title: Differential contribution of the m7G-cap to the 5' end-dependent translation initiation of mammalian mRNAs.
abstract: Many mammalian mRNAs possess long 5' UTRs with numerous stem-loop structures. For some of them, the presence of Internal Ribosome Entry Sites (IRESes) was suggested to explain their significant activity, especially when cap-dependent translation is compromised. To test this hypothesis, we have compared the translation initiation efficiencies of some cellular 5' UTRs reported to have IRES-activity with those lacking IRES-elements in RNA-transfected cells and cell-free systems. Unlike viral IRESes, the tested 5' UTRs with so-called 'cellular IRESes' demonstrate only background activities when placed in the intercistronic position of dicistronic RNAs. In contrast, they are very active in the monocistronic context and the cap is indispensable for their activities. Surprisingly, in cultured cells or cytoplasmic extracts both the level of stimulation with the cap and the overall translation activity do not correlate with the cumulative energy of the secondary structure of the tested 5' UTRs. The cap positive effect is still observed under profound inhibition of translation with eIF4E-BP1 but its magnitude varies for individual 5' UTRs irrespective of the cumulative energy of their secondary structures. Thus, it is not mandatory to invoke the IRES hypothesis, at least for some mRNAs, to explain their preferential translation when eIF4E is partially inactivated.
authors.affiliation: Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow 119992, Russia.
authors.forename: Dmitri E
authors.initials: DE
authors.lastname: Andreev
authors.forename: Sergey E
authors.initials: SE
authors.lastname: Dmitriev
authors.forename: Ilya M
authors.initials: IM
authors.lastname: Terenin
authors.forename: Vladimir S
authors.initials: VS
authors.lastname: Prassolov
authors.forename: William C
authors.initials: WC
authors.lastname: Merrick
authors.forename: Ivan N
authors.initials: IN
authors.lastname: Shatsky
mesh_terms: D020121:5' Untranslated Regions; D053477:Apoptotic Protease-Activating Factor 1 / Q000235:genetics; D016477:Artifacts; D002460:Cell Line; D018387:Codon, Initiator; D039642:Eukaryotic Initiation Factors / Q000378:metabolism; D006801:Humans; D010442:Peptide Chain Initiation, Translational; D012314:RNA Cap Analogs / Q000378:metabolism*; D012367:RNA, Viral / Q000737:chemistry; D012270:Ribosomes / Q000378:metabolism; D014162:Transfection
chemical_list: D020121:5' Untranslated Regions; D053477:Apoptotic Protease-Activating Factor 1; D018387:Codon, Initiator; D039642:Eukaryotic Initiation Factors; D012314:RNA Cap Analogs; D012367:RNA, Viral
references.citation: RNA. 2008 Aug;14(8):1671-80
references.pmid: 18567818
references.citation: J Hum Virol. 2001 Mar-Apr;4(2):74-84
references.pmid: 11437317
references.citation: Nucleic Acids Res. 2000 Feb 1;28(3):687-94
references.pmid: 10637319
references.citation: Mol Cell. 2005 Feb 4;17(3):405-16
references.pmid: 15694341
references.citation: RNA. 2006 Feb;12(2):223-34
references.pmid: 16373480
references.citation: Mol Biol (Mosk). 2009 Jan-Feb;43(1):119-25
references.pmid: 19334534
references.citation: Mol Cell. 2003 Mar;11(3):757-71
references.pmid: 12667457
references.citation: Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7029-36
references.pmid: 11416183
references.citation: Nucleic Acids Res. 1991 Feb 11;19(3):665-71
references.pmid: 1849266
references.citation: J Biol Chem. 2008 Jun 13;283(24):16309-19
references.pmid: 18430730
references.citation: Int J Biochem Cell Biol. 2002 Mar;34(3):286-97
references.pmid: 11849996
references.citation: RNA. 2006 Jun;12(6):1074-83
references.pmid: 16601206
references.citation: RNA. 2006 Oct;12(10):1755-85
references.pmid: 16957278
references.citation: Mol Cell Biol. 2002 Nov;22(21):7372-84
references.pmid: 12370285
references.citation: Oncogene. 2000 Feb 17;19(7):899-905
references.pmid: 10702798
references.citation: Mol Cell Biol. 2001 Dec;21(23):8238-46
references.pmid: 11710333
references.citation: RNA. 2006 Oct;12(10):1790-3
references.pmid: 16921069
references.citation: Mol Cell Biol. 2001 Mar;21(6):1899-907
references.pmid: 11238926
references.citation: Mol Biol (Mosk). 2006 Jan-Feb;40(1):25-30
references.pmid: 16523688
references.citation: RNA. 2005 Nov;11(11):1605-9
references.pmid: 16177136
references.citation: Nucleic Acids Res. 2005 Apr 20;33(7):2248-58
references.pmid: 15843687
references.citation: RNA. 2004 Apr;10(4):720-30
references.pmid: 15037781
references.citation: J Biol Chem. 1997 Aug 22;272(34):21642-6
references.pmid: 9261187
references.citation: PLoS One. 2008 Jun 04;3(6):e2322
references.pmid: 18523580
references.citation: Mol Cell Biol. 1988 Jul;8(7):2737-44
references.pmid: 3405216
references.citation: Oncogene. 2004 Apr 19;23(18):3200-7
references.pmid: 15094769
references.citation: Mol Cell Biol. 1996 Dec;16(12):6859-69
references.pmid: 8943341
references.citation: RNA. 2000 Dec;6(12):1781-90
references.pmid: 11142378
references.citation: J Biol Chem. 1998 Jul 17;273(29):18599-604
references.pmid: 9660832
references.citation: J Virol. 2004 May;78(9):4487-97
references.pmid: 15078929
references.citation: Genes Dev. 2000 Aug 15;14(16):2028-45
references.pmid: 10950867
references.citation: Nucleic Acids Res. 1997 Jul 15;25(14):2869-76
references.pmid: 9207037
references.citation: J Biol Chem. 2005 Jun 24;280(25):23425-8
references.pmid: 15749702
references.citation: J Biol Chem. 1997 Dec 19;272(51):32061-6
references.pmid: 9405401
references.citation: J Mol Biol. 2001 Jun 29;310(1):111-26
references.pmid: 11419940
references.citation: EMBO J. 1992 Nov;11(11):4153-8
references.pmid: 1396596
references.citation: Mol Cell Biol. 2007 Jul;27(13):4685-97
references.pmid: 17470553
references.citation: Nucleic Acids Res. 2003 Feb 15;31(4):1275-81
references.pmid: 12582247
references.citation: J Virol. 1998 Jun;72(6):4775-82
references.pmid: 9573242
references.citation: Proc Natl Acad Sci U S A. 2008 Mar 25;105(12):4733-8
references.pmid: 18326627
references.citation: Nucleic Acids Res. 2005 Nov 28;33(20):6593-602
references.pmid: 16314320
references.citation: Mol Cell Biol. 2000 May;20(10):3558-67
references.pmid: 10779345
references.citation: Genes Dev. 1998 Jan 1;12(1):67-83
references.pmid: 9420332
references.citation: Oncogene. 1998 Jan 22;16(3):423-8
references.pmid: 9467968
references.citation: Nat Rev Mol Cell Biol. 2005 Apr;6(4):318-27
references.pmid: 15803138
references.citation: Nature. 1988 Jul 28;334(6180):320-5
references.pmid: 2839775
references.citation: J Gen Virol. 2008 Mar;89(Pt 3):611-626
references.pmid: 18272751
references.citation: J Cell Biol. 1989 Feb;108(2):229-41
references.pmid: 2645293
references.citation: RNA. 2003 Nov;9(11):1333-44
references.pmid: 14561883
references.citation: J Biol Chem. 2003 Jun 20;278(25):22350-6
references.pmid: 12682055
references.citation: RNA. 2001 Mar;7(3):382-94
references.pmid: 11333019
references.citation: RNA. 2001 Feb;7(2):194-206
references.pmid: 11233977