Processing of prodynorphin by the prohormone convertase PC1 results in high molecular weight intermediate forms

Dupuy, Aurélie; Lindberg, Iris; Yi, Zili; Akil, Huda; Lazure, Claude; Chrétien, Michel; Seidah, Nabil G.; Day, Robert

doi:10.1016/0014-5793(94)80630-6

Cited by 75 publications

(61 citation statements)

References 29 publications

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“…This survey of convertase expression in SCLCs strongly suggests that PCI and PC2 are the two convertases most likely to play a role in the maintenance of the neoplastic phenotype of these cells. They would be involved in the activation of several of the various precursors to growth factors produced by the cells, such as AVP, GRP, EGF and CCK (Cook et al, 1993;Moody and Cuttitta, 1993;Bepler and Garcia-Blanco, 1994); it has been suggested that the release of small bioactive peptides, such as these, from their precursors is mediated by PC2 (Dupuy et al, 1994;Seidah and Chretien, 1994). PC2 has been implicated in the conversion of proGRP to GRP (Dickinson et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Comparative analysis of expression of the proprotein convertases furin, PACE4, PC1 and PC2 in human lung tumours

Mbikay

Sirois²,

Yao³

et al. 1997

Br J Cancer

122

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Summary Proprotein convertases mediate the production of a variety of peptidic mitogens by limited proteolysis of their precursors. These proteases may also participate in the autocrine production of such mitogens by cancer cells and thus contribute to the unchecked proliferation of these cells. As a step towards defining this contribution, we have examined the levels of four convertase mRNAs in human lung neoplasms using semiquantitative Northern blot analysis. Furin mRNA was expressed in all the tumours; its level in squamous cell carcinomas and adenocarcinomas was on average about threefold higher than in small-cell lung carcinomas (SCLCs). PACE4 transcripts were detected in eight of 14 adenocarcinomas and in seven of 17 squamous cell carcinomas; they were detectable in only two of seven SCLCs. PC1 mRNA was undetected in squamous cell carcinomas and in all but two adenocarcinomas; it was present in four of six SCLCs. PC2 mRNA was found in two adenocarcinomas, in one squamous cell carcinoma and in five of seven SCLCs. This preliminary survey indicates that SCLCs often carry more mRNA for the endocrine convertases PC1 and PC2 and less mRNA for the more ubiquitous furin and PACE4, suggesting inverse roles of these convertases in the development of this neoplasm.

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Section: Discussionmentioning

confidence: 99%

Comparative analysis of expression of the proprotein convertases furin, PACE4, PC1 and PC2 in human lung tumours

Mbikay

Sirois²,

Yao³

et al. 1997

Br J Cancer

122

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“…A number of studies (both in vitro as well as in vivo) implicate PC1 and PC2 in ProDyn processing (12)(13)(14). Studies using mice lacking PC2 activity (PC2 K/O) show a complete lack of Dyn A-8 and substantially reduced levels of Dyn A-17 and Dyn B-13 (13,14).…”

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confidence: 99%

Impaired Prohormone Convertases in Cpe fat/Cpe fat Mice

Berman¹,

Mzhavia²,

Polonskaia³

et al. 2001

Journal of Biological Chemistry

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. (1995) Nat. Genet. 10, 135-142). Examination of the level of neuropeptides in these mice showed a decrease in mature bioactive peptides as a result of a decrease in both carboxypeptidase and prohormone convertase activities. A defect in CPE is not expected to affect endoproteolytic processing. In this report we have addressed the mechanism of this unexpected finding by directly examining the expression of the major precursor processing endoproteases, prohormone convertases PC1 and PC2 in Cpe fat mice. We found that the levels of PC1 and PC2 are differentially altered in a number of brain regions and in the pituitary. Since these enzymes have been implicated in the generation of neuroendocrine peptides (dynorphin A-17, ␤-endorphin, and ␣-melanocyte-stimulating hormone) involved in the control of feeding behavior and body weight, we compared the levels of these peptides in Cpe fat and wild type animals. We found a marked increase in the level of dynorphin A-17, a decrease in the level of ␣-melanocyte-stimulating hormone, and an alteration in the level of C-terminally processed ␤-endorphin. These results suggest that the impairment in the level of these and other peptides involved in body weight regulation is mainly due to an alteration in carboxypeptidase and prohormone convertase activities and that this may lead to the development of obesity in these animals.

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“…In addition, the data showed that the intracellular cleavage kinetics of specific bonds in precursors are determined by a multiplicity of factors, including convertase activation, substrate specificity and intracellular environment [9]. Coexpression studies with vaccinia virus recombinants have proven useful to determine if a given precursor substrate can be cleaved intracellularly by a candidate convertase either in constitutive or regulated cells [10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Comparative proteolytic processing of rat prosomatostatin by the convertases PC1, PC2, furin, PACE4 and PC5 in constitutive and regulated secretory pathways

et al. 1995

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Recombinant vaccinia virus vectors were used to coexpress each of the candidate prohormone convertases PC1, PC2, furin, PACFA and PC5 with rat prosomatostatin (rProSOM) in the constitutive secreting cell line LoVo and in the endocrine corticotroph cell line AtT-20, which exhibits regulated secretion. Mammalian ProSOM is cleaved at a dibasic Arg-Lysi site to produce somatostatin-14 (S-14) and at a monobasic Gln-Argi site to yield somatostatin-28 (S-28). The analysis of processed products by gel-permeation high performance liquid chromatography shows that in LoVo cells PCI, furin and PACE4 generate S-14, S-28 and a mixture of S-14 and S-28, respectively, while PC2 is unable to process ProSOM in these constitutive cells. In contrast, PC2 can generate S-14 in AtT-20 cells. The convertase PC5 is unable to process ProSOM in either cell line. These data suggest that PC2, PC1 and PACE4 are candidate S-14 convertases, while PACE4 and furin are candidate S-28 convertases.

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Processing of prodynorphin by the prohormone convertase PC1 results in high molecular weight intermediate forms

Cited by 75 publications

References 29 publications

Comparative analysis of expression of the proprotein convertases furin, PACE4, PC1 and PC2 in human lung tumours

Comparative analysis of expression of the proprotein convertases furin, PACE4, PC1 and PC2 in human lung tumours

Impaired Prohormone Convertases in Cpe fat/Cpe fat Mice

Comparative proteolytic processing of rat prosomatostatin by the convertases PC1, PC2, furin, PACE4 and PC5 in constitutive and regulated secretory pathways

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