title: TOSO promotes β-cell proliferation and protects from apoptosis.
abstract: Decreased β-cell mass reflects a shift from quiescence/proliferation into apoptosis, it plays a crucial role in the pathophysiology of diabetes. A major attempt to restore β-cell mass and normoglycemia is to improve β-cell survival. Here we show that switching off the Fas pathway using Fas apoptotic inhibitory protein (Faim/TOSO), which regulates apoptosis upstream of caspase 8, blocked β-cell apoptosis and increased proliferation in human islets. TOSO was clearly expressed in pancreatic β-cells and down-regulated in T2DM. TOSO expression correlated with β-cell turnover; at conditions of improved survival, TOSO was induced. In contrast, TOSO downregulation induced β-cell apoptosis. Although TOSO overexpression resulted in a 3-fold induction of proliferation, proliferating β-cells showed a very limited capacity to undergo multiple rounds of replication. Our data suggest that TOSO is an important regulator of β-cell turnover and switches β-cell apoptosis into proliferation.
authors.affiliation: Centre for Biomolecular Interactions Bremen, University of Bremen, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Dharmadhikari
authors.forename: M
authors.initials: M
authors.lastname: Mühle
authors.forename: F T
authors.initials: FT
authors.lastname: Schulthess
authors.forename: S
authors.initials: S
authors.lastname: Laue
authors.forename: J
authors.initials: J
authors.lastname: Oberholzer
authors.forename: F
authors.initials: F
authors.lastname: Pattou
authors.forename: J
authors.initials: J
authors.lastname: Kerr-Conte
authors.forename: K
authors.initials: K
authors.lastname: Maedler
keywords: Diabetes; Fas; Islets; TOSO; β-cell proliferation
references.citation: PLoS One. 2012;7(4):e35801
references.pmid: 22563404
references.citation: Diabetologia. 2006 Jan;49(1):83-9
references.pmid: 16323002
references.citation: Proc Natl Acad Sci U S A. 2004 May 25;101(21):8138-43
references.pmid: 15141093
references.citation: J Immunol. 2011 Oct 15;187(8):4040-50
references.pmid: 21908732
references.citation: J Immunol. 1999 Aug 1;163(3):1562-9
references.pmid: 10415060
references.citation: Proc Natl Acad Sci U S A. 1997 Jan 7;94(1):213-8
references.pmid: 8990188
references.citation: J Clin Invest. 2002 Sep;110(6):851-60
references.pmid: 12235117
references.citation: Trends Endocrinol Metab. 2010 May;21(5):261-7
references.pmid: 20096598
references.citation: Diagn Pathol. 2007 Feb 27;2:8
references.pmid: 17326824
references.citation: Diabetes. 1965 Oct;14(10):619-33
references.pmid: 5318831
references.citation: Diabetes. 2001 Aug;50(8):1683-90
references.pmid: 11473025
references.citation: J Biol Chem. 2005 Mar 11;280(10):9618-26
references.pmid: 15632112
references.citation: Curr Biol. 2000 Jun 1;10(11):640-8
references.pmid: 10837247
references.citation: FEBS Lett. 1995 May 1;364(1):5-8
references.pmid: 7538467
references.citation: Diabetes. 2008 Mar;57(3):645-53
references.pmid: 18071026
references.citation: Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13818-22
references.pmid: 9811884
references.citation: Proc Natl Acad Sci U S A. 2002 Jun 11;99(12):8236-41
references.pmid: 12060768
references.citation: Apoptosis. 2006 Feb;11(2):151-9
references.pmid: 16502254
references.citation: Curr Opin Immunol. 1998 Oct;10(5):552-8
references.pmid: 9794838
references.citation: Blood. 2011 Jul 21;118(3):598-608
references.pmid: 21613257
references.citation: Diabetes. 2002 Jun;51(6):1805-14
references.pmid: 12031968
references.citation: Diabetologia. 1999 Nov;42(11):1332-40
references.pmid: 10550417
references.citation: Endocrinology. 1991 Oct;129(4):2067-76
references.pmid: 1717241
references.citation: Cell Metab. 2009 Feb;9(2):125-39
references.pmid: 19187771
references.citation: Diabetes. 2000 Jul;49(7):1116-22
references.pmid: 10909967
references.citation: J Biol Chem. 2011 May 13;286(19):17144-55
references.pmid: 21393239
references.citation: Cell Death Differ. 2009 Jul;16(7):1062-70
references.pmid: 19300454
references.citation: Diabetologia. 2001 Dec;44(12):2115-33
references.pmid: 11793013
references.citation: Hum Mol Genet. 2011 May 15;20(10):1906-15
references.pmid: 21357677
references.citation: Diabetologia. 1996 Nov;39(11):1306-12
references.pmid: 8932996
references.citation: Nature. 2001 Dec 13;414(6865):792-8
references.pmid: 11742411
references.citation: Immunity. 1998 Apr;8(4):461-71
references.pmid: 9586636
references.citation: Diabetologia. 2012 Feb 1;:
references.pmid: 22301943
references.citation: J Mol Med (Berl). 2003 Aug;81(8):455-70
references.pmid: 12879149
references.citation: Proc Natl Acad Sci U S A. 2007 Feb 20;104(8):2861-6
references.pmid: 17299038
references.citation: Dev Cell. 2007 May;12(5):817-26
references.pmid: 17488631
references.citation: Diabetologia. 2005 Nov;48(11):2221-8
references.pmid: 16205882
references.citation: Nature. 1997 Jul 10;388(6638):190-5
references.pmid: 9217161
references.citation: Diabetes. 2005 Sep;54(9):2557-67
references.pmid: 16123343
references.citation: Diabetes. 2006 Oct;55(10):2713-22
references.pmid: 17003335
references.citation: Diabetes Res. 1988 Dec;9(4):151-9
references.pmid: 3073901
references.citation: Cell. 1997 Apr 4;89(1):17-24
references.pmid: 9094710
references.citation: Diabetes. 1998 May;47(5):727-32
references.pmid: 9588443
references.citation: Diabetologia. 2011 Aug;54(8):2056-66
references.pmid: 21567299
references.citation: J Immunol. 2005 Jul 1;175(1):293-301
references.pmid: 15972661
references.citation: Diabetologia. 2010 Aug;53(8):1795-806
references.pmid: 20407745
references.citation: Nature. 2000 Oct 12;407(6805):789-95
references.pmid: 11048730
references.citation: Diabetes. 2003 Jan;52(1):102-10
references.pmid: 12502499