Abstract
miRNA cluster miR-17-92 is known as oncomir-1 due to its potent oncogenic function. miR-17-92 is a polycistronic cluster that encodes 6 miRNAs, and can both facilitate and inhibit cell proliferation. Known targets of miRNAs encoded by this cluster are largely regulators of cell cycle progression and apoptosis. Here, we show that miRNAs encoded by this cluster and sharing the seed sequence of miR-17 exert their influence on one of the most essential cellular processes – endocytic trafficking. By mRNA expression analysis we identified that regulation of endocytic trafficking by miR-17 can potentially be achieved by targeting of a number of trafficking regulators. We have thoroughly validated TBC1D2/Armus, a GAP of Rab7 GTPase, as a novel target of miR-17. Our study reveals regulation of endocytic trafficking as a novel function of miR-17, which might act cooperatively with other functions of miR-17 and related miRNAs in health and disease.
Highlights
MicroRNAs are short non-coding RNAs (18 to 24 nt in length) regulating gene expression in metazoans. miRNAs bind to target mRNAs in a complementary or partially complementary way, resulting in degradation and/or translational repression of mRNAs [1]. miRNAs are postulated to bind to 39 untranslated regions (39UTRs) of transcripts [2]
Regulation of cell cycle progression accounts for the majority of these functions; and miR-17-92 was shown to either facilitate [18,21,22,23] or inhibit cell proliferation depending on different cellular context
After subtracting overlapping transcripts, whose expression was changed at different time points, 138 mRNAs with altered expression levels were identified in this experiment
Summary
MicroRNAs (miRNAs) are short non-coding RNAs (18 to 24 nt in length) regulating gene expression in metazoans. miRNAs bind to target mRNAs in a complementary or partially complementary way, resulting in degradation and/or translational repression of mRNAs [1]. miRNAs are postulated to bind to 39 untranslated regions (39UTRs) of transcripts [2]. Roles of miRNAs in the regulation of cell cycle progression, senescence, development and tumour biology are well established [10,11], with numerous miRNAs identified as key regulators. One of the most studied in this context is the miRNA-17-92 cluster, called oncomir-1 and frequently over-expressed in many tumours [12]. It consists of 6 miRNAs: miR-17-5p, miR-18a-5p, miR-19a3p, miR-20a-5p, miR-19b-3p, and miR-92a-3p (further named as miR-17, miR-18a, miR-19a, miR-20a, miR-19b and miR-92a, respectively). Regulation of cell cycle progression accounts for the majority of these functions; and miR-17-92 was shown to either facilitate [18,21,22,23] or inhibit cell proliferation depending on different cellular context. The majority of known targets of the miR-17-92 cluster have been identified for miR-17 [27], which builds miR-17 seed family with other 5 miRNAs encoded by miR-17-92 (miR-20a) and by paralogues clusters miR-106b-25
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