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Deshpande, A. ; Pastore, A. ; Deshpande, A.J. ; Zimmermann, Y. ; Hutter, G. ; Weinkauf, M. ; Buske, C. ; Hiddemann, W. ; Dreyling, M.

3'UTR mediated regulation of the cyclin D1 proto-oncogene.

Cell Cycle 8, 3592-3600 (2009)
PMC
Open Access Green as soon as Postprint is submitted to ZB.
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords cell cycle; cyclin D1; MCL; AU-rich elements; microRNA
ISSN (print) / ISBN 1538-4101
e-ISSN 1551-4005
Journal Cell Cycle
Quellenangaben Volume: 8, Issue: 21, Pages: 3592-3600 Article Number: , Supplement: ,
Publisher Landes Bioscience
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) CCG Pathogenesis of Acute Myeloid Leukemia (KKG-KPL)