3'UTR mediated regulation of the cyclin D1 proto-oncogene.
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.
Deshpande
Anagha
A
Department of Medicine III, Klinikum Grosshadern, Munich, Germany.
Pastore
Alessandro
A
Deshpande
Aniruddha J
AJ
Zimmermann
Yvonne
Y
Hutter
Grit
G
Weinkauf
Marc
M
Buske
Christian
C
Hiddemann
Wolfgang
W
Dreyling
Martin
M
D020413:3' Untranslated Regions / Q000235:genetics / Q000502:physiology*; D001483:Base Sequence; D002460:Cell Line; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000502:physiology; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000378:metabolism*; D035683:MicroRNAs / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics / Q000502:physiology; D000090063:Proto-Oncogene Mas; D016415:Sequence Alignment; D014161:Transduction, Genetic; D014162:Transfection
D020413:3' Untranslated Regions; C000715470:MAS1 protein, human; D035683:MicroRNAs; D000090063:Proto-Oncogene Mas; D019938:Cyclin D1