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Characterization of C/EBPδ mRNA stability regulation in mouse mammary epithelial cell

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2007, Doctor of Philosophy, Ohio State University, Veterinary Biosciences.
CCAAT/Enhancer binding proteins (C/EBPs) are a family of highly conserved transcription factors that regulate gene expression involved in cellular physiological process including cell growth, differentiation and apoptosis. C/EBPδ, a C/EBP family member, plays an important role in the G0 growth arrest of mouse mammary epithelial cells. The goal of this dissertation was to investigate the mechanism for posttranscriptional and transcriptional regulation of C/EBPä gene expression in G0 growth arrested mammary epithelial cells. First, I demonstrated that C/EBPδ mRNA was stabilized in G0 growth arrest after genotoxic stress such as UV or MMS treatment. p38 MAPK activation was responsible for the induced mRNA stabilization. Using a β-globin transcript reporter, I further demonstrated that the stabilization of C/EBPδ mRNA was partially mediated through its 3’UTR. HuR, a RNA stabilizing factor, increased its binding to the 3’UTR of C/EBPδ mRNA after UV treatment, and the cytoplasmic translocation of HuR was dependent on the p38 MAPK pathway. SiRNA analysis confirmed that HuR was required for the induced stabilization of C/EBPδ mRNA after UV irradiation. Finally, functional analysis of C/EBPδ expression under UV irradiation revealed that increased expression of C/EBPδ was associated with apoptosis. Secondly, I demonstrated that CRE site in the proximal promoter of C/EBPδ was also important for its transcriptional activation under G0 growth arrest. Mutation of the CRE site decreased C/EBPδ promoter activation. Using ChIP assay, I found that CREB was constitutively bound to the proximal promoter of C/EBPδ and promoter-bound CREB was phosphorylated after serum and growth factor withdrawal and/or OSM addition. Further study showed that ERK pathway was activated by OSM in a short period of time. The Blockage of CREB phosphorylation by U0126, a MEK inhibitor, inhibited the C/EBPδ expression. Alternatively, repression of CREB by SiRNA led to reduced expression of C/EBPδ in G0 growth arrest. In summary, this dissertation provided a better understanding of the regulation of C/EBPδ expression under G0 growth arrest conditions, and suggested that pharmacological interventions aimed at activation of the p38 MAP kinase pathway may increase C/EBPδ mRNA stability and promote growth arrest and/or programmed cell death of breast cancer cells.
James DeWille (Advisor)

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Citations

  • Li, B. (2007). Characterization of C/EBPδ mRNA stability regulation in mouse mammary epithelial cell [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1167885575

    APA Style (7th edition)

  • Li, Bin. Characterization of C/EBPδ mRNA stability regulation in mouse mammary epithelial cell. 2007. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1167885575.

    MLA Style (8th edition)

  • Li, Bin. "Characterization of C/EBPδ mRNA stability regulation in mouse mammary epithelial cell." Doctoral dissertation, Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=osu1167885575

    Chicago Manual of Style (17th edition)