Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 4 de 4
Filtrar
Mais filtros











Base de dados
Intervalo de ano de publicação
1.
Front Cell Dev Biol ; 10: 979673, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36340039

RESUMO

Stress-activated mitogen-activated protein kinase kinase 7 (MKK7) is a member of the dual-specificity mitogen-activated protein kinase family. In the human body, MKK7 controls essential physiological processes, including but not limited to proliferation and differentiation in multiple tissues and organs. MKK7, along with the MKK4 pathway, has been implicated in stress-activated activities and biological events that are mediated by c-Jun N-terminal kinase (JNK) signaling. Although numerous studies have been performed to identify the role of JNK in multiple biological processes, there are limited publications that focus on dissecting the independent role of MKK7. Recent research findings have spurred testing via in vivo genetically deficient models, uncovering previously undocumented JNK-independent functions of MKK7. Here we discuss both JNK-dependent and-independent functions of MKK7 in vivo. This review summarizes the role of MKK7 in inflammation, cytokine production, cancer, and neurological diseases.

2.
Arterioscler Thromb Vasc Biol ; 42(1): 19-34, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34789002

RESUMO

OBJECTIVE: Fluid shear stress (FSS) is known to mediate multiple phenotypic changes in the endothelium. Laminar FSS (undisturbed flow) is known to promote endothelial alignment to flow, which is key to stabilizing the endothelium and rendering it resistant to atherosclerosis and thrombosis. The molecular pathways responsible for endothelial responses to FSS are only partially understood. In this study, we determine the role of PGC1α (peroxisome proliferator gamma coactivator-1α)-TERT (telomerase reverse transcriptase)-HMOX1 (heme oxygenase-1) during shear stress in vitro and in vivo. Approach and Results: Here, we have identified PGC1α as a flow-responsive gene required for endothelial flow alignment in vitro and in vivo. Compared with oscillatory FSS (disturbed flow) or static conditions, laminar FSS (undisturbed flow) showed increased PGC1α expression and its transcriptional coactivation. PGC1α was required for laminar FSS-induced expression of TERT in vitro and in vivo via its association with ERRα(estrogen-related receptor alpha) and KLF (Kruppel-like factor)-4 on the TERT promoter. We found that TERT inhibition attenuated endothelial flow alignment, elongation, and nuclear polarization in response to laminar FSS in vitro and in vivo. Among the flow-responsive genes sensitive to TERT status, HMOX1 was required for endothelial alignment to laminar FSS. CONCLUSIONS: These data suggest an important role for a PGC1α-TERT-HMOX1 axis in the endothelial stabilization response to laminar FSS.


Assuntos
Células Endoteliais/enzimologia , Heme Oxigenase-1/metabolismo , Mecanotransdução Celular , Proteínas de Membrana/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Telomerase/metabolismo , Animais , Células Cultivadas , Células Endoteliais/patologia , Transição Epitelial-Mesenquimal , Feminino , Regulação Enzimológica da Expressão Gênica , Heme Oxigenase-1/genética , Células Endoteliais da Veia Umbilical Humana/enzimologia , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Masculino , Proteínas de Membrana/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Fluxo Sanguíneo Regional , Estresse Mecânico , Telomerase/genética
3.
Int J Mol Sci ; 22(17)2021 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-34502275

RESUMO

Mitogen kinase kinase 4 (MKK4) and mitogen kinase kinase 7 (MKK7) are members of the MAP2K family that can activate downstream mitogen-activated protein kinases (MAPKs). MKK4 has been implicated in the activation of both c-Jun N-terminal kinase (JNK) and p38 MAPK, while MKK7 has been reported to activate only JNK in response to different stimuli. The stimuli, as well as the cell type determine which MAP2K member will mediate a given response. In various cell types, MKK7 contributes to the activation of downstream MAPKs, JNK, which is known to regulate essential cellular processes, such as cell death, differentiation, stress response, and cytokine secretion. Previous studies have also implicated the role of MKK7 in stress signaling pathways and cytokine production. However, little is known about the degree to which MKK4 and MKK7 contribute to innate immune responses in macrophages or during inflammation in vivo. To address this question and to elucidate the role of MKK4 and MKK7 in macrophage and in vivo, we developed MKK4- and MKK7-deficient mouse models with tamoxifen-inducible Rosa26 CreERT. This study reports that MKK7 is required for JNK activation both in vitro and in vivo. Additionally, we demonstrated that MKK7 in macrophages is necessary for lipopolysaccharide (LPS)-induced cytokine production, M1 polarization, and migration, which appear to be a major contributor to the inflammatory response in vivo. Conversely, MKK4 plays a significant, but minor role in cytokine production in vivo.


Assuntos
Citocinas/metabolismo , MAP Quinase Quinase 7/metabolismo , Animais , Movimento Celular , Células Cultivadas , Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , MAP Quinase Quinase 4/genética , MAP Quinase Quinase 4/metabolismo , MAP Quinase Quinase 7/genética , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/fisiologia , Macrófagos/efeitos dos fármacos , Macrófagos/fisiologia , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/farmacologia
4.
Nat Commun ; 10(1): 4223, 2019 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-31530804

RESUMO

Diseases related to impaired blood flow such as peripheral artery disease (PAD) impact nearly 10 million people in the United States alone, yet patients with clinical manifestations of PAD (e.g., claudication and limb ischemia) have limited treatment options. In ischemic tissues, stress kinases such as c-Jun N-terminal kinases (JNKs), are activated. Here, we show that inhibition of the JNK3 (Mapk10) in the neural compartment strikingly potentiates blood flow recovery from mouse hindlimb ischemia. JNK3 deficiency leads to upregulation of growth factors such as Vegfa, Pdgfb, Pgf, Hbegf and Tgfb3 in ischemic muscle by activation of the transcription factors Egr1/Creb1. JNK3 acts through Forkhead box O3 (Foxo3a) to suppress the activity of Egr1/Creb1 transcription regulators in vitro. In JNK3-deficient cells, Foxo3a is suppressed which leads to Egr1/Creb1 activation and upregulation of downstream growth factors. Collectively, these data suggest that the JNK3-Foxo3a-Egr1/Creb1 axis coordinates the vascular remodeling response in peripheral ischemia.


Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Membro Posterior/irrigação sanguínea , Isquemia/metabolismo , Proteína Quinase 10 Ativada por Mitógeno/metabolismo , Neurônios/metabolismo , Animais , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína 1 de Resposta de Crescimento Precoce/genética , Proteína Forkhead Box O3/genética , Proteína Forkhead Box O3/metabolismo , Membro Posterior/inervação , Membro Posterior/metabolismo , Humanos , Isquemia/genética , Isquemia/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína Quinase 10 Ativada por Mitógeno/genética , Músculo Esquelético/metabolismo , Fluxo Sanguíneo Regional , Transdução de Sinais
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA