The miR-17-5p microRNA is a key regulator of the G1/S phase cell cycle transition
Open Access
- 14 August 2008
- journal article
- research article
- Published by Springer Nature in Genome Biology
- Vol. 9 (8), R127-14
- https://doi.org/10.1186/gb-2008-9-8-r127
Abstract
MicroRNAs are modifiers of gene expression, acting to reduce translation through either translational repression or mRNA cleavage. Recently, it has been shown that some microRNAs can act to promote or suppress cell transformation, with miR-17-92 described as the first oncogenic microRNA. The association of miR-17-92 encoded microRNAs with a surprisingly broad range of cancers not only underlines the clinical significance of this locus, but also suggests that miR-17-92 may regulate fundamental biological processes, and for these reasons miR-17-92 has been considered as a therapeutic target. In this study, we show that miR-17-92 is a cell cycle regulated locus, and ectopic expression of a single microRNA (miR-17-5p) is sufficient to drive a proliferative signal in HEK293T cells. For the first time, we reveal the mechanism behind this response - miR-17-5p acts specifically at the G1/S-phase cell cycle boundary, by targeting more than 20 genes involved in the transition between these phases. While both pro- and anti-proliferative genes are targeted by miR-17-5p, pro-proliferative mRNAs are specifically up-regulated by secondary and/or tertiary effects in HEK293T cells. The miR-17-5p microRNA is able to act as both an oncogene and a tumor suppressor in different cellular contexts; our model of competing positive and negative signals can explain both of these activities. The coordinated suppression of proliferation-inhibitors allows miR-17-5p to efficiently de-couple negative regulators of the MAPK (mitogen activated protein kinase) signaling cascade, promoting growth in HEK293T cells. Additionally, we have demonstrated the utility of a systems biology approach as a unique and rapid approach to uncover microRNA function.Keywords
This publication has 37 references indexed in Scilit:
- Targeted Deletion Reveals Essential and Overlapping Functions of the miR-17∼92 Family of miRNA ClustersCell, 2008
- Transgenic over-expression of the microRNA miR-17-92 cluster promotes proliferation and inhibits differentiation of lung epithelial progenitor cellsDevelopmental Biology, 2007
- Synergistic action of the microRNA‐17 polycistron and Myc in aggressive cancer developmentCancer Science, 2007
- Augmentation of tumor angiogenesis by a Myc-activated microRNA clusterNature Genetics, 2006
- Downregulation of miR‐122 in the rodent and human hepatocellular carcinomasJournal of Cellular Biochemistry, 2006
- c-Myc-regulated microRNAs modulate E2F1 expressionNature, 2005
- A microRNA polycistron as a potential human oncogeneNature, 2005
- Combinatorial microRNA target predictionsNature Genetics, 2005
- Conserved Seed Pairing, Often Flanked by Adenosines, Indicates that Thousands of Human Genes are MicroRNA TargetsCell, 2005
- Prediction of Mammalian MicroRNA TargetsCell, 2003