The miR-17-5p microRNA is a key regulator of the G1/S phase cell cycle transition
Nicole Cloonan, Mellissa K Brown, Anita L Steptoe, Shivangi Wani, Wei L Chan, Alistair RR Forrest, Gabriel Kolle, Brian Gabrielli, and Sean M Grimmond
Genome Biology 2008, 9:R127
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Abstract
Background
MicroRNAs (miRNAs) are modifiers of gene expression, acting to reduce translation through either translational repression or mRNA cleavage. Recently it has been show that some microRNAs can act to promote or suppress cell transformation, with miR-17-92 described as the first oncogenic miRNA. The association of miR-17-92 encoded miRNAs 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.
Results
In this study, we show that miR-17-92 is a cell cycle regulated locus, and ectopic expression of a single miRNA (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.
Conclusions
The miR-17-5p microRNA is able to act as both an oncogene and a tumour 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 miRNA function.
Supplementary Material
Supplementary Table S1. Genes in the miR-17-5p cell cycle network. [Click Here]
Supplementary Figure S2. Validation of miR-17-5p activity in HEK293T-17-5p stable cell lines. [Click Here]
Supplementary Figure S3. Interaction network of miR-17-5p targets and cell cycle components. [Click Here]
Supplementary Table S4. A list of all primers used in this study. [Click Here]