Regulation of ACE2 in cardiac myocytes and fibroblasts

Angiotensin-converting enzyme 2 (ACE2) preferentially forms angiotensin-(1-7) [ANG-(1-7)] from ANG II. We showed that cardiac ACE2 is elevated following treatment of coronary artery-ligated rats with AT1 receptor blockers (ARBs). Cardiac myocytes and fibroblasts were isolated from neonatal rats to determine the molecular mechanisms for the ACE2 upregulation by ARB treatment. ANG II significantly reduced ACE2 activity and downregulated ACE2 mRNA in cardiac myocytes, effects blocked by the ARB losartan, indicating that ANG II regulates ACE2. ANG II also reduced ACE2 mRNA in cardiac fibroblasts; however, no enzyme activity was detected, reflecting the limited expression of ACE2 in these cells. Endothelin-1 (ET-1) also significantly reduced myocyte ACE2 mRNA. The reduction in ACE2 mRNA by ANG II or ET-1 was blocked by inhibitors of mitogen-activated protein kinase kinase 1, suggesting that ANG II or ET-1 activates extracellular signal-regulated kinase (ERK) 1/ERK2 to reduce ACE2. Although ACE2 mRNA was not affected by ANG-(1-7), both the ANG II- and ET-1-mediated reductions in ACE2 mRNA were blocked by the heptapeptide. The ANG-(1-7) modulatory effect was prevented by the ANG-(1-7) receptor antagonist [d-Ala7]-ANG-(1-7), indicating that the ANG-(1-7) response was mediated by a specific AT(1-7) receptor. Myocyte treatment with atrial natriuretic peptide (ANP) also reversed the ACE2 mRNA downregulation by ANG II or ET-1, whereas treatment with ANP alone was ineffective. These results indicate that multiple hypertrophic and anti-hypertropic peptides regulate ACE2 production in myocytes, suggesting that ACE2 expression in the heart is dependent upon the compliment and concentration of regulatory molecules.

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The role of Raf kinases in malignant transformation

Expert Reviews in Molecular Medicine ◽

10.1017/s1462399402004386 ◽

2002 ◽

Vol 4 (8) ◽

pp. 1-18 ◽

Cited By ~ 41

Author(s):

Walter Kolch ◽

Ashwin Kotwaliwale ◽

Keith Vass ◽

Petra Janosch

Keyword(s):

Molecular Mechanisms ◽

Mitogen Activated Protein Kinase ◽

Ras Proteins ◽

Surface Receptors ◽

Extracellular Signal Regulated Kinase ◽

Raf Kinase ◽

Growth Inhibitory ◽

Extracellular Signal ◽

Mitogen Activated Protein

The Raf kinases are proto-oncogenes that work at the entry point of the mitogen-activated protein kinase/extracellular-signal-regulated kinase (MAPK/ERK) pathway, a signalling module that connects cell-surface receptors and Ras proteins to nuclear transcription factors. The pathway impinges on all the functional hallmarks of cancer cells: immortalisation, growth-factor-independent proliferation, insensitivity to growth-inhibitory signals, ability to invade and metastasise, ability to attract blood vessels, and evasion of apoptosis. Indeed, the pathway is hyperactivated in 30% of all human tumours including prevalent cancers of the colon and lung. The molecular mechanisms underlying the role of Raf kinase in tumourigenesis and the opportunities for therapeutic intervention are reviewed in this article.

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Regulation of Nuclear Translocation of Extracellular Signal-Regulated Kinase 5 by Active Nuclear Import and Export Mechanisms

Molecular and Cellular Biology ◽

10.1128/mcb.26.5.1679-1690.2006 ◽

2006 ◽

Vol 26 (5) ◽

pp. 1679-1690 ◽

Cited By ~ 71

Author(s):

Kunio Kondoh ◽

Kazuya Terasawa ◽

Hiroko Morimoto ◽

Eisuke Nishida

Keyword(s):

Nuclear Import ◽

Nuclear Export ◽

Molecular Mechanisms ◽

Nuclear Translocation ◽

Mitogen Activated Protein Kinase ◽

Growth Factor Signaling ◽

Nucleocytoplasmic Shuttling ◽

Extracellular Signal Regulated Kinase ◽

Extracellular Signal ◽

Mitogen Activated Protein

ABSTRACT Extracellular signal-regulated kinase 5 (ERK5), a member of the mitogen-activated protein kinase family, plays an important role in growth factor signaling to the nucleus. However, molecular mechanisms regulating subcellular localization of ERK5 have remained unclear. Here, we show that nucleocytoplasmic shuttling of ERK5 is regulated by a bipartite nuclear localization signal-dependent nuclear import mechanism and a CRM1-dependent nuclear export mechanism. Our results show that the N-terminal half of ERK5 binds to the C-terminal half and that this binding is necessary for nuclear export of ERK5. They further show that the activating phosphorylation of ERK5 by MEK5 results in the dissociation of the binding between the N- and C-terminal halves and thus inhibits nuclear export of ERK5, causing its nuclear import. These results reveal the mechanism by which the activating phosphorylation of ERK5 induces its nuclear import and suggest a novel example of a phosphorylation-dependent control mechanism for nucleocytoplasmic shuttling of proteins.

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Inhibitory Effects of Ketamine on Lipopolysaccharide-Induced Microglial Activation

Mediators of Inflammation ◽

10.1155/2009/705379 ◽

2009 ◽

Vol 2009 ◽

pp. 1-7 ◽

Cited By ~ 50

Author(s):

Yi Chang ◽

Jie-Jen Lee ◽

Cheng-Ying Hsieh ◽

George Hsiao ◽

Duen-Suey Chou ◽

...

Keyword(s):

Molecular Mechanisms ◽

Interleukin 1 ◽

Mitogen Activated Protein Kinase ◽

Induction Agent ◽

Inhibitory Effects ◽

Extracellular Signal Regulated Kinase ◽

Extracellular Signal ◽

Severe Hypotension ◽

Mitogen Activated Protein ◽

Necrosis Factor

Microglia activated in response to brain injury release neurotoxic factors including nitric oxide (NO) and proinflammatory cytokines such as tumor necrosis factor-α(TNF-α) and interleukin-1β(IL-1β). Ketamine, an anesthetic induction agent, is generally reserved for use in patients with severe hypotension or respiratory depression. In this study, we found that ketamine (100 and 250 μM) concentration-dependently inhibited lipopolysaccharide (LPS)-induced NO and IL-1βrelease in primary cultured microglia. However, ketamine (100 and 250 μM) did not significantly inhibit the LPS-induced TNF-αproduction in microglia, except at the higher concentration (500 μM). Further study of the molecular mechanisms revealed that ketamine markedly inhibited extracellular signal-regulated kinase (ERK1/2) phosphorylation but not c-Jun N-terminal kinase or p38 mitogen-activated protein kinase stimulated by LPS in microglia. These results suggest that microglial inactivation by ketamine is at least partially due to inhibition of ERK1/2 phosphorylation.

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Faculty Opinions recommendation of Sequential activation of the MEK-extracellular signal-regulated kinase and MKK3/6-p38 mitogen-activated protein kinase pathways mediates oncogenic ras-induced premature senescence.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1006218.77810 ◽

2002 ◽

Author(s):

Angel Nebreda

Keyword(s):

Protein Kinase ◽

Mitogen Activated Protein Kinase ◽

Premature Senescence ◽

Extracellular Signal Regulated Kinase ◽

Oncogenic Ras ◽

Extracellular Signal ◽

Mitogen Activated Protein ◽

Sequential Activation

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ERK5 and its role in tumour development

Biochemical Society Transactions ◽

10.1042/bst20110663 ◽

2012 ◽

Vol 40 (1) ◽

pp. 251-256 ◽

Cited By ~ 50

Author(s):

Pamela A. Lochhead ◽

Rebecca Gilley ◽

Simon J. Cook

Keyword(s):

Mitogen Activated Protein Kinase ◽

Invasion And Migration ◽

Extracellular Signal Regulated Kinase ◽

Protein Levels ◽

Extracellular Signal ◽

Mapk Signalling ◽

Mitogen Activated Protein ◽

Tumour Cell Invasion ◽

And Migration

The MEK5 [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase 5]/ERK5 pathway is the least well studied MAPK signalling module. It has been proposed to play a role in the pathology of cancer. In the present paper, we review the role of the MEK5/ERK5 pathway using the ‘hallmarks of cancer’ as a framework and consider how this pathway is deregulated. As well as playing a key role in endothelial cell survival and tubular morphogenesis during tumour neovascularization, ERK5 is also emerging as a regulator of tumour cell invasion and migration. Several oncogenes can stimulate ERK5 activity, and protein levels are increased by a novel amplification at chromosome locus 17p11 and by down-regulation of the microRNAs miR-143 and miR-145. Together, these finding underscore the case for further investigation into understanding the role of ERK5 in cancer.

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