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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.

MiR-24 Tumor Suppressor Activity Is Regulated Independent of p53 and through a Target Site Polymorphism