Dissertation
Investigation into the regulation of Activating Transcription Factor 5 (ATF5) by microRNA under cellular stress in cancer cells
Doctor of Philosophy (PhD), Washington State University
01/2019
Handle:
https://hdl.handle.net/2376/111567
Abstract
Malfunctioning cellular stress responses have been linked to a host of diseases, such as diabetes, neuronal degenerative diseases, and cancer. Cancer cells are faced with a variety of stress conditions resulting from the tumor microenvironment and their highly proliferative state. microRNAs (miRNAs) are endogenous small non-coding RNAs that contribute to post-transcriptional regulation of gene expression by binding to target sites in the 3’ UTR of cognate mRNA, leading to translational inhibition and/or mRNA degradation. miRNA dysregulation leads to aberrant genetic expression and is associated with cellular stress related diseases, including cancer.
Activating transcription factor 5 (ATF5) is a widely expressed transcription factor that modulates survival, proliferation, and differentiation and plays a role in homeostasis and cellular stress response. In unstressed conditions, ATF5 expression is suppressed and has a short half-life. Conversely, ATF5 is upregulated by diverse stress conditions and leads to increased cell survival. ATF5 is overexpressed in a wide range of cancers. Furthermore, silencing ATF5 or interfering with its activity leads to selective apoptosis of cancer cells but not non-transformed cells, and decreased tumor growth in vivo, making it a promising target for cancer therapy. Regulation of ATF5 is not fully understood.
The purpose of this dissertation was to better understand the regulation of ATF5 in the stress phenotype of cancer cells and investigate the potential regulation of ATF5 by miRNA under cellular stress conditions in cancer cells. We focused on three different microRNA predicted by in silico analysis to target the ATF5 3’ UTR: miR-129-5p, mir-433-3p, and miR-520b, and their ability to suppress ATF5 expression, with an added interest in probing for an enhanced combinatorial activity. Although initial findings indicated all three miRNA could interact with ATF5 3’ UTR, functional studies revealed a role for miR-520b alone in modulating ATF5 expression under multiple stress conditions in cancer cells. The implications of these findings will be thoroughly discussed. This is the first study to investigate miRNA regulation of ATF5, a stress-response transcription factor, under cellular stress conditions, and we present the first evidence of the mediation of ATF5 expression by miRNA under the stress phenotype of cancer cells.
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Details
- Title
- Investigation into the regulation of Activating Transcription Factor 5 (ATF5) by microRNA under cellular stress in cancer cells
- Creators
- Kari Ann Gaither
- Contributors
- Philip Lazarus (Advisor)Susan Marsh (Committee Member)Salah-Uddin Ahmed (Committee Member)Zhaokang Cheng (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- College of Pharmacy and Pharmaceutical Sciences
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Number of pages
- 179
- Identifiers
- 99900581707201842
- Language
- English
- Resource Type
- Dissertation