Processing of proendothelin‐1 by human furin convertase

Denault, Jean‐Bernard; Claing, Audrey; D’Orléans-Juste, Pedro; Sawamura, Tatsuya; Kido, Toshiko; Takao, Masaki; Leduc, Richard

doi:10.1016/0014-5793(95)00249-9

Cited by 96 publications

(58 citation statements)

References 39 publications

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“…The translation of preproET mRNA results in the formation of a 203-amino acid preproET peptide [10,20]. PreproETs are cleaved at dibasic sites by furin-like endopeptidase to form biologically inactive 37-to 41-amino acid intermediates, termed big ETs [4,9].…”

Section: Et Synthesismentioning

confidence: 99%

The Vascular Endothelin System in Hypertension - Recent Patents and Discoveries

Hynynen

Khalil²

2006

PRC

107

105

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The discovery of endothelin two decades ago has now evolved into an intricate vascular endothelin (ET) system. Several ET isoforms, receptors, signaling pathways, agonists, antagonists, and clinical applications have been identified and documented in first-rate patents. The role of ET as one of the most potent endothelium-derived vasoconstricting factors is now complemented by a newly discovered role in vascular relaxation. ET synthesis is initiated by the transcription of ET genes in endothelial cells and the generation of the gene products preproET and big ET, which are further cleaved by specific ET converting enzymes into ET-1, -2, -3 and -4 isoforms. ET isoforms bind with different affinities to ET A and ET B2 receptors in vascular smooth muscle, and stimulate [Ca 2+ ] i , protein kinase C, mitogen-activated protein kinase and other signaling mechanisms of smooth muscle contraction, growth and proliferation. ET also binds to endothelial ET B1 receptors, which mediate the release of vasodilator substances such as nitric oxide, prostacyclin and endothelium-derived hyperpolarizing factor. Endothelial ET B1 receptors may also function in ET re-uptake and clearance. Although the effects of ET on vascular function and growth are well-recognized, the role of ET and its receptors in the regulation of blood pressure and in the pathogenesis of hypertension is not clearly established. Salt-dependent hypertension in experimental animals and some forms of moderate to severe hypertension in human may show elevated levels of plasma or vascular ET; however, other forms of hypertension show normal ET levels. The currently available ET receptor antagonists reduce blood pressure in some forms of experimental hypertension. Careful examination of recent patents may identify more effective and specific modulators of the vascular ET system for clinical use in human hypertension.

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Section: Et Synthesismentioning

confidence: 99%

The Vascular Endothelin System in Hypertension - Recent Patents and Discoveries

Hynynen

Khalil²

2006

PRC

107

105

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“…3 are a family of 21 amino-acid peptides enzymatically released from 200-residue prepolypeptides (Inoue et al, 1989) by furin-like activity to produce first inactive big ET (Denault et al, 1995). They are then cleaved by endothelin-converting enzyme (ECE-1) to yield the active peptides (Shimada et al, 1995).…”

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confidence: 99%

The Endothelin System in Human Glioblastoma

Egidy

Eberl

Valdenaire

et al. 2000

Laboratory Investigation

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SUMMARY:Endothelin-1 (ET-1) is a powerful mitogenic and/or anti-apoptotic peptide produced by many cancer cells. To evaluate the potential role of the endothelin system in glioblastoma we first determined the cellular distribution of the mRNA and proteins of the components of the endothelin system, preproendothelin-1 (PPET-1), endothelin-converting enzyme-1 (ECE-1), and ET A and ET B receptors in human glioblastoma tissue and glioblastoma cell lines. PPET-1, ECE-1, and ET A receptor were highly expressed in glioblastoma vessels and in some scattered glioblastoma areas whereas ET B receptor was mainly found in cancer cells. This suggests that glioblastoma vessels constitute an important source of ET-1 that acts on cancer cells via the ET B receptor. Four human glioblastoma cell lines expressed mRNA for all of the components of the ET-1 pathway. Bosentan, a mixed ET A and ET B receptor antagonist, induced apoptosis in these cell lines in a dose-dependent manner. Apoptosis was potentiated by Fas Ligand (APO-1L, CD95L), a pro-apoptotic peptide, only in LNZ308 cells, corresponding to the known functional Fas expression in these cell lines. LNZ308 cells also expressed the long and short forms of the cellular FLICE/caspase-8 inhibitory protein (FLIP). Bosentan and a protein kinase C inhibitor down-regulated short FLIP in these cells. ET-1 induced transient phosphorylation of extracellular signal-regulated kinase but did not induce long-term thymidine incorporation in LNZ308 glioblastoma cells. These results suggest that, in glioblastoma cells, ET-1, mainly acting via the ET B receptor, is a survival/antiapoptotic factor produced by tumor vasculature, but not a proliferation factor, involving protein kinase C and extracellular signal-regulated kinase pathways, and stabilization of the short form of FLIP. (Lab Invest 2000, 80:1681-1689.

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“…' Human preproendothelin-1 is a 212-amino acid protein that is proteolytically cleaved, as in the case of many bioactive peptides, at paired basic amino acids, specifically at adjacent positions of Lys51-Arg52 and Arg92-Arg93 by a dibasic-pairspecific endopeptidase, thereby producing a 38-amino acid residue intermediate peptide, termed "big endothelin-1". As an endopeptidase processing preproendothelin-1, furin appears to be a definite enzyme (27). Big endothelin-1 is subsequently cleaved at Trp21-Va122 by a novel endopeptidase, which appears to be specific for endothelin and was putatively termed endothelin converting enzyme (ECE) (Fig.…”

Section: -1 Endothelin Gene and Regulation Of Its Expressionmentioning

confidence: 99%

“…After more than six years, the cloning and characterization of ECE have finally been successfully achieved. ECE is considered to be a potential target for selectively interrupting the biosynthesis of endothelin; although this approach has proven to be extremely difficult, an N-and C-terminaltruncated analogue of big endothelin-1 , [Phe22] big endothelin-1 [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37], was recently shown to be a potent inhibitor of ECE-1, being at least 30-fold more potent that phosphoramidon in blocking big endothelin-linduced vasoconstriction in the kidney (38).…”

Section: -1 Endothelin Gene and Regulation Of Its Expressionmentioning

confidence: 99%

Molecular Pharmacology and Pathophysiological Significance of Endothelin

Goto

Hama

Kasuya

1996

Japanese Journal of Pharmacology

159

108

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ABSTRACT-Since the discovery of the most potent vasoconstrictor peptide, endothelin, in 1988, explosive investigations have rapidly clarified much of the basic pharmacological, biochemical and molecular biological features of endothelin, including the presence and structure of isopeptides and their genes (endothelin-1, -2 and -3), regulation of gene expression, intracellular processing, specific endothelia converting enzyme (ECE), receptor subtypes (ETA and ETB), intracellular signal transduction following receptor activation, etc. ECE was recently cloned, and its structure was shown to be a single transmembrane protein with a short intracellular N-terminal and a long extracellular C-terminal that contains the catalytic domain and numerous N-glycosylation sites. In addition to acute contractile or secretory actions, endothelin has been shown to exert long-term proliferative actions on many cell types. In this case, intracellular signal transduction appears to converge to activation of mitogen-activated protein kinase. As a recent dramatic advance, a number of non-peptide and orally active receptor antagonists have been developed. They, as well as current peptide antagonists, markedly accelerated the pace of investigations into the true pathophysiological roles of endogenous endothelin-1 in mature animals; e.g., hypertension, pulmonary hypertension, acute renal failure, cerebral vasospasm, vascular thickening, cardiac hypertrophy, chronic heart failure, etc. Thus, the interference with the endothelin pathway by either ECE-inhibition or receptor blockade may

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Processing of proendothelin‐1 by human furin convertase

Cited by 96 publications

References 39 publications

The Vascular Endothelin System in Hypertension - Recent Patents and Discoveries

The Vascular Endothelin System in Hypertension - Recent Patents and Discoveries

The Endothelin System in Human Glioblastoma

Molecular Pharmacology and Pathophysiological Significance of Endothelin

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