scholarly journals Bag3 P209L myopathies and efficacy of blocking signaling pathways with the therapeutic peptide, MMI-0100

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Ashley R. Hacker ◽  
Jessica M. Berthiaume ◽  
Monte S. Willis
Keyword(s):  
P38 Mapk ◽  
Cardiac Dysfunction ◽  
Systolic Function ◽  
Critical Role ◽  
Mapk Signaling ◽  
Signaling Cascade ◽  
Littermate Control ◽  
Cellular Processes ◽  
Established Disease ◽  
First Time

Background and Hypothesis: The Bcl2-associated anthanogene (BAG) 3 protein is a member of the BAG family of cochaperones, which play a critical role in cellular processes, including protein degradation and turnover. Over 30 Bag3 mutations have been identified, including a Proline209Leucine (P209L) missense mutation which causes a severe childhood cardiomyopathy. The mechanism by which Bag3 mutations causes cardiomyopathy is currently unknown, but the p38/MAPK signaling cascade has been shown to be altered in our animal model that coexpresses the human Bag3 P209L gene. We hypothesized the cell-permeant peptide, MMI-0100, which is known to inhibit MAPK-activated protein kinase 2 (MK2) activity in the p38/MAPK signaling cascade, would alleviate or reduce cardiac dysfunction. Experimental Design: Echocardiographic analysis of cardiac function of cardiac-specific Bag3 P209L transgenic (and wildtype littermate control) mice (20 – 22 months of age) was assessed by high-resolution ultrasound echocardiography (VisualSonics Vevo 2100, MS550D probe, cardiology package) to document the established disease-related cardiac dysfunction at baseline. Mice were then treated with 100mg/kg/day MMI-0100 nebulized daily for 30 days. Follow-up echocardiography was performed at 10, 20, and 30 days of MMI-0100 treatment. Echocardiographic analysis was performed to determine the systolic function (EF%, FS%), chamber dimensions, and wall thickness in systole and diastole using Vevo 2100 Workstation software package. Results: Blinded analysis of echocardiographic data identified that Bag3 P209L Tg+ mice had a baseline cardiac dysfunction compared to wildtype controls at 20 months of age (WT= 76% EF, 44% FS; Tg+= 66% EF, 36% FS). MMI-0100 treatment significantly attenuated this dysfunction by 20 days of MMI-0100 treatment (WT= 79% EF, 47% FS; Tg+= 80% EF, 48% FS), consistent with demonstrating for the first time MK2’s role in mediating p38 signaling in the pathogenesis of Bag3 P209L cardiomyopathy. Conclusion and Potential Impact: The MMI-0100 peptide has proven efficacious in several animal models of fibrosis driven by p38 signaling, as MK2 is a p38 downstream mediator. Future studies seek to translate the use of the MMI-0100 peptide in pediatric patients with Bag3 P209L cardiomyopathy through compassionate use FDA pathways.

Resveratrol Ameliorates Diabetes-Induced Cardiac Dysfunction Through AT1R-ERK/p38 MAPK Signaling Pathway

2015 ◽  
Vol 16 (2) ◽  
pp. 130-137 ◽  
Author(s):  
Yonglin Gao ◽  
Le Kang ◽  
Chunmei Li ◽  
Xiaoyan Wang ◽  
Chengfeng Sun ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
P38 Mapk ◽  
Cardiac Dysfunction ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway

p62 as a Therapeutic Target for Myeloma Cell Growth and Osteoclast Formation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2857-2857
Author(s):  
Fumito Ishizuka ◽  
Jolene Windle ◽  
David Roodman ◽  
Noriyoshi Kurihara
Keyword(s):  
Cell Growth ◽  
P38 Mapk ◽  
Stromal Cells ◽  
Stromal Cell ◽  
Critical Role ◽  
Mapk Signaling ◽  
Marrow Stromal Cells ◽  
Fusion Peptides ◽  
Binding Domains ◽  
Cell Support

Abstract Abstract 2857 Poster Board II-833 We reported that sequestosome 1 (p62) plays a critical role in the formation of signaling complexes that result in NF-kB, p38 MAPK, and PI3K activation in the marrow microenvironment of patients with multiple myeloma (MM), and that p62 is a potential therapeutic target for MM. In contrast to treating patients with inhibitors of each of the multiple signaling pathways activated in marrow stromal cells by MM cells (e.g. NF-kB or p38 MAPK), blocking the function of p62 should inhibit the activation of the multiple pathways mediated by p62 and have a broader effect on the bone marrow microenvironment. The goal of this study was to identify the domains of p62 responsible for increased MM cell growth and osteoclast (OCL) formation mediated by NF-kB and p38 MAPK signaling in marrow stromal cells when they interact with myeloma cells, and develop inhibitory peptides as potential therapeutic agents that interfere with p62's role in these signaling complexes. To pursue this objective, we transfected p62−/− stromal cells with p62 deletion constructs and assessed their effects on NF-kB and p38 MAPK signaling induced by MM cells or TNF-a. p62−/− stromal cells support of MM growth or OCL formation was significantly decreased compared to WT stromal cells. We made a series of 5' deletion constructs of p62 that lacked specific p62 domains: ΔPB1 (Δ1) lacks homodimerization domain and binding to PKCz, ΔPB1, ZZ (Δ2) lacks PB1 and RIP1 binding domains, and ΔPB1, ZZ, TBS, (Δ3) the PB1, RIP1, p38 and TRAF6 binding domains have been deleted. These constructs were tested for their capacity to restore p62 function in p62−/−stromal cells and support MM cell growth and OCL formation. GFP-labeled MM1.S myeloma cells were cocultured with p62−/− and WT marrow stromal cells transduced with the different p62 deletion constructs. Transduction of p62−/− stromal cells with the full-length p62 construct restored the capacity of p62−/− stromal cells to enhance the growth of MM cells to levels induced by WT stromal cells. Transduction of p62−/− stromal cells with the Δ1 construct also restored stromal cell support of MM growth. Therefore, the PB1 domain is not important for this function. Transduction of p62−/− stromal cells with the Δ2 construct, resulted in an inability of the stromal cells to support MM cell growth. Additional loss of the p38 and TRAF6 binding domains did not further impair p62−/− stromal cells support of MM cell growth. These results suggest that the RIP1 binding domain plays a critical role in supporting the growth of MM cells by marrow stromal cells. We then examined the capacity of p62−/− stromal cells transduced with various p62 deletion constructs to support OCL formation. Normal CFU-GM, a source of OCL precursors, were cocultured with p62−/− stromal cells transfected with the different p62 cDNA deletion constructs. The Δ1 construct completely rescued p62−/− support of OCL formation. However, Δ2 construct transduced p62−/− stromal cells only partly restored stromal cell support of OCL formation. Transduction of the Δ3 construct did not restore the capacity of the p62−/− stromal cells to support OCL formation. Similarly, transduction of the Δ2 and Δ3 construction decreased WT stromal cell support of MM cell growth. We then tested the feasibility of using transduction domain (PTD) fusion peptides as a potential means of delivering dominant negative p62 constructs into stromal cells in vitro and in vivo to block MM cell growth and VCAM-1 expression induced by marrow stromal cells. PTD binding domain fusion peptides containing NEMO binding protein that blocks NF-kB activity was used as a model system to determine the feasibility of transducing marrow stromal cells with p62 constructs. Addition of PTD-NEMO fusion peptides to stromal cells significantly inhibited WT stromal cell to enhance MM cell growth and VCAM-1 expression on stromal cells, which is the capacity of dependent, in part, on NF-kB signaling. These results demonstrate that the ZZ, p38 MAPK and TRAF-6 domains of p62 together are required for stromal cell support of MM cell growth and OCL formation and suggest that PTD constructs containing dominant negatives for p62 may be a feasible method for blocking p62 function in the MM marrow microenvironment. Disclosures: Roodman: Novartis: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy; Celgene: Consultancy; Acceleron: Consultancy.

TGF-β-activated kinase 1 and TAK1-binding protein 1 cooperate to mediate TGF-β1-induced MKK3-p38 MAPK activation and stimulation of type I collagen

2007 ◽  
Vol 292 (5) ◽  
pp. F1471-F1478 ◽  
Author(s):  
Sung Il Kim ◽  
Joon Hyeok Kwak ◽  
Mareena Zachariah ◽  
Yanjuan He ◽  
Lin Wang ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Type I Collagen ◽  
Mesangial Cells ◽  
Constitutive Expression ◽  
Mapk Signaling ◽  
Signaling Cascade ◽  
Type I ◽  
Protein Levels ◽  
Collagen Expression ◽  
P38α Mapk

We have previously demonstrated that transforming growth factor-β1 (TGF-β1) rapidly activates the mitogen-activated protein kinase kinase 3 (MKK3)-p38 MAPK signaling cascade, leading to the induction of type I collagen synthesis in mouse glomerular mesangial cells (Wang L, Ma R, Flavell RA, Choi ME. J Biol Chem 277: 47257–47262, 2002). In the present study, we investigated the functional role of upstream TGF-β-activated kinase 1 (TAK1) and TAK1-binding protein 1 (TAB1) in the TGF-β1 signaling cascade. Rapid activation of endogenous TAK1 activity by TGF-β1 was observed in mouse mesangial cells. Transient overexpression of TAK1 with TAB1 enhanced the activation of MKK3 and p38 MAPK with or without TGF-β1 stimulation, whereas a dominant-negative mutant of TAK1 (TAK1DN) suppressed TGF-β1-induced activation of MKK3 and p38 MAPK. Moreover, constitutive expression of TAK1DN reduced steady-state protein levels of MKK3 and p38 MAPK as well as MKK3 phosphorylation. Increased p38α MAPK activity by ectopic expression of either TAB1 or wild-type p38α MAPK resulted in enhanced TGF-β1-induced type I collagen expression. In contrast, constitutive expression of TAK1DN inhibited collagen induction. Taken together, our data indicate that TAK1 and TAB1 play a pivotal role as upstream signal transducers activating the MKK3-p38 MAPK signaling cascade that leads to the induction of type I collagen expression by TGF-β1. In addition, our findings also suggest that TAK1 has a novel function in regulation of the steady-state protein levels of MKK3 and p38 MAPK.

Synthesis, characterization and in vitro and in vivo photodynamic activities of a gallium(iii) tris(ethoxycarbonyl)corrole

2017 ◽  
Vol 46 (29) ◽  
pp. 9481-9490 ◽  
Author(s):  
Zhao Zhang ◽  
Hua-Hua Wang ◽  
Hua-Jun Yu ◽  
Yu-Zhen Xiong ◽  
Hai-Tao Zhang ◽  
...  
Keyword(s):  
Cancer Cells ◽  
P38 Mapk ◽  
Mapk Signaling ◽  
Signaling Cascade ◽  
Highly Effective

A gallium(iii) tris(ethoxycarbonyl)corrole is a highly effective photosensitizer against A549 cancer cells via p38 MAPK signaling cascade pathways.

scholarly journals Acquisition of Letrozole Resistance Through Activation of the p38/MAPK Signaling Cascade

2021 ◽  
Vol 41 (2) ◽  
pp. 583-599
Author(s):  
RASHIDRA R. WALKER ◽  
KAREN M. GALLEGOS ◽  
MELYSSA R. BRATTON ◽  
KITANI P. LEMIEUX ◽  
KUN ZHANG ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Mapk Signaling ◽  
Signaling Cascade

Involvement of the p38 MAPK signaling cascade in stress response of RAW 264.7 macrophages

2017 ◽  
Vol 476 (1) ◽  
pp. 203-205 ◽  
Author(s):  
E. G. Novoselova ◽  
O. V. Glushkova ◽  
M. O. Khrenov ◽  
S. B. Parfenyuk ◽  
S. M. Lunin ◽  
...  
Keyword(s):  
Stress Response ◽  
P38 Mapk ◽  
Mapk Signaling ◽  
Signaling Cascade ◽  
Raw 264.7 ◽  
Raw 264.7 Macrophages

scholarly journals p38 MAPK Signaling in Pemphigus: Implications for Skin Autoimmunity

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Athanasios Mavropoulos ◽  
Timoklia Orfanidou ◽  
Christos Liaskos ◽  
Daniel S. Smyk ◽  
Vassiliki Spyrou ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Pemphigus Vulgaris ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Current Evidence ◽  
Pemphigus Foliaceus ◽  
P38 Mapk Inhibitors ◽  
Mapk Inhibitors

p38 mitogen activated protein kinase (p38 MAPK) signaling plays a major role in the modulation of immune-mediated inflammatory responses and therefore has been linked with several autoimmune diseases. The extent of the involvement of p38 MAPK in the pathogenesis of autoimmune blistering diseases has started to emerge, but whether it pays a critical role is a matter of debate. The activity of p38 MAPK has been studied in great detail during the loss of keratinocyte cell-cell adhesions and the development of pemphigus vulgaris (PV) and pemphigus foliaceus (PF). These diseases are characterised by autoantibodies targeting desmogleins (Dsg). Whether autoantibody-antigen interactions can trigger signaling pathways (such as p38 MAPK) that are tightly linked to the secretion of inflammatory mediators which may perpetuate inflammation and tissue damage in pemphigus remains unclear. Yet, the ability of p38 MAPK inhibitors to block activation of the proapoptotic proteinase caspase-3 suggests that the induction of apoptosis may be a consequence of p38 MAPK activation during acantholysis in PV. This review discusses the current evidence for the role of p38 MAPK in the pathogenesis of pemphigus. We will also present data relating to the targeting of these cascades as a means of therapeutic intervention.

scholarly journals R-Fluoxetine Increases Melanin Synthesis Through a 5-HT1A/2A Receptor and p38 MAPK Signaling Pathways

2018 ◽  
Vol 20 (1) ◽  
pp. 80 ◽  
Author(s):  
Li Liu ◽  
Mengsi Fu ◽  
Siran Pei ◽  
Liangliang Zhou ◽  
Jing Shang
Keyword(s):  
P38 Mapk ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Critical Role ◽  
Anxiolytic Effect ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Racemic Mixture ◽  
Melanin Synthesis ◽  
Mitogen Activated Protein

Fluoxetine, a member of the class of selective serotonin reuptake inhibitors, is a racemic mixture and has an anxiolytic effect in rodents. Previously, we have shown that fluoxetine can up-regulate melanin synthesis in B16F10 melanoma cells and normal human melanocytes (NMHM). However, the role of r-fluoxetine and s-fluoxetine, in the regulation of melanin synthesis, is still unknown. Here, we show how r-fluoxetine plays a critical role in fluoxetine enhancing melanogenesis, both in vivo and vitro, by up-regulating tyrosinase (TYR) and the microphthalmia-associated transcription factor (MITF) expression, whereas, s-fluoxetine does not show any effect in the vivo and vitro systems. In addition, we found that r-fluoxetine induced melanin synthesis through the serotonin1A receptor (5-HT1A) and serotonin 2A receptor (5-HT2A). Furthermore, r-fluoxetine increased the phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK), without affecting the phosphorylation of extracellularly responsive kinase (ERK1/2) and c-Jun N-terminal kinase (JNK). These data suggest that r-fluoxetine may be used as a drug for skin hypopigmentation disorders.

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