Estrogen-induced upregulation and 3 '-UTR shortening of CDC6

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2012-11-01

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AKMAN, Begum H.
Can, Tolga
Erson Bensan, Ayşe Elif

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3'-Untranslated region (UTR) shortening of mRNAs via alternative polyadenylation (APA) has important ramifications for gene expression. By using proximal APA sites and switching to shorter 3'-UTRs, proliferating cells avoid miRNA-mediated repression. Such APA and 3'-UTR shortening events may explain the basis of some of the proto-oncogene activation cases observed in cancer cells. In this study, we investigated whether 17 beta-estradiol (E2), a potent proliferation signal, induces APA and 3'-UTR shortening to activate proto-oncogenes in estrogen receptor positive (ER+) breast cancers. Our initial probe based screen of independent expression arrays suggested upregulation and 3'-UTR shortening of an essential regulator of DNA replication, CDC6 (cell division cycle 6), upon E2 treatment. We further confirmed the E2- and ER-dependent upregulation and 3'UTR shortening of CDC6, which lead to increased CDC6 protein levels and higher BrdU incorporation. Consequently, miRNA binding predictions and dual luciferase assays suggested that 3'-UTR shortening of CDC6 was a mechanism to avoid 3'-UTR-dependent negative regulations. Hence, we demonstrated CDC6 APA induction by the proliferative effect of E2 in ER+ cells and provided new insights into the complex regulation of APA. E2-induced APA is likely to be an important but previously overlooked mechanism of E2-responsive gene expression.

Subject Keywords

Breast-Cancer Cells, Alternative Polyadenylation, Dna-Replication, Gene, Expression, Identification, Growth, Database, Complexes, Transcription

URI

https://hdl.handle.net/11511/41135

Journal

NUCLEIC ACIDS RESEARCH

DOI

https://doi.org/10.1093/nar/gks855

Collections

Department of Computer Engineering, Article

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Citation Formats

B. H. AKMAN, T. Can, and A. E. Erson Bensan, “Estrogen-induced upregulation and 3 ’-UTR shortening of CDC6,” NUCLEIC ACIDS RESEARCH, pp. 10679–10688, 2012, Accessed: 00, 2020. [Online]. Available: https://hdl.handle.net/11511/41135.