ERK5

BACKGROUND: The deSUMOylase sentrin-specific isopeptidase 2 (SENP2) plays a crucial role in atheroprotection. However, the phosphorylation of SENP2 at T368 under disturbed flow (D-flow) conditions hinders its nuclear function and promotes endothelial cell (EC) activation. SUMOylation has been implicated in D-flow-induced endothelial-to-mesenchymal transition (endoMT), but the precise role of SENP2 in counteracting this process remains unclear. METHOD: We developed a phospho-specific SENP2 S344 antibody and generated knock-in (KI) mice with a phospho-site mutation of SENP2 S344A using CRISPR/Cas9 technology...

BACKGROUND: Melatonin plays a role in repairing damaged cartilage and regulating immune cells. The anti-inflammatory effect of Melatonin involves multiple pathways and molecular activation, which directly or indirectly inhibits inflammatory reaction. M2 macrophages have the ability to anti-inflammatory response and repair damaged tissues, secrete IL10 and IL-4, and participate in tissue repair and remodeling. Erk5 is a recently discovered member of the MAPK family and one of the least studied members...

The polarized distribution of membrane proteins into apical and basolateral domains provides the basis for specialized functions of epithelial tissues. The EGF receptor (EGFR) plays important roles in embryonic development, adult epithelial tissue homeostasis, and growth and survival of many carcinomas. Typically targeted to basolateral domains, there is also considerable evidence of EGFR sorting plasticity but very limited knowledge regarding domain-specific EGFR substrates. Here we have investigated effects of selective EGFR mis-targeting because of inactive basolateral sorting signals on epithelial cell homeostatic responses to growth-induced stress in MDCK cell models...

Extracellular signal-regulated kinase 5 (ERK5), also known as BMK1 or MAPK7, represents a recent addition to the classical mitogen-activated protein kinase (MAPK) family. This family includes well-known members such as ERK1/2, c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (p38 MAPK), as well as atypical MAPKs such as ERK3, ERK4, ERK7 (ERK8), and Nemo-like kinase (NLK). Comprehensive reviews available elsewhere provide detailed insights into ERK5, which interested readers can refer to for in-depth knowledge (Nithianandarajah-Jones et al...

Targeted deletion of TRAF7 revealed that it is a crucial part of shear stress-responsive MEKK3-MEK5-ERK5 signaling pathway induced in endothelial cells by blood flow. Similar to Mekk3- , Mek5- or Erk5 -deficient mice, Traf7 -deficient embryos died in utero around midgestation due to impaired endothelium integrity. They displayed significantly lower expression of transcription factor Klf2 , an essential regulator of vascular hemodynamic forces downstream of the MEKK3-MEK-ERK5 signaling pathway. In addition, deletion of Traf7 in endothelial cells of postnatal mice was associated with severe cerebral hemorrhage...

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The practical and facile Mn(OAc)2 -promoted [3+2] cycloaddition reaction of enaminones with isocyanoacetate was developed, that delivered a diversity of 3-aroyl pyrrole-2-carboxylic esters with broad substrates scope. The most of the newly synthesized compounds exhibit moderate antiproliferative activity against four cancer cells. Notably, compound 2n demonstrate the most potent activity with average IC50 values of 5.61 μM against four distinct cancer cell lines. Moreover, 2n exhibit favorable anti-migration activity and drug-like properties...

Modifiable host factors have demonstrated promise to enhance responses to immunotherapy. In this issue, Savage et al. investigated the use of aerobic exercise to enhance antitumor immunity in a murine model of melanoma. They show that treadmill running improves tumor vasculature and alters both T-cell and myeloid-cell infiltration of the tumor via an ERK5-dependent mechanism, adding to the growing evidence supporting the immune-mediated antitumor effects of exercise. See related article by Savage et al. (3)...

Leydig cells produce hormones required for the development and maintenance of sex characteristics and fertility in males. MEF2 transcription factors are important regulators of Leydig cell gene expression and steroidogenesis. ERK5 is an atypical member of the MAP kinase family that modulates transcription factor activity either by direct phosphorylation or by acting as a transcriptional co-activator. While MEF2 and ERK5 are known to cooperate transcriptionally, the presence and role of ERK5 in Leydig cells remained unknown...

Extracellular signal-regulated kinase 5 (ERK5), a member of the mitogen-activated protein kinase (MAPK) family, is involved in key cellular processes. However, overexpression and upregulation of ERK5 have been reported in various cancers, and ERK5 is associated with almost every biological characteristic of cancer cells. Accordingly, ERK5 has become a novel target for the development of anticancer drugs as inhibition of ERK5 shows suppressive effects of the deleterious properties of cancer cells. Herein, we report the synthesis and identification of a novel ERK5 inhibitor, MHJ-627, and verify its potent anticancer efficacy in a yeast model and the cervical cancer HeLa cell line...

Newts have the extraordinary ability to fully regenerate lost or damaged cardiac, neural and retinal tissues, and even amputated limbs. In contrast, mammals lack these broad regenerative capabilities. While the molecular basis of newts' regenerative ability is the subject of active study, the underlying paracrine signaling factors involved remain largely uncharacterized. Extracellular vesicles (EVs) play an important role in cell-to-cell communication via EV cargo-mediated regulation of gene expression patterns within the recipient cells...

Therapy Induced Senescence (TIS) leads to sustained growth arrest of cancer cells. The associated cytostasis has been shown to be reversible and cells escaping senescence further enhance the aggressiveness of cancers. Chemicals specifically targeting senescent cells, so-called senolytics, constitute a promising avenue for improved cancer treatment in combination with targeted therapies. Understanding how cancer cells evade senescence is needed to optimise the clinical benefits of this therapeutic approach. Here we characterised the response of three different NRAS mutant melanoma cell lines to a combination of CDK4/6 and MEK inhibitors over 33 days...

BACKGROUND: Na+ /K+ -ATPase α1 subunit (ATP1A1) exhibits aberrant expression in various types of cancer. Moreover, its levels in specific tissues are associated with the development of cancer. Nevertheless, the mechanism and signaling pathways underlying the effects of ATP1A1 in colon cancer (CC) have not been elucidated, and its prognostic impact remains unknown. METHODS: Knockdown of ATP1A1 expression was performed in human CC cell lines HT29 and Caco2 using small interfering RNA...

Endometriosis is a chronic gynecological disease affecting ~10% women in the reproductive age characterized by the growth of endometrial glands and stroma outside the uterine cavity. The inflammatory process has a key role in the initiation and progression of the disorder. Currently, there are no available early diagnostic tests and therapy relies exclusively on symptomatic drugs, so that elucidation of the complex molecular mechanisms involved in the pathogenesis of endometriosis is an unmet need. The signaling of the bioactive sphingolipid sphingosine 1-phosphate (S1P) is deeply dysregulated in endometriosis...

Sarcomas constitute a heterogeneous group of rare and difficult-to-treat tumors that can affect people of all ages, representing one of the most common forms of cancer in childhood and adolescence. Little is known about the molecular entities involved in sarcomagenesis. Therefore, the identification of processes that lead to the development of the disease may uncover novel therapeutic opportunities. Here, we show that the MEK5/ERK5 signaling pathway plays a critical role in the pathogenesis of sarcomas. By developing a mouse model engineered to express a constitutively active form of MEK5, we demonstrate that the exclusive activation of the MEK5/ERK5 pathway can promote sarcomagenesis...

Following the publication of the above article, an interested reader drew to the authors' attention that, for the Transwell invasion assays shown in Fig. 5D on p. 1326, the images selected for the '0 μM benzidine / 0 μM curcumin' and '0 μM benzidine / 1 μM curcumin' experiments were overlapping, such that these data appeared to have been derived from the same original source. After having consulted their original data, the authors have realized that the '0 μM benzidine / 1 μM curcumin' data panel was selected incorrectly...

Exercise changes the tumor microenvironment by remodeling blood vessels and increasing infiltration by cytotoxic immune cells. The mechanisms driving these changes remain unclear. Herein, we demonstrate that exercise normalizes tumor vasculature and upregulates endothelial expression of VCAM1 in YUMMER 1.7 and B16F10 murine models of melanoma but differentially regulates tumor growth, hypoxia, and the immune response. We found that exercise suppressed tumor growth and increased CD8+ T-cell infiltration in YUMMER but not in B16F10 tumors...

Nav1.8, a tetrodotoxin-resistant voltage-gated sodium channels (VGSCs) subtype encoded by SCN10A, which plays an important role in the production and transmission of peripheral neuropathic pain signals. Studies have shown that VGSCs may be key targets of MicroRNAs (miRNAs) in the regulation of neuropathic pain. In our study, bioinformatics analysis showed that the targeting relationship between miR-3584-5p and Nav1.8 was the most closely. The purpose of this study was to investigate the roles of miR-3584-5p and Nav1...

BACKGROUND: ERK5 (extracellular signal-regulated kinase 5) is a dual kinase transcription factor containing an N-terminal kinase domain and a C-terminal transcriptional activation domain. Many ERK5 kinase inhibitors have been developed and tested to treat cancer and inflammatory diseases. However, recent data have raised questions about the role of the catalytic activity of ERK5 in proliferation and inflammation. We aimed to investigate how ERK5 reprograms myeloid cells to the proinflammatory senescent phenotype, subsequently leading to atherosclerosis...

The intestine of zebrafish consists of mucosa, muscularis and serosa. Intestinal epithelial cells (IECs) act as a physical and biochemical barrier to protect against invasion by external commensal bacteria. Cell junction is one of the crucial basis of the barrier function. When cell junctions were disrupted, intestinal permeability would be naturally impeded. Extracellular signal-regulated kinase 5 (ERK5), belonging to the Mitogen-activated protein kinase (MAPK) family, is involved in the normal physiological development of the cardiovascular system and nervous system...