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CCR4-NOT複合体の膵臓β細胞における機能解析
https://doi.org/10.15102/1394.00001210
https://doi.org/10.15102/1394.0000121073039038-8da5-4d39-bdd8-aa052f4d0303
名前 / ファイル | ライセンス | アクション |
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Full Text (4.0 MB)
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Final Exam Abstract (97.8 kB)
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Item type | 学位論文 / Thesis or Dissertation(1) | |||||||
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公開日 | 2020-04-02 | |||||||
タイトル | ||||||||
言語 | ja | |||||||
タイトル | CCR4-NOT複合体の膵臓β細胞における機能解析 | |||||||
タイトル | ||||||||
言語 | en | |||||||
タイトル | Functional Analysis of CCR4-NOT Complex in Pancreatic β Cell | |||||||
言語 | ||||||||
言語 | eng | |||||||
資源タイプ | ||||||||
資源タイプ識別子 | http://purl.org/coar/resource_type/c_db06 | |||||||
資源タイプ | doctoral thesis | |||||||
ID登録 | ||||||||
ID登録 | 10.15102/1394.00001210 | |||||||
ID登録タイプ | JaLC | |||||||
アクセス権 | ||||||||
アクセス権 | open access | |||||||
アクセス権URI | http://purl.org/coar/access_right/c_abf2 | |||||||
著者 (英) |
Mostafa, Dina
× Mostafa, Dina
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抄録 | ||||||||
内容記述タイプ | Other | |||||||
内容記述 | Functional analysis of CCR4-NOT complex in pancreatic β cell Pancreatic 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. |
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言語 | en | |||||||
口頭試問日 | ||||||||
2020-01-23 | ||||||||
学位授与年月日 | ||||||||
学位授与年月日 | 2020-02-29 | |||||||
学位名 | ||||||||
学位名 | Doctor of Philosophy | |||||||
学位授与番号 | ||||||||
学位授与番号 | 甲第43号 | |||||||
学位授与機関 | ||||||||
学位授与機関識別子Scheme | kakenhi | |||||||
学位授与機関識別子 | 38005 | |||||||
学位授与機関名 | Okinawa Institute of Science and Technology Graduate University | |||||||
著者版フラグ | ||||||||
出版タイプ | VoR | |||||||
出版タイプResource | http://purl.org/coar/version/c_970fb48d4fbd8a85 | |||||||
権利 | ||||||||
権利情報 | © 2020 The Author. |