Developmental expression of proprotein convertase 1/3 in the rat

Lee, Y C; Damholt, Anders; Billestrup, Nils; Kisbye, T; Galante, Philip; Michelsen, Birgitte; Kofod, Hans; Nielsen, Jens Høiriis

doi:10.1016/s0303-7207(99)00119-7

Cited by 26 publications

(14 citation statements)

References 38 publications

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“…These results mirror those from in vivo experiments that showed an increase in PC1/3 expression and GLP-1 production in pancreatic ␣-cells after treatment with streptozotocin (28). It is possible that an increase in PC1/3 expression could be an indication of de-differentiation of the ␣-cell phenotype after prolonged exposure to high glucose levels, because immature ␣-cells show an increase in PC1/3 expression (42). However, in our culture system, high glucose did not induce differentiation of ␣TC1-6 cells, nor did de-differentiation to an immature phenotype occur, because there was no difference in the number of cells expressing brn-4 or pdx-1, markers for mature (43) and immature (44) ␣-cells, respectively.…”

Section: Discussionsupporting

confidence: 82%

Glucose Dependence of the Regulated Secretory Pathway in αTC1-6 Cells

McGirr¹,

Ejbick²,

Carter³

et al. 2005

Endocrinology

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We have investigated the effects of chronically elevated glucose concentrations on the pancreatic alpha-cell line alphaTC1-6. We show that basal glucagon secretion and proglucagon gene expression were increased in response to high glucose levels. The extent of acute stimulated secretion of glucagon was also increased in response to high glucose, as was the transcription of the prohormone processing enzymes PC1/3 and PC2. The secretion of GLP-1, a proglucagon-derived peptide produced by cleavage of proglucagon by PC1/3, was also increased in response to high glucose. Gene expression profiling experiments showed that a number of components of the regulated secretory pathway were up-regulated at high glucose concentrations, including processing enzymes and exocytotic proteins. Immunoblot analysis showed that the expression of the exocytotic SNARE proteins, as well as that of PC1/3, chromogranin A, and 7B2, were all increased after chronic exposure to high glucose levels. Immunocytochemistry showed no changes in the expression of the mature alpha-cell markers glucagon and brn-4 and no induction of the immature alpha-cell marker pdx-1. We conclude that chronically elevated glucose concentrations up-regulate the regulated secretory response of the alpha-cell.

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Section: Discussionsupporting

confidence: 82%

Glucose Dependence of the Regulated Secretory Pathway in αTC1-6 Cells

McGirr¹,

Ejbick²,

Carter³

et al. 2005

Endocrinology

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“…However, no such elevation of PC1/3 was observed in the ␣-cells of PC2 null mice (42). Whether the low level expression of PC1/3 and PDX-1 observed in these cells is an indication of their possible developmental immaturity (48,49,50) is an issue currently under investigation. FIG.…”

Section: Discussionmentioning

confidence: 96%

Altered Proglucagon Processing in an α-Cell Line Derived from Prohormone Convertase 2 Null Mouse Islets

Webb

Dey²,

Wang³

et al. 2004

Journal of Biological Chemistry

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The endoproteolytic processing of proproteins in the secretory pathway depends on the expression of selected members of a family of subtilisin-like endoproteases known as the prohormone convertases (PCs). The main PC family members expressed in mammalian neuroendocrine cells are PC2 and PC1/3. The differential processing of proglucagon in pancreatic ␣-cells and intestinal L cells leads to production of distinct hormonal products with opposing physiological effects from the same precursor. Here we describe the establishment and characterization of a novel ␣-cell line (␣TC-⌬PC2) derived from PC2 homozygous null animals. The ␣TC-⌬PC2 cells are shown to be similar to the well characterized ␣TC1-6 cell line in both morphology and overall gene expression. However, the absence of PC2 activity in ␣TC-⌬PC2 leads to a complete block in the production of mature glucagon. Surprisingly, ␣TC-⌬PC2 cells are able to efficiently cleave the interdomain site in proglucagon (KR 70 -71). Further analysis reveals that ␣TC-⌬PC2 cells, unlike ␣TC1-6 cells, express low levels of PC1/3 that lead to the generation of glicentin as well as low amounts of oxyntomodulin, GLP-1, truncated GLP-1, and N-terminally extended GLP-2. We conclude that ␣TC-⌬PC2 cells provide additional evidence for PC2 as the major convertase in ␣-cells leading to mature glucagon production and provide a robust model for further analysis of the mechanisms of proprotein processing by the prohormone convertases.

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“…Glp-1 and the analog exendin-4 have also been reported to stimulate the expression of Pdx-1 in INS-1 cells (38) and to induce expression of insulin and glucagon in the pancreatic tumor cell line AR42J (39), suggesting that Glp-1 is involved in the differentiation of islet stem cells to endocrine cells. In this context, it is interesting that we demonstrated expression of the prohormone converting enzyme proprotein convertase 1/3 in the glucagon-containing cells in the embryonic rat pancreas, suggesting that proglucagon may be processed to Glp-1 during pancreas development (40). Thus, Glp-1 may promote ␤-cell differentiation and growth via a paracrine effect at this stage, in contrast to the postnatal period when Glp-1 is produced only in the intestinal L-cells.…”

Section: Glp-1 In ␤-Cell Growth and Developmentmentioning

confidence: 91%