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    請使用永久網址來引用或連結此文件: http://libir.tmu.edu.tw/handle/987654321/53527


    題名: IGF-1R 訊息傳遞路徑藉由 PI3K/Akt/mTOR 以及 MAPK/ERK 維持鹼性磷酸酶活性之配子幹細胞之 Oct-4 表現
    IGF-1R Signaling Maintains the Oct-4 Expression through PI3K/Akt/mTOR and MAPK/ERK in Alkaline Phosphatase Positive Germline Stem Cells
    作者: 王鵬証
    WANG, PENG-CHENG
    關鍵詞: IGF-1R 訊息;HIF-2α;Oct-4;配子幹細胞;IGF-1R signaling;HIF-2α;Oct-4;germline stem cells
    日期: 2013-07-05
    上傳時間: 2018-11-12 14:52:26 (UTC+8)
    摘要: 近年來研究證實，HIF-2α (Hypoxia inducible factor-2α) 基因剃除小鼠降低了生殖脊 (Genital ridge) 中原生殖細胞 (Primordial germ cell, PGCs) 之 Oct-4 (Octamer-binding transcription factor-4) 蛋白表現以及細胞遷移的數量。然而，低氧環境 (Hypoxia O2) 經由何種路徑調控原生殖細胞的自我更新以及遷移則尚未明瞭。因此我們建立了無血清培養系統，培養同時表現 CD49f 細胞表面抗原 (CD49f+) 以及鹼性磷酸酶 (Alkaline phosphatase, AP) 活性之新生小鼠生殖幹細胞 (CD49f+AP+GSCs)，並利用磁性細胞分選技術 (MACS) 純化 CD49f+AP+GSC。我們發現，低氧環境會促進細胞分泌 IGF-1，同時隨著 IGF-1 劑量上升而促進 HIF-2α 與 Oct-4 之蛋白表現。此結果支持在 CD49f+AP+GSC 中，利用蛋白酶體抑制劑 (MG132) 可以維持 IGF-1 誘導之 HIF-2α 與 Oct-4 蛋白表現。然而，在低氧或外加 IGF-1 環境下，knockdown IGF-1R 會降低 HIF-2α 與 Oct-4 之蛋白表現。此外，IGF-1R 磷酸化之抑制劑 (PPP)、PI3K 之抑制劑 (LY294002)、mTOR 之抑制劑 (Rapamycin)、ERK 之抑制劑 (PD98059) 皆會抑制低氧環境或 IGF-1 誘導之 HIF-2α 與 Oct-4 蛋白表現。有趣的是 knockdown HIF-2α 也會降低 IGF-1R 蛋白表現。總結以上敘述，我們證明 IGF-1/IGF-1R 經由 PI3K/Akt/mTOR 以及 MAPK/ERK 之訊息傳遞路徑，促進 HIF-2α 蛋白表現進而調控 Oct-4 在 CD49f+AP+GSCs 中之表現。此發現提供我們了解微環境 (Niche) 對於生殖幹細胞之早期發育的重要性。

    Recent studies using a transgenic mice model showed that knockout of hypoxia inducible factor-2α (HIF-2α) decreases Oct-4 protein expression levels and the number of migrated primordial germ cells (PGC) in genital ridge. However, the hypoxia-induced endocrinal signals which mediating PGC self-renewal still remain largely unknown. For this purpose, we have previously established a serum-free culture system to generate pluripotent CD49f/alkaline phosphatase positive germline stem cells (CD49f+AP+GSCs) in vitro from neonatal mouse testis. The CD49f+AP+GSCs were purified using a MACS magnetic beads system. We found hypoxia increased the IGF-1 secretion, and the IGF-1 increased the HIF-2α and Oct-4 protein expression levels in a dose-dependent manner. This result was supported using a proteasome inhibitor MG132 which maintains the IGF-1-induced HIF-2α and Oct-4 protein expressions in AP+CD49+GSCs. Furthermore, knockdown IGF-1R also reduced HIF-2α and Oct-4 protein expression levels in both of the hypoxia and IGF-1 treatment condition. In addition, the blockage of PPP (IGF-1R phosphorylation inhibitor), LY294002 (PI3K inhibiter), Rapamycin (mTOR inhibitor), and PD98059 (ERK inhibitor) decreased the hypoxoia- and/or IGF-1-induced HIF-2α and Oct-4 protein expressions. Interestingly, knockdown HIF-2α also decreased the IGF-1R protein expression. In summary, we demonstrated that IGF-1/IGF-1R promoted the HIF-2α expression through PI3K/Akt/mTOR and MAPK/ERK pathway by which to regulate the Oct-4 expression in CD49f+AP+GSCs. This finding provides insights into the niche endocrinology in early pluripotent germ cell development.
    描述: 碩士
    指導教授-黃彥華
    委員-楊慕華
    委員-曾啟瑞
    資料類型: thesis
    顯示於類別:[醫學科學研究所] 博碩士論文

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