Abstract
MicroRNAs (miRNAs) are predicted to regulate approximately 30% of all human genes; however, only a few miRNAs have been assigned their targets and specific functions. Here we demonstrate that miR-24, a ubiquitously expressed miRNA, has an anti-proliferative effect independent of p53 function. Cell lines with differential p53 status were used as a model to study the effects of miR-24 on cell proliferation, cell cycle control, gene regulation and cellular transformation. Overexpression of miR-24 in six different cell lines, independent of p53 function, inhibited cell proliferation and resulted in G2/S cell cycle arrest. MiR-24 over expression in cells with wt-p53 upregulated TP53 and p21 protein; however, in p53-null cells miR-24 still induced cell cycle arrest without the involvement of p21. We show that miR-24 regulates p53-independent cellular proliferation by regulating an S-phase enzyme, dihydrofolate reductase (DHFR) a target of the chemotherapeutic drug methotrexate (MTX). Of interest, we found that a miR-24 target site polymorphism in DHFR 3′ UTR that results in loss of miR-24-function and high DHFR levels in the cell imparts a growth advantage to immortalized cells and induces neoplastic transformation. Of clinical significance, we found that miR-24 is deregulated in human colorectal cancer tumors and a subset of tumors has reduced levels of miR-24. A novel function for miR-24 as a p53-independent cell cycle inhibitory miRNA is proposed.
Highlights
MicroRNAs are small non-coding RNAs, processed from longer transcripts by Drosha and Dicer, that mostly bind to the 39 untranslated regions (39UTR) of target genes and inhibit gene expression translationally and/or by destabilizing the target mRNA [1,2,3,4,5]
We determined if the effect of miR-24 on cellular proliferation was related to cell cycle control
MiR-24 regulates dihydrofolate reductase, a gene associated with cell proliferation, independent of p53 function
Summary
MicroRNAs (miRNAs) are small non-coding RNAs, processed from longer transcripts by Drosha and Dicer, that mostly bind to the 39 untranslated regions (39UTR) of target genes and inhibit gene expression translationally and/or by destabilizing the target mRNA [1,2,3,4,5]. As miRNA expression is altered in many human diseases, including cancer, the discovery of miRNAs has added an entirely new dimension to antitumor therapeutic approaches [6]. MiRNAs are differentially expressed in many cancers and play a critical role in oncogenesis [7]. MiRNAs have been predicted to regulate approximately 30% of all human genes, few miRNAs have been assigned to their target mRNAs and specific functions [10]. MiR-24 was found to be upregulated during the stationary phase of growth in CHO-K1 cells [16], and in sodium butyrate differentiated embryonic stem cells [17]. MiR-24 plays a role in erythropoiesis by regulating ALK4 and in replicative senescence by regulating p16 [20,21]
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