Abstract
Mature mRNA is generated by the 3ʹ end cleavage and polyadenylation of its precursor pre-mRNA. Eukaryotic genes frequently have multiple polyadenylation sites, resulting in mRNA isoforms with different 3ʹ-UTR lengths that often encode different C-terminal amino acid sequences. It is well-known that this form of post-transcriptional modification, termed alternative polyadenylation, can affect mRNA stability, localization, translation, and nuclear export. We focus on the alternative polyadenylation of pre-mRNA for vascular endothelial growth factor receptor-1 (VEGFR-1), the receptor for VEGF. VEGFR-1 is a transmembrane protein with a tyrosine kinase in the intracellular region. Secreted forms of VEGFR-1 (sVEGFR-1) are also produced from the same gene by alternative polyadenylation, and sVEGFR-1 has a function opposite to that of VEGFR-1 because it acts as a decoy receptor for VEGF. However, the mechanism that regulates the production of sVEGFR-1 by alternative polyadenylation remains poorly understood. In this review, we introduce and discuss the mechanism of alternative polyadenylation of VEGFR-1 mediated by protein arginine methylation.
Highlights
Mature mRNA is generated by endonucleolytic cleavage of the 3 end of pre-mRNA, followed by the synthesis of a polyadenosine tail
The polyadenylation machinery is composed of four subcomplexes: (1) cleavage and polyadenylation specificity factor (CPSF), which contains CPSF160 (CPSF1), CPSF100 (CPSF2), CPSF73 (CPSF3), CPSF30 (CPSF4), WDR33, and factor interacting with poly(A) polymerase (FIP1); (2) cleavage stimulation factor (CSTF), which contains CSTF55 (CSTF1), CSTF64 (CSTF2), and CSTF77 (CSTF3); (3) cleavage factor I (CFIm), which contains CFIm25 (CPSF5), CFIm68 (CPSF6), and/or CFIm59 (CPSF7); and (4) cleavage factor II (CFIIm), which contains PCF11 and CLP1
These results indicated that hypoxia regulates the levels of sVEGFR-1 mRNA, and the alternative polyadenylation (APA) of vascular endothelial growth factor receptor-1 (VEGFR-1) is independent of hypoxia-inducible factor-1α (HIF-1α) in human microvascular endothelial cells (HMVEC)
Summary
Mature mRNA is generated by endonucleolytic cleavage of the 3 end of pre-mRNA, followed by the synthesis of a polyadenosine tail. Most APA sites are located in the same terminal exon (3 -UTR), resulting in mRNA isoforms with differing 3 -UTR lengths. Many APA sites are located in introns This type of APA leads to the expression of alternative terminal exons, resulting in different C-terminal coding sequences and 3 -UTRs in mRNAs. Alternative terminal exons can be divided into two subtypes. The EST (expressed sequence tag) database was queried by intronic sequences in the 5 region around or upstream of the exon encoding the transmembrane domain, following the identification of 31 mRNA variants from 19 of 24 RTK genes. Soluble VEGFR-2 (sVEGFR-2) is encoded by a VEGFR-2 mRNA isoform that is produced by cleavage and polyadenylation in intron 13 of the VEGFR-2 pre-mRNA, identically to VEGFR-1 [9,10]. We will focus on the mechanism of sVEGFR-1 production
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