scholarly journals VRK2 Inhibits Mitogen-Activated Protein Kinase Signaling and Inversely Correlates with ErbB2 in Human Breast Cancer

2010 ◽  
Vol 30 (19) ◽  
pp. 4687-4697 ◽  
Author(s):  
Isabel F. Fernández ◽  
Sandra Blanco ◽  
José Lozano ◽  
Pedro A. Lazo
Keyword(s):  
Breast Cancer ◽  
Protein Kinase ◽  
Signaling Pathway ◽  
Protein Interactions ◽  
Human Cancer ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Human Breast ◽  
Erk Phosphorylation ◽  
Mitogen Activated Protein

ABSTRACT The epidermal growth factor (EGF)-ErbB-mitogen-activated protein kinase (MAPK) transcription signaling pathway is altered in many types of carcinomas, and this pathway can be regulated by new protein-protein interactions. Vaccinia-related kinase (VRK) proteins are Ser-Thr kinases that regulate several signal transduction pathways. In this work, we study the effect of VRK2 on MAPK signaling using breast cancer as a model. High levels of VRK2 inhibit EGF and ErbB2 activation of transcription by the serum response element (SRE). This effect is also detected in response to H-Ras(G12V) or B-Raf(V600E) oncogenes and is accompanied by a reduction in phosphorylated extracellular signal-regulated kinase (ERK) levels, p90RSK levels, and SRE-dependent transcription. Furthermore, VRK2 knockdown has the opposite effect, increasing the transcriptional response to stimulation with EGF and leading to increased levels of ERK phosphorylation. The molecular mechanism lies between MAPK/ERK kinase (MEK) and ERK, since MEK remains phosphorylated while ERK phosphorylation is blocked by VRK2A. This inhibition of the ERK signaling pathway is a consequence of a direct protein-protein interaction between VRK2A, MEK, and kinase suppressor of Ras 1 (KSR1). Identification of new correlations in human cancer can lead to a better understanding of the biology of individual tumors. ErbB2 and VRK2 protein levels were inversely correlated in 136 cases of human breast carcinoma. In ErbB2+ tumors, there is a significant reduction in the VRK2 level, suggesting a role for VRK2A in ErbB2-MAPK signaling. Thus, VRK2 downregulation in carcinomas permits signal transmission through the MEK-ERK pathway without affecting AKT signaling, causing a signal imbalance among pathways that contributes to the phenotype of breast cancer.

Preparation of Snake Neurotoxin Nanocapsules and the Analgesic Mechanism of P38 Mitogen-Activated Protein Kinase Signal Pathway Combining Snake Neurotoxin Nanocapsules with Gabapentin

2021 ◽  
Vol 13 (3) ◽  
pp. 463-472
Author(s):  
Fengting Yin ◽  
Xiaokun Li ◽  
Weili Zhang
Keyword(s):  
Neuropathic Pain ◽  
Protein Kinase ◽  
Signaling Pathway ◽  
Glycolic Acid ◽  
Mapk Signaling ◽  
Signal Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Water Phase ◽  
Mitogen Activated Protein ◽  
Snake Neurotoxin

This study aimed to explore the analgesic effect of snake neurotoxin combined with gabapentin (Gab) on neuropathic pain in rats with chronic compression injury (CCI) of the sciatic nerve based on the nanotechnology. Firstly, various solutions were prepared to obtain the inner water phase, the oil phase, the outer water phase, and the dilution phase. Poly(lactic-co-glycolic) Acid (PLGA) and polyethylene glycol-poly(lactic-co-glycolic) acid (PEG-PLGA) were added to the prepared oil phase solution to obtain the PLGA snake neurotoxin nanocapsule and PEG-PLGA snake neurotoxin nanocapsule, respectively. After the nanocapsules were obtained, a rat CCI model was further modelled, and the reactive oxygen species (ROS) content in the rat brain tissue was analyzed and tested by the kit, and the optimal physical conditions for preparing the nanocapsules were tested. In order to test the effect of nanocapsules on the p38 mitogen-activated protein kinase (MAPK) signaling pathway, the rats were divided into Control group, Sham group, CCI group, Gabapentin (Gab) group, and PEG-PLGA snake neurotoxin nanocapsule + Gab group. The rats in different groups were given abdominal injections to compare relevant indicators of signal pathway. In the experiment, neuropathic pain was related to changes in ROS content, and snake neurotoxin nanocapsules could reduce the ROS content; PLGA snake neurotoxin nanocapsules and PEG-PLGA snake neurotoxin nanocapsules had encapsulation efficiencys of 24.7% and 22.8% and drug loading of 3.28% and 3.02%, respectively, and the particle sizes of prepared nanocapsules were 760 nm~1,150 nm. Besides, the phase transition temperature of about 50 °C and the light time of 1 h can accelerate the release of nanocapsules to the greatest extent; and the snake neurotoxin could inhibit the activation of p38 MAPK signaling pathway so as to play the analgesic effects on neuropathic pain.

scholarly journals Identification of RAS-Mitogen-Activated Protein Kinase Signaling Pathway Modulators in an ERF1 Redistribution® Screen

2006 ◽  
Vol 11 (4) ◽  
pp. 423-434 ◽  
Author(s):  
Charlotta Grånäs ◽  
Betina Kerstin Lundholt ◽  
Frosty Loechel ◽  
Hans-Christian Pedersen ◽  
Sara Petersen Bjørn ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Signaling Pathway ◽  
Kinase Inhibitors ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
A Cell ◽  
Protein Kinase Signaling

The RAS-mitogen-activated protein kinase (MAPK) signaling pathway has a central role in regulating the proliferation and survival of both normal and tumor cells. This pathway has been 1 focus area for the development of anticancer drugs, resulting in several compounds, primarily kinase inhibitors, in clinical testing. The authors have undertaken a cell-based, high-throughput screen using a novel ERF1 Redistribution® assay to identify compounds that modulate the signaling pathway. The hit compounds were subsequently tested for activity in a functional cell proliferation assay designed to selectively detect compounds inhibiting the proliferation of MAPK pathway-dependent cancer cells. The authors report the identification of 2 cell membrane-permeable compounds that exhibit activity in the ERF1 Redistribution® assay and selectively inhibit proliferation of MAPK pathway-dependent malignant melanoma cells at similar potencies (IC50 =< 5 μM). These compounds have drug-like structures and are negative in RAF, MEK, and ERK in vitro kinase assays. Drugs belonging to these compound classes may prove useful for treating cancers caused by excessive MAPK pathway signaling. The results also show that cell-based, high-content Redistribution® screens can detect compounds with different modes of action and reveal novel targets in a pathway known to be disease relevant.

scholarly journals Mitogen-Activated Protein Kinase Phosphatase-1 in Human Breast Cancer Independently Predicts Prognosis and Is Repressed by Doxorubicin

2009 ◽  
Vol 15 (10) ◽  
pp. 3530-3539 ◽  
Author(s):  
Federico Rojo ◽  
Irene González-Navarrete ◽  
Rafael Bragado ◽  
Alba Dalmases ◽  
Silvia Menéndez ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Protein Kinase ◽  
Human Breast Cancer ◽  
Mitogen Activated Protein Kinase ◽  
Human Breast ◽  
Mitogen Activated Protein

scholarly journals Chicken avian β-defensin 8 modulates immune response via the mitogen-activated protein kinase signaling pathways in a chicken macrophage cell line

2019 ◽  
Author(s):  
Yeojin Hong ◽  
Thu Thao Pham ◽  
Jiae Lee ◽  
Hyun S. Lillehoj ◽  
Yeong Ho Hong
Keyword(s):  
Protein Kinase ◽  
Signaling Pathway ◽  
Proinflammatory Cytokines ◽  
Interferon Γ ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Macrophage Cell ◽  
Mitogen Activated Protein ◽  
Chicken Macrophage

Abstract Background Defensins are antimicrobial peptides composed of three conserved disulfide bridges, a β-sheet, and both hydrophobic and cationic amino acids. In this study, we aimed to demonstrate the immunomodulation role of avian β-defensin 8 (AvBD8) in a chicken macrophage cell line.Results Chicken AvBD8 stimulated the expression of proinflammatory cytokines (interleukin (IL)-1β, interferon-γ, and IL-12p40) and chemokines (CCL4, CXCL13, and CCL20) in macrophages. Furthermore, by western blotting and immunocytochemistry, we confirmed that AvBD8 activated the mitogen-activated protein kinase (MAPK) signaling pathway via extracellular regulated kinases 1/2 (ERK1/2) and p38 signaling molecules.Conclusion Overall, AvBD8 plays a crucial role in host defense as not only an antimicrobial peptide, but also an immunomodulator by activating the MAPK signaling pathway and inducing the expression of proinflammatory cytokines and chemokines.

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