Transglutaminase 2 protects against ischemic stroke.
Transglutaminase 2 (TG2) is a multifunctional protein that modulates cell survival and death pathways. It is upregulated in numerous ischemic models, and protects primary neurons from oxygen and glucose deprivation. TG2 binds to the hypoxia inducible factor (HIF) 1beta and decreases the upregulation of hypoxic-induced proapoptotic genes. To investigate the role of TG2 in ischemic stroke in vivo, we used the murine, permanent middle cerebral artery (MCA) ligation model. TG2 mRNA levels are increased after MCA ligations, and transgenic mice that express human TG2 in neurons had significantly smaller infarct volumes than wild type littermates. Further, TG2 translocates into the nucleus within 2h post ligation. Nuclear-localized TG2 is also apparent in human stroke cases. TG2 suppressed the upregulation of the HIF-induced, proapoptotic gene, Noxa. The findings of this study indicate that TG2 plays a role in attenuating ischemic-induced cell death possibly by modulating hypoxic-induced transcriptional processes.
Filiano
A J
AJ
Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL 35294-0017, USA.
Tucholski
J
J
Dolan
P J
PJ
Colak
G
G
Johnson
G V W
GV
D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D002545:Brain Ischemia / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020521:Stroke / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D011503:Transglutaminases / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
C408009:Pmaip1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins
Oncogene. 2010 Jan 21;29(3):356-67
19838207
Nature. 1999 May 20;399(6733):271-5
10353251
Mol Cell Neurosci. 2007 Jan;34(1):40-7
17101276
J Cereb Blood Flow Metab. 1981;1(1):53-60
7328138
Neurobiol Dis. 2006 Jan;21(1):18-28
16040250
Exp Cell Res. 2006 Oct 1;312(16):2973-82
16914140
Neuroscience. 1995 Apr;65(4):1063-76
7617162
J Neurosci. 2007 Jun 6;27(23):6320-32
17554006
J Neurosci. 2005 Apr 20;25(16):4099-107
15843612
Brain Res. 1992 Apr 3;576(2):203-7
1381261
Neurobiol Dis. 2009 Mar;33(3):509-17
19166937
FASEB J. 2008 Aug;22(8):2662-75
18375543
Neuroreport. 1998 May 11;9(7):1317-9
9631421
Proc Natl Acad Sci U S A. 2006 Dec 26;103(52):19683-8
17179049
Mol Cell Neurosci. 2004 Mar;25(3):493-503
15033177
J Neurochem. 2006 Apr;97(2):582-94
16539654
J Biol Chem. 2004 Jun 4;279(23):23863-8
15069073
FEBS Lett. 1999 Mar 5;446(1):35-9
10100610
PLoS One. 2009 Jul 01;4(7):e6123
19568436
EMBO J. 2005 Nov 16;24(22):3846-58
16237459
Proc Natl Acad Sci U S A. 1995 Jun 6;92(12):5510-4
7539918
PLoS Biol. 2007 Dec;5(12):e327
18092889
J Biol Chem. 1998 May 15;273(20):11991-4
9575137
Surg Neurol. 2007 Sep;68(3):297-303; discussion 303
17368520
Int J Dev Neurosci. 1993 Jun;11(3):325-37
8102831
J Biol Chem. 2002 Jun 7;277(23):20127-30
11956182
Proc Natl Acad Sci U S A. 2002 Mar 5;99(5):2743-7
11867708
Nat Rev Neurosci. 2004 Jun;5(6):437-48
15152194
J Neurosci. 1999 Aug 15;19(16):6818-24
10436039
J Biol Chem. 2004 Mar 5;279(10):8715-22
14670969
Exp Neurol. 2006 Dec;202(2):357-72
16996500
Brain Res. 2003 Jul 18;978(1-2):24-30
12834894
Cell Death Differ. 2006 Oct;13(10):1827-9
16528383
J Biol Chem. 1999 Oct 22;274(43):30715-21
10521460
Curr Mol Med. 2004 Mar;4(2):137-47
15032710
Neurosci Lett. 2004 Jun 10;363(2):173-7
15172109
Trends Biochem Sci. 2002 Oct;27(10):534-9
12368090
J Biol Chem. 2003 Jul 18;278(29):26838-43
12743114
J Cereb Blood Flow Metab. 2000 Jul;20(7):1011-32
10908035
Neurobiol Dis. 2008 Sep;31(3):433-41
18602008
Mol Biol Cell. 2007 Nov;18(11):4528-42
17804822
Cell Cycle. 2006 Jan;5(2):142-6
16357535
J Neurosci. 2008 Feb 20;28(8):1988-93
18287515
Biochem J. 2003 Aug 1;373(Pt 3):793-803
12737632
Brain Res. 2008 Sep 16;1230:281-9
18657523
Mol Cell Biol. 2004 May;24(9):3918-27
15082785
Cell Death Differ. 2001 Apr;8(4):367-76
11550088
J Am Soc Nephrol. 2005 Apr;16(4):986-96
15743999
J Biol Chem. 2010 Mar 5;285(10):6904-12
20051518
J Exp Med. 2004 Jan 5;199(1):113-24
14699081
Stroke. 2009 Feb;40(2):610-7
19023096
J Neurochem. 1999 Nov;73(5):2018-27
10537061
Biochemistry. 1995 Dec 5;34(48):15863-71
7495818
FASEB J. 2004 Sep;18(12):1462-4
15240563
PLoS One. 2008 Mar 26;3(3):e1861
18365016
Angiogenesis. 2008;11(2):121-40
18327686
Brain Pathol. 2009 Oct;19(4):612-22
18673368
Cancer Res. 2006 Apr 1;66(7):3688-98
16585195
Nat Rev Mol Cell Biol. 2003 Feb;4(2):140-56
12563291
J Neurochem. 2002 Jun;81(5):1061-72
12065619
Biochem Biophys Res Commun. 2008 Nov 28;376(4):743-7
18809380
J Biol Chem. 2005 Feb 4;280(5):3996-4003
15557337
J Neurochem. 2004 Jun;89(5):1301-7
15147523