title: 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.
authors.affiliation: Retinal Biology Research Laboratory, Veterans Administration Medical Center, Kansas City, Missouri, United States of America ; Department of Neurology, Kansas University Medical Center, Kansas City, Kansas, United States of America.
authors.forename: Irina
authors.initials: I
authors.lastname: Surgucheva
authors.forename: Sumedha
authors.initials: S
authors.lastname: Gunewardena
authors.forename: H Shanker
authors.initials: HS
authors.lastname: Rao
authors.forename: Andrei
authors.initials: A
authors.lastname: Surguchov
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics*; D001483:Base Sequence; D015153:Blotting, Western; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D008957:Models, Genetic; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D059467:Transcriptome; D051845:gamma-Synuclein / Q000235:genetics* / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; C000589190:MIRN-4437 microRNA, human; C546110:MIRN138 microRNA, human; C000589191:MIRN4674 microRNA, human; C559640:MIRN497 microRNA, human; C574934:MIRN885 microRNA, human; D035683:MicroRNAs; D051845:gamma-Synuclein; D008156:Luciferases
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