title: The N-terminal Set-β Protein Isoform Induces Neuronal Death.
abstract: Set-β protein plays different roles in neurons, but the diversity of Set-β neuronal isoforms and their functions have not been characterized. The expression and subcellular localization of Set-β are altered in Alzheimer disease, cleavage of Set-β leads to neuronal death after stroke, and the full-length Set-β regulates retinal ganglion cell (RGC) and hippocampal neuron axon growth and regeneration in a subcellular localization-dependent manner. Here we used various biochemical approaches to investigate Set-β isoforms and their role in the CNS, using the same type of neurons, RGCs, across studies. We found multiple alternatively spliced isoforms expressed from the Set locus in purified RGCs. Set transcripts containing the Set-β-specific exon were the most highly expressed isoforms. We also identified a novel, alternatively spliced Set-β transcript lacking the nuclear localization signal and demonstrated that the full-length (∼39-kDa) Set-β is localized predominantly in the nucleus, whereas a shorter (∼25-kDa) Set-β isoform is localized predominantly in the cytoplasm. Finally, we show that an N-terminal Set-β cleavage product can induce neuronal death.
authors.affiliation: From the Neuroscience Program and Bascom Palmer Eye Institute and Interdisciplinary Stem Cell Institute, and Ephraim.Trakhtenberg@childrens.harvard.edu.
authors.forename: Ephraim F
authors.initials: EF
authors.lastname: Trakhtenberg
authors.affiliation: Bascom Palmer Eye Institute and Interdisciplinary Stem Cell Institute, and the Shiley Eye Center, University of California San Diego, La Jolla, California 92093.
authors.forename: Melina I
authors.initials: MI
authors.lastname: Morkin
authors.affiliation: Bascom Palmer Eye Institute and Interdisciplinary Stem Cell Institute, and.
authors.forename: Karan H
authors.initials: KH
authors.lastname: Patel
authors.affiliation: Bascom Palmer Eye Institute and Interdisciplinary Stem Cell Institute, and.
authors.forename: Stephanie G
authors.initials: SG
authors.lastname: Fernandez
authors.affiliation: the Shiley Eye Center, University of California San Diego, La Jolla, California 92093.
authors.forename: Alan
authors.initials: A
authors.lastname: Sang
authors.affiliation: the Shiley Eye Center, University of California San Diego, La Jolla, California 92093.
authors.forename: Peter
authors.initials: P
authors.lastname: Shaw
authors.affiliation: Bascom Palmer Eye Institute and Interdisciplinary Stem Cell Institute, and.
authors.forename: Xiongfei
authors.initials: X
authors.lastname: Liu
authors.affiliation: Bascom Palmer Eye Institute and Interdisciplinary Stem Cell Institute, and the Shiley Eye Center, University of California San Diego, La Jolla, California 92093.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Bascom Palmer Eye Institute and Interdisciplinary Stem Cell Institute, and.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Mlacker
authors.affiliation: From the Neuroscience Program and.
authors.forename: Han
authors.initials: H
authors.lastname: Gao
authors.affiliation: Molecular and Cellular Pharmacology Program,University of Miami Miller School of Medicine, Miami, Florida 33136.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Velmeshev
authors.affiliation: Genomatix Software, Ann Arbor, Michigan 48108, the Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan 48201.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Dombrowski
authors.affiliation: Oncotide Pharmaceuticals Inc., Durham, North Carolina 27709, and the Department of Neurology, Duke University Medical Center, Durham, North Carolina 27708.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Vitek
authors.affiliation: From the Neuroscience Program and Bascom Palmer Eye Institute and Interdisciplinary Stem Cell Institute, and the Shiley Eye Center, University of California San Diego, La Jolla, California 92093, JLGoldberg@ucsd.edu.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Goldberg
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D005455:Fluorescent Antibody Technique; D056488:Histone Chaperones; D007124:Immunoenzyme Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000235:genetics; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D012165:Retinal Ganglion Cells / Q000378:metabolism / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D056488:Histone Chaperones; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; C557500:SET protein, mouse; C554285:SET protein, rat
keywords: Set-β; alternative splicing; cell death; neuron; protein translocation; subcellular fractionation
references.citation: Mol Cell. 2011 Mar 18;41(6):636-48
references.pmid: 21419339
references.citation: Neuron. 1995 Oct;15(4):805-19
references.pmid: 7576630
references.citation: J Biol Chem. 1996 May 10;271(19):11059-62
references.pmid: 8626647
references.citation: J Neurosci. 1997 Aug 1;17(15):5726-37
references.pmid: 9221771
references.citation: Nat Struct Mol Biol. 2007 Nov;14(11):997-1007
references.pmid: 17984962
references.citation: Neurobiol Aging. 2011 Jun;32(6):1099-113
references.pmid: 19570594
references.citation: Oncogene. 2011 Jun 2;30(22):2504-13
references.pmid: 21297667
references.citation: Biochemistry. 1995 Feb 14;34(6):1988-96
references.pmid: 7531497
references.citation: J Neurosci. 2012 May 30;32(22):7734-44
references.pmid: 22649251
references.citation: PLoS One. 2012;7(9):e45155
references.pmid: 23028815
references.citation: J Cell Sci. 2012 Sep 1;125(Pt 17):4137-46
references.pmid: 22685328
references.citation: FEBS Lett. 2013 Jan 16;587(2):111-9
references.pmid: 23195690
references.citation: Neurobiol Aging. 2013 Jul;34(7):1748-58
references.pmid: 23374587
references.citation: J Neurosci. 2014 May 21;34(21):7361-74
references.pmid: 24849368
references.citation: Mol Cell. 2008 Mar 28;29(6):665-78
references.pmid: 18374643
references.citation: Cell. 2001 Jan 12;104(1):119-30
references.pmid: 11163245
references.citation: J Biol Chem. 2001 Nov 16;276(46):43285-93
references.pmid: 11555662
references.citation: J Biol Chem. 2002 Jul 12;277(28):25026-31
references.pmid: 11978794
references.citation: Cell. 2003 Mar 7;112(5):659-72
references.pmid: 12628186
references.citation: Mol Cell Biol. 1992 Aug;12(8):3346-55
references.pmid: 1630450
references.citation: J Biol Chem. 1994 Jan 21;269(3):2258-62
references.pmid: 8294483
references.citation: Biol Chem Hoppe Seyler. 1994 Feb;375(2):113-26
references.pmid: 8192856
references.citation: Exp Cell Res. 1998 May 1;240(2):274-81
references.pmid: 9597000
references.citation: Biochem Biophys Res Commun. 1999 Jun 7;259(2):471-5
references.pmid: 10362532
references.citation: Am J Pathol. 2005 Jun;166(6):1761-71
references.pmid: 15920161
references.citation: FEBS Lett. 2006 Jul 10;580(16):3973-9
references.pmid: 16806196
references.citation: Mol Cell. 2006 Jul 7;23(1):133-42
references.pmid: 16818237
references.citation: EMBO J. 2007 Jan 24;26(2):336-45
references.pmid: 17245428
references.citation: J Neurosci. 2007 Mar 14;27(11):2751-9
references.pmid: 17360897
references.citation: J Neurochem. 2007 May;101(4):959-71
references.pmid: 17394530
references.citation: Nat Struct Mol Biol. 2007 Jun;14(6):548-55
references.pmid: 17529993
references.citation: J Neurochem. 2007 Oct;103(1):408-22
references.pmid: 17608644
references.citation: J Neurosci. 2008 Jan 2;28(1):100-5
references.pmid: 18171927
references.citation: FASEB J. 2010 Nov;24(11):4420-32
references.pmid: 20651003
references.citation: J Immunol. 2011 Feb 15;186(4):2535-42
references.pmid: 21289314
references.citation: Proc Natl Acad Sci U S A. 1995 May 9;92(10):4279-83
references.pmid: 7753797