A polymorphism in a conserved posttranscriptional regulatory motif alters bone morphogenetic protein 2 (BMP2) RNA:protein interactions.
The bone morphogenetic protein (BMP)2 gene has been genetically linked to osteoporosis and osteoarthritis. We have shown that the 3'-untranslated regions (UTR) of BMP2 genes from mammals to fishes are extraordinarily conserved. This indicates that the BMP2 3'-UTR is under stringent selective pressure. We present evidence that the conserved region is a strong posttranscriptional regulator of BMP2 expression. Polymorphisms in cis-regulatory elements have been proven to influence susceptibility to a growing number of diseases. A common single nucleotide polymorphism (SNP) disrupts a putative posttranscriptional regulatory motif, an AU-rich element, within the BMP2 3'-UTR. The affinity of specific proteins for the rs15705 SNP sequence differs from their affinity for the normal human sequence. More importantly, the in vitro decay rate of RNAs with the SNP is higher than that of RNAs with the normal sequence. Such changes in mRNA:protein interactions may influence the posttranscriptional mechanisms that control BMP2 gene expression. The consequent alterations in BMP2 protein levels may influence the development or physiology of bone or other BMP2-influenced tissues.
Fritz
David T
DT
Biochemistry and Molecular Biology, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, New Jersey 07101-1709, USA.
Jiang
Shan
S
Xu
Junwang
J
Rogers
Melissa B
MB
D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn / Q000378:metabolism; D001846:Bone Development; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000235:genetics*; D001842:Bone and Bones / Q000378:metabolism; D017124:Conserved Sequence; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009928:Organ Specificity; D010024:Osteoporosis / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D012313:RNA / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional; D020871:RNA Stability; D011944:Receptors, Androgen / Q000378:metabolism; D050436:Regulatory Elements, Transcriptional / Q000235:genetics; D014018:Tissue Distribution; D015534:Trans-Activators / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics*; D019076:Transgenes; D015854:Up-Regulation / Q000235:genetics
D020413:3' Untranslated Regions; C525718:BMP2 protein, human; C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D011944:Receptors, Androgen; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D012313:RNA