Transcriptional and translational regulation of the Leri-Weill and Turner syndrome homeobox gene SHOX

被引:42
作者
Blaschke, RJ [1 ]
Töpfer, C [1 ]
Marchini, A [1 ]
Steinbeisser, H [1 ]
Janssen, JWG [1 ]
Rappold, GA [1 ]
机构
[1] Univ Heidelberg, Inst Human Genet, D-69120 Heidelberg, Germany
关键词
D O I
10.1074/jbc.M306685200
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
Regulation of gene expression is particularly important for gene dosage-dependent diseases and the phenomenon of clinical heterogeneity frequently associated with these phenotypes. We here report on the combined transcriptional and translational regulatory mechanisms controlling the expression of the Leri-Weill and Turner syndrome gene SHOX. We define an alternative promotor within exon 2 of the SHOX gene by transient transfections of mono- and bicistronic reporter constructs and demonstrate substantial differences in the translation efficiency of the mRNAs transcribed from these alternative promotors by in vitro translation assays and direct mRNA transfections into different cell lines. Although transcripts generated from the intragenic promotor (P-2) are translated with high efficiencies, mRNA originating from the upstream promotor (P-1) exhibit significant translation inhibitory effects due to seven AUG codons upstream of the main open reading frame (uAUGs). Site-directed mutagenesis of these uAUGs confers full translation efficiency to reporter mRNAs in different cell lines and after injection of Xenopus embryos. In conclusion, our data support a model where functional SHOX protein levels are regulated by a combination of transcriptional and translational control mechanisms.
引用
收藏
页码:47820 / 47826
页数:7
相关论文
共 40 条
[1]   SHOX mutations in dyschondrosteosis (Leri-Weill syndrome) [J].
Belin, V ;
Cusin, V ;
Viot, G ;
Girlich, D ;
Toutain, A ;
Moncla, A ;
Vekemans, M ;
Le Merrer, M ;
Munnich, A ;
Cormier-Daire, V .
NATURE GENETICS, 1998, 19 (01) :67-69
[2]   SHOX:: Growth, Leri-Weill and Turner syndromes [J].
Blaschke, RJ ;
Rappold, GA .
TRENDS IN ENDOCRINOLOGY AND METABOLISM, 2000, 11 (06) :227-230
[3]   Enhancer-promoter specificity mediated by DPE or TATA core promoter motifs [J].
Butler, JEF ;
Kadonaga, JT .
GENES & DEVELOPMENT, 2001, 15 (19) :2515-2519
[4]  
Cai HNN, 2001, DEVELOPMENT, V128, P4339
[5]   Translational control of gene expression and disease [J].
Calkhoven, CF ;
Müller, C ;
Leutz, A .
TRENDS IN MOLECULAR MEDICINE, 2002, 8 (12) :577-583
[6]   The short stature homeobox gene SHOX is involved in skeletal abnormalities in Turner syndrome [J].
Clement-Jones, M ;
Schiller, S ;
Rao, E ;
Blaschke, RJ ;
Zuniga, A ;
Zeller, R ;
Robson, SC ;
Binder, G ;
Glass, I ;
Strachan, T ;
Lindsay, S ;
Rappold, GA .
HUMAN MOLECULAR GENETICS, 2000, 9 (05) :695-702
[7]   CART classification of human 5′ UTR sequences [J].
Davuluri, RV ;
Suzuki, Y ;
Sugano, S ;
Zhang, MQ .
GENOME RESEARCH, 2000, 10 (11) :1807-1816
[8]   PHOG, a candidate gene for involvement in the short stature of Turner syndrome [J].
Ellison, JW ;
Wardak, Z ;
Young, MF ;
Robey, PG ;
LaigWebster, M ;
Chiong, W .
HUMAN MOLECULAR GENETICS, 1997, 6 (08) :1341-1347
[9]   Control of translation initiation in animals [J].
Gray, NK ;
Wickens, M .
ANNUAL REVIEW OF CELL AND DEVELOPMENTAL BIOLOGY, 1998, 14 :399-458
[10]   Regulation of gene expression by internal ribosome entry sites or cryptic promoters: the eIF4G story [J].
Han, BG ;
Zhang, JT .
MOLECULAR AND CELLULAR BIOLOGY, 2002, 22 (21) :7372-7384