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Alternative RNA structure-coupled gene regulations in tumorigenesis.

Chen FC - Int J Mol Sci (2014)

Bottom Line: In addition to generating functionally diverse protein isoforms from a single gene, ARS can alter the sequence contents of 5'/3' untranslated regions (UTRs) and intronic regions, thus also affecting the regulatory effects of these regions.Accumulating evidence indicates that ARS-coupled regulations play important roles in tumorigenesis.Here I will review our current knowledge in this field, and discuss potential future directions.

View Article: PubMed Central - PubMed

Affiliation: Institute of Population Health Sciences, National Health Research Institutes, Miaoli County 350, Taiwan. fcchen@nrhi.org.tw.

ABSTRACT
Alternative RNA structures (ARSs), or alternative transcript isoforms, are critical for regulating cellular phenotypes in humans. In addition to generating functionally diverse protein isoforms from a single gene, ARS can alter the sequence contents of 5'/3' untranslated regions (UTRs) and intronic regions, thus also affecting the regulatory effects of these regions. ARS may introduce premature stop codon(s) into a transcript, and render the transcript susceptible to nonsense-mediated decay, which in turn can influence the overall gene expression level. Meanwhile, ARS can regulate the presence/absence of upstream open reading frames and microRNA targeting sites in 5'UTRs and 3'UTRs, respectively, thus affecting translational efficiencies and protein expression levels. Furthermore, since ARS may alter exon-intron structures, it can influence the biogenesis of intronic microRNAs and indirectly affect the expression of the target genes of these microRNAs. The connections between ARS and multiple regulatory mechanisms underline the importance of ARS in determining cell fate. Accumulating evidence indicates that ARS-coupled regulations play important roles in tumorigenesis. Here I will review our current knowledge in this field, and discuss potential future directions.

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Related in: MedlinePlus

Possible outcomes of AS-NMD dysregulation. Misregulations of AS-NMD may occur because of mutations in the splicing factors or the genes of interest, which can lead to changes in the proportion of NMD-sensitive transcripts and subsequently the overall gene expression level (left pathway). Alternatively, aberrant AS-NMD can occur because of mutations in the NMD regulators. The resulting decreases in NMD activity cause truncated peptides to accumulate in the cell (right pathway). Generally, truncated peptides are detrimental and potentially pathogenic. However, in cases where truncated peptides are partially functional, decreases in NMD activity may turn out to be beneficial (bottom panel). The dashed curves indicate that the mRNA sequences are not translated.
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ijms-16-00452-f003: Possible outcomes of AS-NMD dysregulation. Misregulations of AS-NMD may occur because of mutations in the splicing factors or the genes of interest, which can lead to changes in the proportion of NMD-sensitive transcripts and subsequently the overall gene expression level (left pathway). Alternatively, aberrant AS-NMD can occur because of mutations in the NMD regulators. The resulting decreases in NMD activity cause truncated peptides to accumulate in the cell (right pathway). Generally, truncated peptides are detrimental and potentially pathogenic. However, in cases where truncated peptides are partially functional, decreases in NMD activity may turn out to be beneficial (bottom panel). The dashed curves indicate that the mRNA sequences are not translated.

Mentions: Figure 3 shows possible reasons for NMD dysregulations and the phenotypic consequences. NMD dysregulation may result from mutations in splicing factors or the genes of interest (the left pathway in Figure 3), both of which can result in the occurrences of PTCs and thus altered ratios in NMD-sensible transcript isoforms. Alternatively, the dysregulation can be induced by mutations in NMD regulators, which usually lead to decreased NMD activities and the accumulation of truncated peptides (the right pathway in Figure 3). Of note, the phenotypic effects of NMD dysregulations depend on whether the truncated peptides are deleterious or partially functional (inset table at the bottom of Figure 3). If the truncated peptides are detrimental, the left pathway may yield normal phenotypes, whereas the right pathway can cause diseased phenotypes. Notably, however, in the left pathway, normal NMD activities may significantly reduce the overall gene expression level. In this case, the phenotypic effects will depend on the functional contexts of the affected genes, and no simple predictions can be made. Meanwhile, if the truncated peptides are partially functional, elimination (left pathway) and retention (right pathway) of these peptides may lead to diseased and partially normal phenotypes, respectively (Figure 3).


Alternative RNA structure-coupled gene regulations in tumorigenesis.

Chen FC - Int J Mol Sci (2014)

Possible outcomes of AS-NMD dysregulation. Misregulations of AS-NMD may occur because of mutations in the splicing factors or the genes of interest, which can lead to changes in the proportion of NMD-sensitive transcripts and subsequently the overall gene expression level (left pathway). Alternatively, aberrant AS-NMD can occur because of mutations in the NMD regulators. The resulting decreases in NMD activity cause truncated peptides to accumulate in the cell (right pathway). Generally, truncated peptides are detrimental and potentially pathogenic. However, in cases where truncated peptides are partially functional, decreases in NMD activity may turn out to be beneficial (bottom panel). The dashed curves indicate that the mRNA sequences are not translated.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4307256&req=5

ijms-16-00452-f003: Possible outcomes of AS-NMD dysregulation. Misregulations of AS-NMD may occur because of mutations in the splicing factors or the genes of interest, which can lead to changes in the proportion of NMD-sensitive transcripts and subsequently the overall gene expression level (left pathway). Alternatively, aberrant AS-NMD can occur because of mutations in the NMD regulators. The resulting decreases in NMD activity cause truncated peptides to accumulate in the cell (right pathway). Generally, truncated peptides are detrimental and potentially pathogenic. However, in cases where truncated peptides are partially functional, decreases in NMD activity may turn out to be beneficial (bottom panel). The dashed curves indicate that the mRNA sequences are not translated.
Mentions: Figure 3 shows possible reasons for NMD dysregulations and the phenotypic consequences. NMD dysregulation may result from mutations in splicing factors or the genes of interest (the left pathway in Figure 3), both of which can result in the occurrences of PTCs and thus altered ratios in NMD-sensible transcript isoforms. Alternatively, the dysregulation can be induced by mutations in NMD regulators, which usually lead to decreased NMD activities and the accumulation of truncated peptides (the right pathway in Figure 3). Of note, the phenotypic effects of NMD dysregulations depend on whether the truncated peptides are deleterious or partially functional (inset table at the bottom of Figure 3). If the truncated peptides are detrimental, the left pathway may yield normal phenotypes, whereas the right pathway can cause diseased phenotypes. Notably, however, in the left pathway, normal NMD activities may significantly reduce the overall gene expression level. In this case, the phenotypic effects will depend on the functional contexts of the affected genes, and no simple predictions can be made. Meanwhile, if the truncated peptides are partially functional, elimination (left pathway) and retention (right pathway) of these peptides may lead to diseased and partially normal phenotypes, respectively (Figure 3).

Bottom Line: In addition to generating functionally diverse protein isoforms from a single gene, ARS can alter the sequence contents of 5'/3' untranslated regions (UTRs) and intronic regions, thus also affecting the regulatory effects of these regions.Accumulating evidence indicates that ARS-coupled regulations play important roles in tumorigenesis.Here I will review our current knowledge in this field, and discuss potential future directions.

View Article: PubMed Central - PubMed

Affiliation: Institute of Population Health Sciences, National Health Research Institutes, Miaoli County 350, Taiwan. fcchen@nrhi.org.tw.

ABSTRACT
Alternative RNA structures (ARSs), or alternative transcript isoforms, are critical for regulating cellular phenotypes in humans. In addition to generating functionally diverse protein isoforms from a single gene, ARS can alter the sequence contents of 5'/3' untranslated regions (UTRs) and intronic regions, thus also affecting the regulatory effects of these regions. ARS may introduce premature stop codon(s) into a transcript, and render the transcript susceptible to nonsense-mediated decay, which in turn can influence the overall gene expression level. Meanwhile, ARS can regulate the presence/absence of upstream open reading frames and microRNA targeting sites in 5'UTRs and 3'UTRs, respectively, thus affecting translational efficiencies and protein expression levels. Furthermore, since ARS may alter exon-intron structures, it can influence the biogenesis of intronic microRNAs and indirectly affect the expression of the target genes of these microRNAs. The connections between ARS and multiple regulatory mechanisms underline the importance of ARS in determining cell fate. Accumulating evidence indicates that ARS-coupled regulations play important roles in tumorigenesis. Here I will review our current knowledge in this field, and discuss potential future directions.

Show MeSH
Related in: MedlinePlus