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標題: Study on the Mechanism How Adducin Distributes at Different Subcellular Localization and Its Biological Significance
作者: 陳鴻震
關鍵字: 基礎研究;Adducin;基礎醫學類, 生物技術;Adducin;肌動蛋白結合蛋白;細胞內分布;細胞增生;actin-binding protein;subcellular localization;cell proliferation
Adducin proteins (α, β, and γ) are the major components in the membrane cortical cytoskeleton where they binds to the barbed ends and the sides of F-actin, thereby promotes the association of spectrin with F-actin to form a spectrin-actin meshwork beneath the plasma membrane. Adducins are known to play a crucial role in assembly of the membrane skeleton of erythrocytes and in morphological regulation during platelet activation. In epithelial cells, α-adducin is found to localize at cell-cell contacts and membrane protrusions such as lamellipodia, important for stabilizing cell-cell junctions and promoting cell migration. Recently, we found that α-adducin is mainly localized in nuclei of sparsely cultured epithelial cells, whereas it is localized at cell-cell junctions when the cells are grown to confluence. Disruption of cell-cell adhesions induces translocation of α-adducin from cell-cell junctions to the nucleus. Conversely, α-adducin is redistributed to cell-cell junctions in the process to establish cell-cell adhesions. Moreover, we found that α-adducin depletion by small-hairpin RNA causes adverse effects on several cell functions including cell junctional stability, cell motility, and cell proliferation. These results suggest that α-adducin may be involved in both cytoplamic and nuclear events. The goal of this study is to investigate the mechanisms how α-adducin shuttles between the cytoplasm and the nucleus and to examine the biological significance of α-adducin in different subcellular localizations. As adducin is an actin-binding protein, which has never been described to localize and function in the nucleus, its role in cell proliferation and chromosome stability will be emphasized. Three specific aims are proposed:Aim 1. Examination of the mechanisms by which α-adducin shuttles between the cytoplasm and the nucleus. (1st year)Aim 2. Examination of the biological significance of α-adducin in conjunction with its subcellular localization (2nd year)Aim 3. Examination of the mechanisms by which α-adducin regulates cell proliferation and chromosome stability (3rd year)

Adducin蛋白(α, β, 及 γ)是構成細胞膜骨架的主要成分,他們與肌動蛋白絲(F-actin)結合,進而促進另一蛋白spectrin與肌動蛋白絲在細胞膜下方形成網狀結構。Adducin已知對於紅血球的細胞膜強度及血小板活化之形態改變扮演重要的角色。另外,在上皮細胞,adducin被發現會分布於細胞與細胞間的附著及細胞膜的突出構造,例如lamellipodia。最近,我們發現,當上皮細胞失去細胞與細胞間的附著,α−adducin的分布會從細胞間附著轉移到細胞核內;若上皮細胞重新建立細胞間的附著,α−adducin則又重新分布在細胞間的附著。此外,利用shRNA將α−adducin的表現抑制,對多種細胞功能造成不利的影響,包括細胞間附著的強度,細胞遷移,及細胞增生。這些結果顯示adducin參與細胞質及細胞核內的功能調控。本計劃的目的在於探討α−adducin分布在細胞內不同位置的機轉,及其在細胞內不同位置的功能。由於α−adducin是一肌動蛋白結合蛋白,其在細胞核內的分布非常特殊,因此我們將著重探討α−adducin在細胞增生及染色體穩定度的重要性。我們在此三年期計畫中提出以下三個具體研究目標:目標一、 探討α−adducin分布在細胞質及細胞核的機轉。 (第一年)目標二、 探討α−adducin 在細胞內不同位置的分布,所參與的細胞功能。(第二年)目標三、 探討α−adducinh參與調控細胞增生及染色體穩定度的機轉。(第三年)
其他識別: NSC99-2628-B005-010-MY3
Appears in Collections:生命科學系所

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