Cell-Specific Post-Transcriptional Regulation of γ-Synuclein Gene by Micro-RNAs

Abstract

γ-Synuclein is a member of the synucleins family of small proteins, which consists of three members:α, β- and γ-synuclein. γ-Synuclein is abnormally expressed in a high percentage of advanced and metastatic tumors, but not in normal or benign tissues. Furthermore, γ-synuclein expression is strongly correlated with disease progression, and can stimulate proliferation, induce invasion and metastasis of cancer cells. γ-Synuclein transcription is regulated basically through the binding of AP-1 to specific sequences in intron 1. Here we show that γ-synuclein expression may be also regulated by micro RNAs (miRs) on post-transcriptional level. According to prediction by several methods, the 3′-untranslated region (UTR) of γ-synuclein gene contains targets for miRs. Insertion of γ-synuclein 3′-UTR downstream of the reporter luciferase (LUC) gene causes a 51% reduction of LUC activity after transfection into SKBR3 and Y79 cells, confirming the presence of efficient targets for miRs in this fragment. Expression of miR-4437 and miR-4674 for which putative targets in 3′-UTR were predicted caused a 61.2% and 60.1% reduction of endogenous γ-synuclein expression confirming their role in gene expression regulation. On the other hand, in cells overexpressing γ-synuclein no significant effect of miRs on γ-synuclein expression was found suggesting that miRs exert their regulatory effect only at low or moderate, but not at high level of γ-synuclein expression. Elevated level of γ-synuclein differentially changes the level of several miRs expression, upregulating the level of some miRs and downregulating the level of others. Three miRs upregulated as a result of γ-synuclein overexpression, i.e., miR-885-3p, miR-138 and miR-497 have putative targets in 3′-UTR of the γ-synuclein gene. Some of miRs differentially regulated by γ-synuclein may modulate signaling pathways and cancer related gene expression. This study demonstrates that miRs might provide cell-specific regulation of γ-synuclein expression and set the stage to further evaluate their role in pathophysiological processes.

Upregulation of miR‐200a and miR‐204 in MPP+‐treated differentiated PC12 cells as a model of Parkinson’s disease

“…miR‐204 is one of the known tumor suppressors found to modulate apoptosis and be remarkably downregulated in many types of cancers (Surgucheva, Gunewardena, Rao, & Surguchov, ). Here, we demonstrated that similar to miR‐200a, the expression level of miR‐204 was increased in differentiated PC12 cells following MPP + treatment (Figure b).…”

MiR‐885‐3p is down‐regulated in peripheral blood mononuclear cells from T1D patients and regulates the inflammatory response via targeting TLR4/NF‐κB signaling

“…12 MiR-885-3p could target γ-synuclein 3'-UTR and repress γ-synuclein, which may be involved in the tumor metastasis. 13 MiR-885-3p exerted its tumor suppressive effects in colon cancer via the disruption of angiogenesis. 14 MiR-885-3p could target the 3'-UTR of vitamin D receptor and contributed to the development of pressure ulcers.…”

Identification and functional characterisation of a novel dopamine beta hydroxylase gene variant associated with attention deficit hyperactivity disorder

“…Interestingly, the DBH rs129882 SNP maps within seed regions of miRNAs including hsa-miR-1268, hsa-miR-1268b, hsa-miR-4468 and hsa-miR-585 (by Target Scan 6.2, Lewis et al 2005). Further, hsa-miR-1268b is predominantly expressed in the brain tissue (intragenic microRNA database) and in the neuroblastoma SH-SY5Y cell line (Surgucheva et al 2013;Hinske et al 2014). Thus the putative DBH -3 ʹ UTR binding of hsa-miR-1268b and its expression in SH-SY5Y cells suggests that the C/T substitution of rs129882 could impact hsa-miR-1268b binding and affect the expression of DBH .…”