title: Distinct 5' UTRs regulate XIAP expression under normal growth conditions and during cellular stress.
abstract: X-chromosome linked inhibitor of apoptosis, XIAP, is cellular caspase inhibitor and a key regulator of apoptosis. We and others have previously shown that XIAP expression is regulated primarily at the level of protein synthesis; the 5' untranslated region (UTR) of XIAP mRNA contains an Internal Ribosome Entry Site (IRES) that supports cap-independent expression of XIAP protein during conditions of pathophysiological stress, such as serum deprivation or gamma irradiation. Here, we show that XIAP is encoded by two distinct mRNAs that differ in their 5' UTRs. We further show that the dominant, shorter, 5' UTR promotes a basal level of XIAP expression under normal growth conditions. In contrast, the less abundant longer 5' UTR contains an IRES and supports cap-independent translation during stress. Our data suggest that the combination of alternate regulatory regions and distinct translational initiation modes is critical in maintaining XIAP levels in response to cellular stress and may represent a general mechanism of cellular adaptation.
authors.affiliation: Apoptosis Research Centre, Children's Hospital of Eastern Ontario, Ottawa, Canada.
authors.forename: Alura
authors.initials: A
authors.lastname: Riley
authors.forename: Lindsay E
authors.initials: LE
authors.lastname: Jordan
authors.forename: Martin
authors.initials: M
authors.lastname: Holcik
mesh_terms: D020121:5' Untranslated Regions; D002460:Cell Line; D016895:Culture Media, Serum-Free; D005786:Gene Expression Regulation; D006801:Humans; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D013312:Stress, Physiological / Q000235:genetics; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: D020121:5' Untranslated Regions; D016895:Culture Media, Serum-Free; D012333:RNA, Messenger; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human
references.citation: RNA. 2006 Jun;12(6):1074-83
references.pmid: 16601206
references.citation: Nucleic Acids Res. 2005 May 20;33(9):2929-41
references.pmid: 15908588
references.citation: RNA. 2009 Jun;15(6):1164-76
references.pmid: 19398494
references.citation: Mol Biol Cell. 2002 May;13(5):1792-801
references.pmid: 12006670
references.citation: Genes Dev. 2001 Jul 1;15(13):1593-612
references.pmid: 11445534
references.citation: Oncogene. 2000 Aug 24;19(36):4174-7
references.pmid: 10962579
references.citation: RNA. 2009 Nov;15(11):1980-5
references.pmid: 19713328
references.citation: Nucleic Acids Res. 2007;35(14):4664-77
references.pmid: 17591613
references.citation: Science. 2006 May 12;312(5775):902-6
references.pmid: 16690864
references.citation: Mol Cell Biol. 2004 Aug;24(16):7003-14
references.pmid: 15282301
references.citation: Mol Cell Biol. 2000 Apr;20(7):2297-307
references.pmid: 10713153
references.citation: RNA. 2005 Nov;11(11):1605-9
references.pmid: 16177136
references.citation: Genomics. 2001 Oct;77(3):181-8
references.pmid: 11597143
references.citation: RNA. 2004 Apr;10(4):720-30
references.pmid: 15037781
references.citation: BMC Genomics. 2002;3:5
references.pmid: 11860601
references.citation: J Clin Oncol. 2009 Oct 1;27(28):4741-6
references.pmid: 19652057
references.citation: Clin Cancer Res. 2000 May;6(5):1796-803
references.pmid: 10815900
references.citation: J Clin Oncol. 2009 Apr 1;27(10):1660-6
references.pmid: 19237630
references.citation: J Biol Chem. 2004 Jul 9;279(28):29066-74
references.pmid: 15123638
references.citation: Nat Cell Biol. 2009 Jul;11(7):903-8
references.pmid: 19525934
references.citation: Nature. 2006 Nov 2;444(7115):110-4
references.pmid: 17080092
references.citation: Mol Cell Biol. 2004 Sep;24(17):7622-35
references.pmid: 15314170
references.citation: Ann N Y Acad Sci. 2003 Dec;1010:249-58
references.pmid: 15033729
references.citation: Nat Rev Mol Cell Biol. 2001 Jul;2(7):550-6
references.pmid: 11433370
references.citation: Mol Biol Cell. 2007 Apr;18(4):1302-11
references.pmid: 17287399
references.citation: Mol Cell. 2007 Nov 9;28(3):501-12
references.pmid: 17996713
references.citation: Nat Cell Biol. 1999 Jul;1(3):190-2
references.pmid: 10559907
references.citation: Proc Natl Acad Sci U S A. 2008 Mar 25;105(12):4733-8
references.pmid: 18326627
references.citation: Methods Mol Biol. 1991;7:217-35
references.pmid: 21416358
references.citation: Cancer Cell. 2009 May 5;15(5):363-75
references.pmid: 19411066
references.citation: Nat Rev Mol Cell Biol. 2005 Apr;6(4):318-27
references.pmid: 15803138
references.citation: J Cell Biol. 1989 Feb;108(2):229-41
references.pmid: 2645293
references.citation: Mol Cell Biol. 2003 Nov;23(21):7600-10
references.pmid: 14560006