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osu1167885575.pdf (2.09 MB)
ETD Abstract Container
Abstract Header
Characterization of C/EBPδ mRNA stability regulation in mouse mammary epithelial cell
Author Info
Li, Bin
Permalink:
http://rave.ohiolink.edu/etdc/view?acc_num=osu1167885575
Abstract Details
Year and Degree
2007, Doctor of Philosophy, Ohio State University, Veterinary Biosciences.
Abstract
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 G
0
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 G
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growth arrested mammary epithelial cells. First, I demonstrated that C/EBPδ mRNA was stabilized in G
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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 G
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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 G
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growth arrest. In summary, this dissertation provided a better understanding of the regulation of C/EBPδ expression under G
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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.
Committee
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)
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Document number:
osu1167885575
Download Count:
580
Copyright Info
© 2007, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.