Ablation of MEK Kinase 1 Suppresses Intimal Hyperplasia by Impairing Smooth Muscle Cell Migration and Urokinase Plasminogen Activator Expression in a Mouse Blood-Flow Cessation Model

Li, Yan; Minamino, Tetsuo; Tsukamoto, Osamu; Yujiri, Toshiaki; Shintani, Yasunori; Okada, Ken; Nagamachi, Y.; Fujita, Masashi; Hirata, Akio; Shoji, Shuichi; Asanuma, Hiroshi; Takashima, Seiji; Hori, Masatsugu; Johnson, Gary L.; Kitakaze, Masafumi

doi:10.1161/01.cir.0000160350.20810.0f

Cited by 14 publications

(12 citation statements)

References 37 publications

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“…However, complete ligation of the right common carotid artery in mekk1 -/-mice resulted in a significant decrease in intimal regions compared to WT mice. These results indicate that Mekk1 plays a role in vascular remodelling after blood-flow cessation (Li et al 2005;Minamino et al 2002).…”

Section: Mekk1mentioning

confidence: 60%

In vivo functions of mitogen-activated protein kinases: conclusions from knock-in and knock-out mice

2007

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Multicellular organisms achieve intercellular communication by means of signalling molecules whose effect on the target cell is mediated by signal transduction pathways. Such pathways relay, amplify and integrate signals to elicit appropriate biological responses. Protein kinases form crucial intermediate components of numerous signalling pathways. One group of protein kinases, the mitogen-activated protein kinases (MAP kinases) are kinases involved in signalling pathways that respond primarily to mitogens and stress stimuli. In vitro studies revealed that the MAP kinases are implicated in several cellular processes, including cell division, differentiation, cell survival/apoptosis, gene expression, motility and metabolism. As such, dysfunction of specific MAP kinases is associated with diseases such as cancer and immunological disorders. However, the genuine in vivo functions of many MAP kinases remain elusive. Genetically modified mouse models deficient in a specific MAP kinase or expressing a constitutive active or a dominant negative variant of a particular MAP kinase offer valuable tools for elucidating the biological role of these protein kinases. In this review, we focus on the current status of MAP kinase knock-in and knock-out mouse models and their phenotypes. Moreover, examples of the application of MAP kinase transgenic mice for validating therapeutic properties of specific MAP kinase inhibitors, and for investigating the role of MAP kinase in pathogen-host interactions will be discussed.

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Section: Mekk1mentioning

confidence: 60%

In vivo functions of mitogen-activated protein kinases: conclusions from knock-in and knock-out mice

2007

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“…Because pericyte recruitment represents another important step in tumor angiogenesis that involves MEK signaling (21,45,46), we hypothesized that …”

Section: Discussionmentioning

confidence: 99%

Dual targeting of Raf and VEGF receptor 2 reduces growth and metastasis of pancreatic cancer through direct effects on tumor cells, endothelial cells, and pericytes

Lang¹,

Schachtschneider²,

Moser³

et al. 2008

Molecular Cancer Therapeutics

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The Ras/Raf/MEK pathway represents an important oncogenic signaling pathway in gastrointestinal malignancies, including pancreatic cancer. Although activating B-Raf mutations are infrequent in pancreatic cancer, we hypothesized that targeting Raf could be valuable for therapy of this cancer entity. Moreover, as vascular endothelial growth factor receptor 2 (VEGFR2) is involved in tumor angiogenesis, we sought to investigate the effects of dual inhibition of Raf and VEGFR2 on pancreatic tumor growth, vascularization, and metastasis. Effects of a Raf/VEGFR2 inhibitor (NVP-AAL881) on pancreatic cancer cells, endothelial cells, and vascular smooth muscle cells were determined by Western blotting, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide analysis, and migration assays, respectively. Changes in the expression of VEGF-A or survivin were investigated by ELISA and/or real-time PCR. The growthinhibitory effects of Raf/VEGFR2 inhibition were additionally evaluated in orthotopic tumor models. Results showed that various Raf isoforms were activated in pancreatic cancer cells and NVP-AAL881 diminished the activation of MEK, Akt, Erk, and also STAT3. Moreover, dual inhibition of Raf/VEGFR2 significantly reduced VEGF expression and impaired cancer cell migration. Importantly, besides blocking VEGF-induced Erk and SAPK phosphorylation in endothelial cells, the Raf inhibitor diminished STAT3 phosphorylation, independent of a VEGFR2 blockade, and reduced the expression of survivin. In addition, cell proliferation and migration of both endothelial cells and vascular smooth muscle cells were significantly reduced. In vivo, blocking Raf/VEGFR2 significantly inhibited orthotopic tumor growth and vascularization and reduced cancer metastasis. In conclusion, blocking Raf exerts growth-inhibitory effects on pancreatic tumor cells, endothelial cells, and pericytes and elicits antiangiogenic properties. Dual targeting of Raf and VEGFR2 appears to be a valid strategy for therapy of pancreatic cancer.

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“…MAP3K1 (also known as MEKK1) plays a role in lymphocyte differentiation and function [Suddason and Gallagher, 2016], vasculature remodeling [Li et al, 2005], cardiogenesis [Minamino et al, 2002], as well as injury repair [Deng et al, 2006]. The MAP3K1 protein contains an amino terminal plant homeodomain (PHD) motif that has E3 Ub ligase activity, a caspase-3 cleavage site, and a conserved kinase domain.…”

Section: Map3k1mentioning

confidence: 99%

Mechanism of Sex Determination in Humans: Insights from Disorders of Sex Development

Bashamboo

2016

Sex Dev

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In this review we will consider the gene mutations responsible for the non-syndromic forms of disorders of sex development (DSD) and how recent genetic findings are providing insights into the mechanism of sex determination. High-throughput sequencing technologies are having a major impact on our understanding of the genetic basis of rare human disorders, including DSD. The study of human DSD is progressively revealing subtle differences in the genetics of the sex-determining system between the mouse and the human. This plasticity of the sex-determining pathway is apparent in (a) the difference in phenotypes in human and mouse associated with the same gene, (b) the different gene regulatory mechanisms between human and mouse, and finally (c) the different and unexpected reproductive phenotypes seen in association with mutations in well-studied sex-determining genes.

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Ablation of MEK Kinase 1 Suppresses Intimal Hyperplasia by Impairing Smooth Muscle Cell Migration and Urokinase Plasminogen Activator Expression in a Mouse Blood-Flow Cessation Model

Cited by 14 publications

References 37 publications

In vivo functions of mitogen-activated protein kinases: conclusions from knock-in and knock-out mice

In vivo functions of mitogen-activated protein kinases: conclusions from knock-in and knock-out mice

Dual targeting of Raf and VEGF receptor 2 reduces growth and metastasis of pancreatic cancer through direct effects on tumor cells, endothelial cells, and pericytes

Mechanism of Sex Determination in Humans: Insights from Disorders of Sex Development

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