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Hyperosmotic stress activates the expression of members of the miR-15/107 family and induces downregulation of anti-apoptotic genes in rat liver.

Santosa D, Castoldi M, Paluschinski M, Sommerfeld A, Häussinger D - Sci Rep (2015)

Bottom Line: It was also identified that hyperosmolarity significantly reduces the expression of anti-apoptotic genes including Bcl2, Ccnd1, Mcl1, Faim, Aatf, Bfar and Ikbkb, which are either validated or predicted targets of these microRNAs.Moreover, through the application of NOX and JNK inhibitors as well as benzylamine it is shown that the observed response is mediated by reactive oxygen species (ROS), suggesting that miR-15a, miR-15b and miR-16 are novel redoximiRs.It is concluded that the response of these three microRNAs to osmotic stress is ROS-mediated and that it might contribute to the development of a proapoptotic phenotype.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Moorenstrasse 5, 40225 Düsseldorf, Germany.

ABSTRACT
microRNAs are an abundant class of small non-coding RNAs that negatively regulate gene expression. Importantly, microRNA activity has been linked to the control of cellular stress response. In the present study, we investigated whether the expression of hepatic microRNAs is affected by changes in ambient osmolarity. It is shown that hyperosmotic exposure of perfused rat liver induces a rapid upregulation of miR-15a, miR-15b and miR-16, which are members of the miR-15/107 microRNAs superfamily. It was also identified that hyperosmolarity significantly reduces the expression of anti-apoptotic genes including Bcl2, Ccnd1, Mcl1, Faim, Aatf, Bfar and Ikbkb, which are either validated or predicted targets of these microRNAs. Moreover, through the application of NOX and JNK inhibitors as well as benzylamine it is shown that the observed response is mediated by reactive oxygen species (ROS), suggesting that miR-15a, miR-15b and miR-16 are novel redoximiRs. It is concluded that the response of these three microRNAs to osmotic stress is ROS-mediated and that it might contribute to the development of a proapoptotic phenotype.

No MeSH data available.


Related in: MedlinePlus

Schematic representation of short and long term hyperosmotic signaling towards apoptosis.Hyperosmotic hepatocyte shrinkage induces Nox-driven generation of ROS through a signaling pathway involving endosomal acidification, acidic sphingomyelinase activation, ceramide-dependent PKCζ activation and serine phosphorylation of p47phox, the regulatory subunit of Nox452843. ROS formation activates JNK4 which may directly or indirectly regulate transcription factors being required for the regulation of apoptotic genes and the biogenesis of the miR-15/107 family. Activated miRNAs in turn repress anti-apoptotic genes on a posttranscriptional level. In contrast to the short term signaling pathway towards CD95 activation (involving EGFR activation, EGFR/CD95 association, CD95 tyrosine phosphorylation and oligomerization, translocation of the CD95/EGFR complex to the plasma membrane and recruitment of the death-inducing signaling complex45628444546), miR-15a/b/-16 upregulation is a long-term proapoptotic regulatory mechanism. Furthermore, ROS is generated by benzylamine through the monoamine oxidase reaction30 and may inhibit the expression of anti-apoptotic genes.
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f12: Schematic representation of short and long term hyperosmotic signaling towards apoptosis.Hyperosmotic hepatocyte shrinkage induces Nox-driven generation of ROS through a signaling pathway involving endosomal acidification, acidic sphingomyelinase activation, ceramide-dependent PKCζ activation and serine phosphorylation of p47phox, the regulatory subunit of Nox452843. ROS formation activates JNK4 which may directly or indirectly regulate transcription factors being required for the regulation of apoptotic genes and the biogenesis of the miR-15/107 family. Activated miRNAs in turn repress anti-apoptotic genes on a posttranscriptional level. In contrast to the short term signaling pathway towards CD95 activation (involving EGFR activation, EGFR/CD95 association, CD95 tyrosine phosphorylation and oligomerization, translocation of the CD95/EGFR complex to the plasma membrane and recruitment of the death-inducing signaling complex45628444546), miR-15a/b/-16 upregulation is a long-term proapoptotic regulatory mechanism. Furthermore, ROS is generated by benzylamine through the monoamine oxidase reaction30 and may inhibit the expression of anti-apoptotic genes.

Mentions: Up to now, regulation of miRNA transcription is still poorly understood. Reason for this is that with the exclusion of intronic miRNAs, which are supposedly co-transcribed from the promoter of the host gene, there has been very little progress in the field of miRNA promoters. With the purpose to identify putative transcription factors that could mediate regulation of miRNA transcription, GO term enrichment was applied to the upregulated genes after 180 minutes of hyperosmotic stress (Supplementary Figure 4b). Importantly, our analysis suggests that the transcription factors Foxo3 and Egr1 could be possible drivers of the hyperosmotic-specific activation of miR-15/16 expression. Specifically, both Foxo3 and Egr1 have been described as stress-responsive TFs, mediating the activation of stress responsive genes3940. Figure 12 summarizes our current view on the role of miRNA in hyperosmotic signaling in the liver.


Hyperosmotic stress activates the expression of members of the miR-15/107 family and induces downregulation of anti-apoptotic genes in rat liver.

Santosa D, Castoldi M, Paluschinski M, Sommerfeld A, Häussinger D - Sci Rep (2015)

Schematic representation of short and long term hyperosmotic signaling towards apoptosis.Hyperosmotic hepatocyte shrinkage induces Nox-driven generation of ROS through a signaling pathway involving endosomal acidification, acidic sphingomyelinase activation, ceramide-dependent PKCζ activation and serine phosphorylation of p47phox, the regulatory subunit of Nox452843. ROS formation activates JNK4 which may directly or indirectly regulate transcription factors being required for the regulation of apoptotic genes and the biogenesis of the miR-15/107 family. Activated miRNAs in turn repress anti-apoptotic genes on a posttranscriptional level. In contrast to the short term signaling pathway towards CD95 activation (involving EGFR activation, EGFR/CD95 association, CD95 tyrosine phosphorylation and oligomerization, translocation of the CD95/EGFR complex to the plasma membrane and recruitment of the death-inducing signaling complex45628444546), miR-15a/b/-16 upregulation is a long-term proapoptotic regulatory mechanism. Furthermore, ROS is generated by benzylamine through the monoamine oxidase reaction30 and may inhibit the expression of anti-apoptotic genes.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4508667&req=5

f12: Schematic representation of short and long term hyperosmotic signaling towards apoptosis.Hyperosmotic hepatocyte shrinkage induces Nox-driven generation of ROS through a signaling pathway involving endosomal acidification, acidic sphingomyelinase activation, ceramide-dependent PKCζ activation and serine phosphorylation of p47phox, the regulatory subunit of Nox452843. ROS formation activates JNK4 which may directly or indirectly regulate transcription factors being required for the regulation of apoptotic genes and the biogenesis of the miR-15/107 family. Activated miRNAs in turn repress anti-apoptotic genes on a posttranscriptional level. In contrast to the short term signaling pathway towards CD95 activation (involving EGFR activation, EGFR/CD95 association, CD95 tyrosine phosphorylation and oligomerization, translocation of the CD95/EGFR complex to the plasma membrane and recruitment of the death-inducing signaling complex45628444546), miR-15a/b/-16 upregulation is a long-term proapoptotic regulatory mechanism. Furthermore, ROS is generated by benzylamine through the monoamine oxidase reaction30 and may inhibit the expression of anti-apoptotic genes.
Mentions: Up to now, regulation of miRNA transcription is still poorly understood. Reason for this is that with the exclusion of intronic miRNAs, which are supposedly co-transcribed from the promoter of the host gene, there has been very little progress in the field of miRNA promoters. With the purpose to identify putative transcription factors that could mediate regulation of miRNA transcription, GO term enrichment was applied to the upregulated genes after 180 minutes of hyperosmotic stress (Supplementary Figure 4b). Importantly, our analysis suggests that the transcription factors Foxo3 and Egr1 could be possible drivers of the hyperosmotic-specific activation of miR-15/16 expression. Specifically, both Foxo3 and Egr1 have been described as stress-responsive TFs, mediating the activation of stress responsive genes3940. Figure 12 summarizes our current view on the role of miRNA in hyperosmotic signaling in the liver.

Bottom Line: It was also identified that hyperosmolarity significantly reduces the expression of anti-apoptotic genes including Bcl2, Ccnd1, Mcl1, Faim, Aatf, Bfar and Ikbkb, which are either validated or predicted targets of these microRNAs.Moreover, through the application of NOX and JNK inhibitors as well as benzylamine it is shown that the observed response is mediated by reactive oxygen species (ROS), suggesting that miR-15a, miR-15b and miR-16 are novel redoximiRs.It is concluded that the response of these three microRNAs to osmotic stress is ROS-mediated and that it might contribute to the development of a proapoptotic phenotype.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Moorenstrasse 5, 40225 Düsseldorf, Germany.

ABSTRACT
microRNAs are an abundant class of small non-coding RNAs that negatively regulate gene expression. Importantly, microRNA activity has been linked to the control of cellular stress response. In the present study, we investigated whether the expression of hepatic microRNAs is affected by changes in ambient osmolarity. It is shown that hyperosmotic exposure of perfused rat liver induces a rapid upregulation of miR-15a, miR-15b and miR-16, which are members of the miR-15/107 microRNAs superfamily. It was also identified that hyperosmolarity significantly reduces the expression of anti-apoptotic genes including Bcl2, Ccnd1, Mcl1, Faim, Aatf, Bfar and Ikbkb, which are either validated or predicted targets of these microRNAs. Moreover, through the application of NOX and JNK inhibitors as well as benzylamine it is shown that the observed response is mediated by reactive oxygen species (ROS), suggesting that miR-15a, miR-15b and miR-16 are novel redoximiRs. It is concluded that the response of these three microRNAs to osmotic stress is ROS-mediated and that it might contribute to the development of a proapoptotic phenotype.

No MeSH data available.


Related in: MedlinePlus