinase (MAPK) signaling have allowed the increased use of targeted treatments. Before the advent of drugs that interfere with this pathway, investigations concerning the tyrosine kinase inhibitor imatinib opened the way to a rationale-based therapeutic approach to the disease. Imatinib block the binding site of ATP in the BCR/ABL protein and is also a platelet-derived growth factor receptor (PDGFR) and a KIT (CD117) kinase inhibitor. A case of refractory LCH with brain involvement was reported to be successfully treated with imatinib. Thereafter, we further explored the role of this tyrosine kinase inhibitor. The present study is composed of an immunohistochemical evaluation of PDGFRβ expression and a clinical evaluation of imatinib in a series of LCH patients. In the first part, a series of 10 samples obtained from LCH patients was examined and a strong immunohistochemistry expression of PDGFRβ was found in 40% of the cases. In the clinical part of the study, five patients were enrolled. Long-lasting disease control was obtained. These results may suggest a potential role for this drug in the current age.

scholarly journals Adenosine Triphosphate Activates Mitogen-Activated Protein Kinase in Human Granulosa-Luteal Cells*

Endocrinology ◽  
2001 ◽  
Vol 142 (4) ◽  
pp. 1554-1560 ◽  
Author(s):  
Chen-Jei Tai ◽  
Sung Keun Kang ◽  
Chii-Ruey Tzeng ◽  
Peter C. K. Leung
Keyword(s):  
Protein Kinase ◽  
Signaling Pathway ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Intracellular Camp ◽  
Human Ovary ◽  
Luteal Cells ◽  
Mitogen Activated Protein

Abstract ATP has been shown to activate the phospholipase C/diacylglycerol/protein kinase C (PKC) pathway. However, little is known about the downstream signaling events. The present study was designed to examine the effect of ATP on activation of the mitogen-activated protein kinase (MAPK) signaling pathway and its physiological role in human granulosa-luteal cells. Western blot analysis, using a monoclonal antibody that detected the phosphorylated forms of extracellular signal-regulated kinase-1 and -2 (p42mapk and p44 mapk, respectively), demonstrated that ATP activated MAPK in a dose- and time-dependent manner. Treatment of the cells with suramin (a P2 purinoceptor antagonist), neomycin (a phospholipase C inhibitor), staurosporin (a PKC inhibitor), or PD98059 (an MAPK/ERK kinase inhibitor) significantly attenuated the ATP-induced activation of MAPK. In contrast, ATP-induced MAPK activation was not significantly affected by pertussis toxin (a Gi inhibitor). To examine the role of Gs protein, the intracellular cAMP level was determined after treatment with ATP or hCG. No significant elevation of intracellular cAMP was noted after ATP treatment. To determine the role of MAPK in steroidogenesis, human granulosa-luteal cells were treated with ATP, hCG, or ATP plus hCG in the presence or absence of PD98059. RIA revealed that ATP alone did not significantly affect the basal progesterone concentration. However, hCG-induced progesterone production was reduced by ATP treatment. PD98059 reversed the inhibitory effect of ATP on hCG-induced progesterone production. To our knowledge, this is the first demonstration of ATP-induced activation of the MAPK signaling pathway in the human ovary. These results support the idea that the MAPK signaling pathway is involved in mediating ATP actions in the human ovary.

CypA: a Potential Target of Tumor Radiotherapy and/or Chemotherapy

2020 ◽  
Vol 27 ◽  
Author(s):  
Man-Yu Chu ◽  
He-Cheng Huang ◽  
En-Ming Li ◽  
Li-Yan Xu
Keyword(s):  
Cancer Chemotherapy ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Cycle Arrest ◽  
Mitogen Activated Protein ◽  
Intracellular Target ◽  
Related Proteins ◽  
The Impact ◽  
Mapk Signaling Pathways

: Cyclophilin A (CypA) is a ubiquitous and highly conserved protein. CypA, the intracellular target protein for the immunosuppressant cyclosporine A (CsA), plays important cellular roles through peptidyl-prolyl cis-trans isomerase (PPIase). Increasing evidence shows that CypA is up-regulated in a variety of human cancers. In addition to being involved in the occurrence and development of multiple tumors, overexpression of CypA also has been shown to be strongly associated with malignant transformation. Surgery, chemotherapy and radiotherapy are the three main treatments for cancer. Chemotherapy and radiotherapy are often used as direct or adjuvant treatments for cancer. However, various side effects and resistance to both chemotherapy and radiotherapy bring great challenges to these two forms of treatment. According recent reports, CypA can improve the chemosensitivity and/or radiosensitivity of cancers, possibly by affecting the expression of drug-resistant related proteins, cell cycle arrest and activation of the mitogen-activated protein kinase (MAPK) signaling pathways. In this review, we focus on the role of CypA in cancer, the impact on cancer chemotherapeutic and radiotherapy sensitivity, and the mechanism of action. It is suggested that CypA may be a novel potential therapeutic target for cancer chemotherapy and/or radiotherapy.

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