Gene fusion and overlapping reading frames in the mammalian genes for 4E-BP3 and MASK

被引:48
作者
Poulin, F
Brueschke, A
Sonenberg, N
机构
[1] McGill Univ, Dept Biochem, Montreal, PQ H3G 1Y6, Canada
[2] McGill Univ, McGill Canc Ctr, Montreal, PQ H3G 1Y6, Canada
关键词
D O I
10.1074/jbc.M310761200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
4E-BP3 is a member of the eukaryotic initiation factor (eIF) 4F-binding protein family of translational repressors. eIF4E-binding proteins (4E-BPs) inhibit translation initiation by sequestering eIF4E, the cap-binding protein, from eIF4G thus preventing ribosome recruitment to the mRNA. Previous analysis of 4E-BP3 expression uncovered an 8.5-kb mRNA variant of unknown origin. To study this splice variant, we determined the structure of the genomic locus encoding human 4E-BP3 (EIF4EBP3). EIF4EBP3 is located on human chromosome 5q31.3 and comprises three exons (A, B, and C) and two introns. Exon B contains the region of the open reading frame responsible for eIF4E binding. GenBank(TM) searches revealed multiple expressed sequence tags originating from the alternative splicing of exon B with unidentified upstream exons. Further studies revealed that the 8.5-kb transcript arises from the fusion of EIF4EBP3 with the mammalian homologue of Drosophila MASK ( multiple ankyrin repeats, single KH domain), which is crucial for photoreceptor differentiation, cell survival, and proliferation. Surprisingly, the open reading frame of the MASK-BP3 transcript is different from that of 4E-BP3, which indicates that exon B is translated using an alternative reading frame. A gene fusion similar to that of MASK and EIF4EBP3 has been reported only once in mammals for the UEV1-Kua transcript. The use of an alternative reading frame is also very rare, having been described for two loci, INK4a/ARF and XLalphas/ALEX. The simultaneous exploitation of both mechanisms underscores the flexibility of mammalian genomes and has important implications for the functional analysis of 4E-BP3 and MASK. Interestingly, both eIF4E and MASK are downstream effectors of the Ras/MAPK pathway, which provides a rationale for the MASK-BP3 fusion in mammals.
引用
收藏
页码:52290 / 52297
页数:8
相关论文
共 32 条
[1]   Rapamycin stimulates viral protein synthesis and augments the shutoff of host protein synthesis upon picornavirus infection [J].
Beretta, L ;
Svitkin, YV ;
Sonenberg, N .
JOURNAL OF VIROLOGY, 1996, 70 (12) :8993-8996
[2]   Protein interaction maps for complete genomes based on gene fusion events [J].
Enright, AJ ;
Iliopoulos, I ;
Kyrpides, NC ;
Ouzounis, CA .
NATURE, 1999, 402 (6757) :86-90
[3]  
Enright AJ, 2001, GENOME BIOL, V2
[4]   eIF4 initiation factors: Effectors of mRNA recruitment to ribosomes and regulators of translation [J].
Gingras, AC ;
Raught, B ;
Sonenberg, N .
ANNUAL REVIEW OF BIOCHEMISTRY, 1999, 68 :913-963
[5]  
Gingras AC, 2001, GENE DEV, V15, P2852
[6]   Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism [J].
Gingras, AC ;
Gygi, SP ;
Raught, B ;
Polakiewicz, RD ;
Abraham, RT ;
Hoekstra, MF ;
Aebersold, R ;
Sonenberg, N .
GENES & DEVELOPMENT, 1999, 13 (11) :1422-1437
[7]   4E-BP1, a repressor of mRNA translation, is phosphorylated and inactivated by the Akt(PKB) signaling pathway [J].
Gingras, AC ;
Kennedy, SG ;
O'Leary, MA ;
Sonenberg, N ;
Hay, N .
GENES & DEVELOPMENT, 1998, 12 (04) :502-513
[8]   REPRESSION OF CAP-DEPENDENT TRANSLATION BY 4E-BINDING PROTEIN-1 - COMPETITION WITH P220 FOR BINDING TO EUKARYOTIC INITIATION FACTOR-4E [J].
HAGHIGHAT, A ;
MADER, S ;
PAUSE, A ;
SONENBERG, N .
EMBO JOURNAL, 1995, 14 (22) :5701-5709
[9]  
Horoszewicz J S, 1980, Prog Clin Biol Res, V37, P115
[10]   Localisation and regulation of the eIF4E-binding protein 4E-BP3 [J].
Kleijn, M ;
Scheper, GC ;
Wilson, ML ;
Tee, AR ;
Proud, CG .
FEBS LETTERS, 2002, 532 (03) :319-323