Abstract
MicroRNAs (miRNAs) play important roles under multiple cellular conditions including endoplasmic reticulum (ER) stress. We found that miR-3648, a human specific microRNA, was induced under ER stress. Moreover, Adenomatous polyposis coli 2 (APC2), a tumor suppressor and a negative regulator of Wnt signaling, was found to be the direct target of miR-3648. Levels of APC2 were downregulated when cells were under ER stress or after overexpressing miR-3648. Inhibition of miR-3648 by antagomir increased APC2 levels and decreased cell proliferation. Conversely, when miR-3648 was overexpressed, APC2 levels were decreased and the cell growth increased. Our data demonstrated that ER stress mediated induction of miR-3648 in human cells, which then downregulated APC2 to increase cell proliferation.
Highlights
Introductionendoplasmic reticulum (ER) is responsible for folding and maturation of a large number of proteins [10,11]
We find increased expression level of target genes of Wnt/β-catenin signaling pathway (Figure 4E), and our data regarding miR-3648 and Adenomatous polyposis coli 2 (APC2) add a novel link between endoplasmic reticulum (ER) stress and Wnt/β catenin signaling in human cells
We found that miR-3648, a human specific microRNA, was upregulated upon ER stress
Summary
ER is responsible for folding and maturation of a large number of proteins [10,11]. Protein folding is both regulated and sensed by ER resident chaperones, such as GRP78/Bip and Grp94 [12,13,14]. Mammalian UPR is controlled by inositol-requiring enzymes 1 (IRE1), protein kinase-like ER kinase (PERK), and the activating transcription factor 6 (ATF6) [11,17,18]. IRE1 trigger increased expression of various ER chaperones by activating the X box binding protein 1 (XBP1) transcription factor [19]. PERK is activated in a manner similar to IRE1 It catalyzes serine 51 phosphorylation of eIF2α, resulting in global repression of protein synthesis [20]. ATF6 is involved in the transcriptional induction of ER chaperones [21]
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