MAP Kinase Phosphatase-5 Deficiency Protects Against Pressure Overload-Induced Cardiac Fibrosis

Cardiac fibrosis, a pathological condition due to excessive extracellular matrix (ECM) deposition in the myocardium, is associated with nearly all forms of heart disease. The processes and mechanisms that regulate cardiac fibrosis are not fully understood. In response to cardiac injury, macrophages undergo marked phenotypic and functional changes and act as crucial regulators of myocardial fibrotic remodeling. Here we show that the mitogen-activated protein kinase (MAPK) phosphatase-5 (MKP-5) in macrophages is involved in pressure overload-induced cardiac fibrosis. Cardiac pressure overload resulting from transverse aortic constriction (TAC) leads to the upregulation of Mkp-5 gene expression in the heart. In mice lacking MKP-5, p38 MAPK and JNK were hyperactivated in the heart, and TAC-induced cardiac hypertrophy and myocardial fibrosis were attenuated. MKP-5 deficiency upregulated the expression of the ECM-degrading matrix metalloproteinase-9 (Mmp-9) in the Ly6Clow (M2-type) cardiac macrophage subset. Consistent with in vivo findings, MKP-5 deficiency promoted MMP-9 expression and activity of pro-fibrotic macrophages in response to IL-4 stimulation. Furthermore, using pharmacological inhibitors against p38 MAPK, JNK, and ERK, we demonstrated that MKP-5 suppresses MMP-9 expression through a combined effect of p38 MAPK/JNK/ERK, which subsequently contributes to the inhibition of ECM-degrading activity. Taken together, our study indicates that pressure overload induces MKP-5 expression and facilitates cardiac hypertrophy and fibrosis. MKP-5 deficiency attenuates cardiac fibrosis through MAPK-mediated regulation of MMP-9 expression in Ly6Clow cardiac macrophages.

The MAP Kinase Phosphatase MKP-1 Modulates Neurogenesis via Effects on BNIP3 and Autophagy

Inherited and acquired defects in neurogenesis contribute to neurodevelopmental disorders, dysfunctional neural plasticity, and may underlie pathology in a range of neurodegenerative conditions. Mitogen-activated protein kinases (MAPKs) regulate the proliferation, survival, and differentiation of neural stem cells. While the balance between MAPKs and the family of MAPK dual-specificity phosphatases (DUSPs) regulates axon branching and synaptic plasticity, the specific role that DUSPs play in neurogenesis remains unexplored. In the current study, we asked whether the canonical DUSP, MAP Kinase Phosphatase-1 (MKP-1), influences neural stem cell differentiation and the extent to which DUSP-dependent autophagy is operational in this context. Under basal conditions, Mkp-1 knockout mice generated fewer doublecortin (DCX) positive neurons within the dentate gyrus (DG) characterized by the accumulation of LC3 puncta. Analyses of wild-type neural stem cell (NSC) differentiation in vitro revealed increased Mkp-1 mRNA expression during the initial 24-h period. Notably, Mkp-1 KO NSC differentiation produced fewer Tuj1-positive neurons and was associated with increased expression of the BCL2/adenovirus E1B 19-kD protein-interacting protein 3 (BNIP3) and levels of autophagy. Conversely, Bnip3 knockdown in differentiated Mkp-1 KO NSCs reduced levels of autophagy and increased neuronal yields. These results indicate that MKP-1 exerts a pro-neurogenic bias during a critical window in NSC differentiation by regulating BNIP3 and basal autophagy levels.

Circular RNA 0006349 Augments Glycolysis and Malignance of Non-small Cell Lung Cancer Cells Through the microRNA-98/MKP1 Axis

Background: The involvement of dysregulated circular RNAs (circRNAs) in human diseases has been increasingly recognized. In this study, we focused on the function of a newly screened circRNA, circ_0006349, in the progression of non-small-cell lung cancer (NSCLC) and the molecules of action.Methods: The NSCLC circRNA dataset GSE101684, microRNA (miRNA) dataset GSE29250, and mRNA dataset GSE51852 obtained from the GEO database were used to identify the differentially expressed genes in NSCLC samples. Tumor and normal tissues were collected from 59 patients with NSCLC. The expression of circ_0006349, miR-98, and MAP kinase phosphatase 1 (MKP1) in collected tissue samples and in acquired cells was determined. The binding relationships between miR-98 and circ_0006349/MKP1 were predicted and validated. Altered expression of circ_0006349, miR-98, and MKP1 was introduced in NSCLC cells to examine their roles in cell growth, apoptosis, and glycolysis.Results: Circ_0006349 and MKP1 were upregulated, and miR-98 was poorly expressed in the collected tumor tissues and the acquired NSCLC cell lines. Circ_0006349 was identified as a sponge for miR-98 to elevate MKP1 expression. Silencing of circ_0006349 suppressed proliferation and increased apoptosis of Calu-3 and H1299 cells, and it reduced glycolysis, glucose uptake, and the production of lactate in cells. Upon circ_0006349 knockdown, further downregulation of miR-98 or upregulation of MKP1 restored the malignant behaviors of cells.Conclusion: This research demonstrated that circ_0006349 derepressed MKP1 expression by absorbing miR-98, which augmented the proliferation and glycolysis of NSCLC cells and promoted cancer development.

MAP kinase phosphatase MKP-1 regulates p-ERK1/2 signaling pathway with fluoride treatment

Background Dental fluorosis is characterized by hypomineralization of tooth enamel caused by ingestion of excessive fluoride during enamel formation. Excess fluoride could have effects on the ERK signaling, which is essential for the ameloblasts differentiation and tooth development. MAP kinase phosphatase-1 (MKP-1) plays a critical role in regulating ERK related kinases. However, the role of MKP-1 in ameloblast and the mechanisms of MKP-1/ERK signaling in the pathogenesis of dental fluorosis are incompletely understood. Results Here, we adopted an in vitro fluorosis cell model using murine ameloblasts-like LS8 cells by employing sodium fluoride (NaF) as inducer. Using this system, we demonstrated that fluoride exposure led to an inhibition of p- MEK and p-ERK1/2 with a subsequent increase in MKP-1 expression in a dose-dependent manner. We further identified, under high dose fluoride, MKP-1 acted as a negative regulator of the fluoride-induced p-ERK1/2 signaling, leading to downregulation of CREB, c-myc, and Elk-1. Conclusion Our results identify a novel MKP-1/ERK signaling mechanism that regulates dental fluorosis and provide a framework for studying the molecular mechanisms of intervention and fluorosis remodeling under normal and pathological conditions. MKP-1 inhibitors may prove to be a benefit therapeutic strategy for dental fluorosis treatment.

MKP1 phosphatase is recruited by CXCL12 in glioblastoma cells and plays a role in DNA strand breaks repair

Glioblastoma (GBM) is the most frequent and aggressive primary tumor in the central nervous system. Previously, the secretion of CXCL12 in the brain subventricular zones has been shown to attract GBM cells and protect against irradiation. However, the exact molecular mechanism behind this radioprotection is still unknown. Here, we demonstrate that CXCL12 modulates the phosphorylation of MAP kinases and their regulator, the nuclear MAP kinase phosphatase 1 (MKP1). We further show that MKP1 is able to decrease GBM cell death and promote DNA repair after irradiation by regulating major apoptotic players, such as Jun-N-terminal kinase, and by stabilizing the DNA repair protein RAD51. Increases in MKP1 levels caused by different corticoid treatments should be reexamined for GBM patients, particularly during their radiotherapy sessions, in order to prevent or to delay the relapses of this tumor.