title: Transcription factor ZBED6 affects gene expression, proliferation, and cell death in pancreatic beta cells.
abstract: We have investigated whether the recently discovered transcription factor, zinc finger BED domain-containing protein 6 (ZBED6), is expressed in insulin-producing cells and, if so, to what extent it affects beta cell function. ZBED6 was translated from a ZC3H11A transcript in which the ZBED6-containing intron was retained. ZBED6 was present in mouse βTC-6 cells and human islets as a double nuclear band at 115/120 kDa and as a single cytoplasmic band at 95-100 kDa, which lacked N-terminal nuclear localization signals. We propose that ZBED6 supports proliferation and survival of beta cells, possibly at the expense of specialized beta cell function-i.e., insulin production-because (i) the nuclear ZBED6 were the predominant forms in rapidly proliferating βTC-6 cells, but not in human islet cells; (ii) down-regulation of ZBED6 in βTC-6 cells resulted in altered morphology, decreased proliferation, a partial S/G2 cell-cycle arrest, increased expression of beta cell-specific genes, and higher rates of apoptosis; (iii) silencing of ZBED6 in the human PANC-1 duct cell line reduced proliferation rates; and (iv) ZBED6 binding was preferentially to genes that control transcription, macromolecule biosynthesis, and apoptosis. Furthermore, it is possible that beta cells, by switching from full length to a truncated form of ZBED6, can decide the subcellular localization of ZBED6, thereby achieving differential ZBED6-mediated transcriptional regulation.
authors.affiliation: Science for Life Laboratory, Department of Medical Cell Biology, and Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, SE-75123 Uppsala, Sweden.
authors.forename: Xuan
authors.initials: X
authors.lastname: Wang
authors.forename: Lin
authors.initials: L
authors.lastname: Jiang
authors.forename: Ola
authors.initials: O
authors.lastname: Wallerman
authors.forename: Ulla
authors.initials: U
authors.lastname: Engström
authors.forename: Adam
authors.initials: A
authors.lastname: Ameur
authors.forename: Rajesh Kumar
authors.initials: RK
authors.lastname: Gupta
authors.forename: Yu
authors.initials: Y
authors.lastname: Qi
authors.forename: Leif
authors.initials: L
authors.lastname: Andersson
authors.forename: Nils
authors.initials: N
authors.lastname: Welsh
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D013058:Mass Spectrometry; D051379:Mice; D011485:Protein Binding; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017423:Sequence Analysis, RNA
chemical_list: D012097:Repressor Proteins; C547913:ZBED6 protein, mouse
references.citation: Endocrinology. 2010 May;151(5):2030-9
references.pmid: 20215568
references.citation: Biochem Biophys Res Commun. 2012 Feb 10;418(2):307-12
references.pmid: 22266316
references.citation: Diabetes. 1995 Aug;44(8):863-70
references.pmid: 7621989
references.citation: PLoS One. 2012;7(5):e37055
references.pmid: 22606327
references.citation: Nature. 2003 Oct 23;425(6960):832-6
references.pmid: 14574411
references.citation: PLoS Biol. 2009 Dec;7(12):e1000256
references.pmid: 20016685
references.citation: EMBO Rep. 2010 Apr;11(4):305-11
references.pmid: 20134481
references.citation: Proc Natl Acad Sci U S A. 2009 Oct 13;106(41):17419-24
references.pmid: 19805079
references.citation: Diabetes. 2007 Apr;56(4):1069-77
references.pmid: 17395747
references.citation: J Biol Chem. 2003 Jun 20;278(25):22928-38
references.pmid: 12663651
references.citation: PLoS One. 2011;6(5):e19546
references.pmid: 21625588
references.citation: Dev Biol. 2010 Feb 15;338(2):226-36
references.pmid: 20005870
references.citation: Diabetes. 2011 Dec;60(12):3279-88
references.pmid: 21984578
references.citation: Mol Cell Endocrinol. 2008 Nov 6;294(1-2):1-9
references.pmid: 18687378
references.citation: Lab Invest. 2010 Sep;90(9):1373-84
references.pmid: 20531294
references.citation: Diabetologia. 2007 Jul;50(7):1463-71
references.pmid: 17476475