HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 30, 31068-31075, July 23, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/30/31068    most recent M404110200v2 M404110200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Webb, G. C. Articles by Steiner, D. F. Search for Related Content PubMed PubMed Citation Articles by Webb, G. C. Articles by Steiner, D. F. Social Bookmarking                      What's this?

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

Gene C. Webb¶||, Arunangsu Dey||**, Jie Wang**, Jeffrey Stein**, Margaret Milewski, and Donald F. Steiner**

From the Department of Medicine, the Committee on Genetics, the ^¶Committee on Human Nutrition and Nutritional Biology, the ^**Department of Biochemistry and Molecular Biology, and the Howard Hughes Medical Institute, University of Chicago, Chicago, Illinois 60637

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.

Received for publication, April 13, 2004 , and in revised form, May 6, 2004.

^* This research was supported by the Howard Hughes Medical Institute and Grants DK-13914 and DK-20595 from the National Institutes of Health (to D. F. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| Both authors contributed equally to this work.

To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, the Howard Hughes Medical Institute, University of Chicago, 5841 S. Maryland Ave., N216/MC1028, Chicago, IL 60637. Tel.: 773-702-1334; Fax: 773-702-4292; E-mail: dfsteine{at}midway.uchicago.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				R. D. Wideman, S. D. Covey, G. C. Webb, D. J. Drucker, and T. J. Kieffer A Switch From Prohormone Convertase (PC)-2 to PC1/3 Expression in Transplanted {alpha}-Cells Is Accompanied by Differential Processing of Proglucagon and Improved Glucose Homeostasis in Mice Diabetes, November 1, 2007; 56(11): 2744 - 2752. [Abstract] [Full Text] [PDF]

				E. A. Nillni Regulation of Prohormone Convertases in Hypothalamic Neurons: Implications for ProThyrotropin-Releasing Hormone and Proopiomelanocortin Endocrinology, September 1, 2007; 148(9): 4191 - 4200. [Abstract] [Full Text] [PDF]

				W. Wei, X. Qi, J. Reed, J. Ceci, H.-Q. Wang, G. Wang, E. W. Englander, and G. H. Greeley Jr. Effect of chronic hyperghrelinemia on ingestive action of ghrelin Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2006; 290(3): R803 - R808. [Abstract] [Full Text] [PDF]

				K. Masur, E. C. Tibaduiza, C. Chen, B. Ligon, and M. Beinborn Basal Receptor Activation by Locally Produced Glucagon-Like Peptide-1 Contributes to Maintaining {beta}-Cell Function Mol. Endocrinol., May 1, 2005; 19(5): 1373 - 1382. [Abstract] [Full Text] [PDF]

				A. Dey, G. M. Lipkind, Y. Rouille, C. Norrbom, J. Stein, C. Zhang, R. Carroll, and D. F. Steiner Significance of Prohormone Convertase 2, PC2, Mediated Initial Cleavage at the Proglucagon Interdomain Site, Lys70-Arg71, to Generate Glucagon Endocrinology, February 1, 2005; 146(2): 713 - 727. [Abstract] [Full Text] [PDF]

				F. Yi, P. L. Brubaker, and T. Jin TCF-4 Mediates Cell Type-specific Regulation of Proglucagon Gene Expression by {beta}-Catenin and Glycogen Synthase Kinase-3{beta} J. Biol. Chem., January 14, 2005; 280(2): 1457 - 1464. [Abstract] [Full Text] [PDF]