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

Download

index.pdf

Date

2013

Author

Akman, H. Begüm

Metadata

Show full item record

Item Usage Stats

196
views

115
downloads

Alternative polyadenylation (APA) may cause mRNA 3’-UTR (untranslated region) shortening in different physiological conditions and/or disease states. About half of mammalian genes use alternative cleavage and polyadenylation to generate multiple mRNA isoforms differing in their 3′-UTRs. Consequently, 3’-UTR shortening of mRNAs via APA has important consequences for gene expression. Studies showed that, by preferential use of proximal APA sites and switching to shorter 3’-UTRs, proliferating cells can avoid 3’-UTR dependent negative post-transcriptional regulations. Hence, such APA and 3’-UTR shortening events may explain the basis of some of the proto-oncogene activation cases observed in cancer cells. Based on the fact that certain cell types switch to more proximal poly(A) sites to rapidly increase translation rates by escaping from miRNAs, we hypothesized that upon estradiol (E2) treatment in estrogen receptor positive (ER+) breast cancer cells, such proximal poly(A) sites may be preferred to provide a rapid growth pattern. 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. Further investigations 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 likely mechanism to avoid 3’-UTR dependent negative regulations. In summary, 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

Gene expression., Genetic regulation., Messenger RNA., DNA., Cell division.

URI

http://etd.lib.metu.edu.tr/upload/12615922/index.pdf
https://hdl.handle.net/11511/22621

Collections

Graduate School of Natural and Applied Sciences, Thesis

Suggestions

OpenMETU
Core

Estrogen-induced upregulation and 3 '-UTR shortening of CDC6 AKMAN, Begum H.; Can, Tolga; Erson Bensan, Ayşe Elif (2012-11-01) 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 ...
Alternative polyadenylation dependent 3’-UTR changes in triple negative breast cancers Tuncer, Taner; Erson Bensan, Ayşe Elif; Can, Tolga; Department of Biotechnology (2014) Alternative polyadenylation (APA) may cause mRNA 3’-UTR (untranslated region) length changes in different physiological conditions and/or disease states. About half of mammalian genes use alternative polyadenylation to generate multiple mRNA isoforms differing in their 3′-UTRs. APA has been attracting attention due to roles in gene expression regulation by shortening or lengthening of 3'-UTRs upon proliferative signals. Triple Negative Breast Cancers (TNBCs) are aggressive subtypes of breast cancers with po...
Analysis of motifs in microRNA-transcription factor gene regulatory networks Sürün, Bilge; Acar, Aybar Can; Purutçuoğlu Gazi, Vilda; Department of Bioinformatics (2014) MicroRNAs are small non-coding RNA molecules which contain 21-25 nucleotides, and function in post transcriptional regulation by inhibiting the translation of mRNA targets. miRNAs typically affect gene regulation by forming composite feed forward circuits (cFFCs) which also comprise a transcription factor (TF) and a target gene. By analyzing these cFFCs, the contribution of miRNAs in altering TF networks can be revealed. These contributions could either be the de-escalation of the target gene repertoire or ...
Differential activation of immune cells by commensal versus pathogen-derived bacterial DNA Günalp, Sinem; Gürsel, Mayda; Department of Biology (2015) Immunological mechanisms making contribution to discriminating signals obtained from commensal versus pathogenic bacteria is an active area of research and recent evidence proposes that commensals and pathogens might express discrete variants of pathogen associated molecular patterns (PAMP). We hypothesized that as a major member of PAMP, bacterial DNA (bacDNA) originating from commensals versus pathogens might possess distinct immunostimulatory activities, enabling their dis- crimination by the immune syst...
The regulatory effect of CcaR activator on the cephamycin C gene cluster of streptomyces clavuligerus Kurt, Aslıhan; Özcengiz, Gülay; Department of Biology (2011) Streptomyces clavuligerus produces industrially important secondary metabolites such as cephamycin C (a β-lactam antibiotic) and clavulanic acid (a potent β-lactamase inhibitor). Cephamycin C is active against penicillin-resistant bacteria due to presence of methoxyl group in C-7 position of cephalosporin nucleus. Clavulanic acid is prescribed in combination with β-lactams for treatment of various bacterial infections. Cephamycin C and clavulanic acid gene clusters form β-lactam supercluster in S. clavulige...

Citation Formats

H. B. Akman, “Estrogen-induced upregulation and 3’-UTR shortening of CDC6,” Ph.D. - Doctoral Program, Middle East Technical University, 2013.