In
mantle cell lymphoma (MCL), overexpression of
cyclin D1 is the hallmark of malignant transformation and results from it's juxtaposition to the
immunoglobulin heavy chain enhancer. In addition, genomic deletions or point mutations leading to premature truncation of the
cyclin D1 3' untranslated region (UTR) have been reported in a several MCL patients as well as in cell lines isolated from various
tumors types. We demonstrate that the expression of
cyclin D1 with or without the
3'UTR has different phenotypic consequences in stably transduced fibroblasts, with the hyper-proliferative phenotype of
cyclin D1 closely linked to the deletion of its
3'UTR. In our study, the loss of the
cyclin D1 3'UTR led to a significant upregulation of the
protein. However, the loss of AU-rich elements (AREs) from the
cyclin D1 3'UTR results in a significant decrease in
cyclin D1 protein and UTR-tagged reporter expression. In contrast, the levels of
cyclin D1 protein can be significantly reduced by
microRNAs of the miR-15/16 family and the miR17-92 cluster that directly target the
cyclin D1 3'UTR. Most importantly, these
microRNAs regulated the levels of the endogenous
cyclin D1 protein encoded by an
mRNA with a full
3'UTR but not with
3' UTR deletions. Taken together, our data highlight the regulatory role of the
cyclin D1 3'UTR in the expression and phenotype of
cyclin D1 and suggest that in MCL and solid
tumors with
cyclin D1 3'UTR mutations, the loss of
microRNA target sites, rather than ARE elements contribute to the pathogenic overexpression of the
cyclin D1 protein.