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


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AKMAN B. H., CAN T., Erson-Bensan A. E.

NUCLEIC ACIDS RESEARCH, vol.40, no.21, pp.10679-10688, 2012 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 40 Issue: 21
  • Publication Date: 2012
  • Doi Number: 10.1093/nar/gks855
  • Journal Name: NUCLEIC ACIDS RESEARCH
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Page Numbers: pp.10679-10688
  • Middle East Technical University Affiliated: Yes

Abstract

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.