CCR4-NOT複合体の膵臓β細胞における機能解析

• Material Type: 博士論文
• Title: CCR4-NOT複合体の膵臓β細胞における機能解析
• Author/Editor: Mostafa, Dina
• Author Heading: Mostafa, Dina
• Publication Date: 2020-02-29
• Publication Date (W3CDTF): 2020-02-29
• Alternative Title: Functional Analysis of CCR4-NOT Complex in Pancreatic β Cell
• Degree grantor/type: Okinawa Institute of Science and Technology Graduate University
• Date Granted: 2020-02-29
• Date Granted (W3CDTF): 2020-02-29
• Dissertation Number: 甲第43号
• Degree Type: Doctor of Philosophy
• Conferring No. (Dissertation): 甲第43号
• Text Language Code: eng
• Target Audience: 一般
• Note (General): Functional analysis of CCR4-NOT complex in pancreatic β cellPancreatic β cells are responsible for production and secretion of insulin in response to increasing blood glucose levels. Therefore, defects in pancreatic β cell function lead to hyperglycemia and diabetes mellitus. While extensive research has focused on signaling, transcriptional, and epigenetic regulation in β cells, how post-transcriptional mechanisms influence the β cell gene expression program is largely unknown. The carbon catabolite repression 4 (CCR4)–negative on TATA-less (NOT) complex (CCR4-NOT complex), a major deadenylase conserved in eukaryotes, catalyzes mRNA deadenylation which is the rate limiting step in mRNA decay pathway. The CCR4-NOT complex has been implicated in the development of metabolic diseases. However, whether the CCR4-NOT complex affects β cell function is not addressed. In this thesis, I aim to understand the importance of post-transcriptional regulation in β cells by generating mice lacking the Cnot3 gene, which encodes an essential CCR4-NOT complex subunit, in β cells. Suppression of CNOT3 in β cells caused β cell dysfunction and diabetes. This was associated with the decreased expression of β cell-specific genes and increased expression of genes specifically repressed in β cells, called “β cell disallowed genes”. By combining whole transcriptome and proteome analyses and subsequent validations using quantitative PCR (qPCR) and immunoblot analyses, I found that mRNA and protein expression patterns were largely different from normal β cells upon CNOT3 suppression, which was clearly relevant to the observed phenotypes. I also found that some β cell disallowed genes were stabilized in the absence of CNOT3, suggesting that their expression was maintained at low levels under the control of the CCR4-NOT complex. Together, this study uncovered mRNA deadenylation by CCR4-NOT complex as a novel molecular mechanism by which β cell identity and function are regulated.
• DOI: 10.15102/1394.00001210; https://doi.org/10.15102/1394.00001210
• Persistent ID (NDL): info:ndljp/pid/11490378; https://dl.ndl.go.jp/pid/11490378
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• Collection (particular): 国立国会図書館デジタルコレクション > デジタル化資料 > 博士論文; https://dl.ndl.go.jp/collections/A00014
• Acquisition Basis: 博士論文（自動収集）
• Date Accepted (W3CDTF): 2020-05-25T09:38:44+09:00
• Date Created (W3CDTF): 2020-04-02
• Format (IMT): application/pdf
• Access Restrictions: 国立国会図書館内限定公開
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• Periodical Title (URI): http://dx.doi.org/10.15102/1394.00001210; https://oist.repo.nii.ac.jp/records/1340
• Data Provider (Database): 国立国会図書館 : 国立国会図書館デジタルコレクション; https://dl.ndl.go.jp