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Title: 探討A23187藥物經由BNIP3誘導神經母細胞瘤死亡
BNIP3 mediates A23187-induced cell death in neuroblastoma cells
Authors: Gow-Wei Huang
黃國維
Contributors: NTOU:Institute of Bioscience and Biotechnology
國立臺灣海洋大學:生物科技研究所
Keywords: 神經母細胞瘤;細胞凋亡
A23187;BNIP3
Date: 2010
Issue Date: 2011-07-04
Abstract: BNIP3屬於Bcl-2家族中pro-apoptotic類之BH3 domain only基因的其中之一成員,C端含有一個TM domain。藉由transmembrane domain 插入粒線體以及內質網的外膜上,調控細胞死亡。已有文獻指出,PKC能受鈣離子載體(calcium ionophore)活化並磷酸化BNIP3幫助穩定在細胞中累積。在本研究中證實,BNIP3參與了A23187造成Neuro2a細胞死亡扮有重要角色。之前學者已證實,處理A23187,一種鈣離子載體,能造成Neuro2細胞發生ER stress以及細胞凋亡。 實驗中,利用A23187處理Neuro2a細胞會誘導BNIP3的大量表現,相對地,當轉染BNIP3ΔTM可以抑制A23187造成Neuro2的細胞凋亡,顯示A231787造成細胞凋亡與BNIP3有關。並以Mitocapture染色觀察,發現大量表現的BNIP3會聚集在粒線體膜上造成粒線體喪失電位。當轉染BNIP3ΔTM可以降低A23187誘導細胞內質網壓力標誌蛋白GRP78的大量表現,顯示A23187造成ER stress與BNIP3有關。進一步使用MTT和Hoechst 染色觀察,細胞前處理chelerythrine (PKC inhibitor) 可以降低A23187造成細胞細凋亡。從這些實驗結果顯示,A23187經由活化PKC促進BNIP3在細胞內的累積,而細胞內大量表現的BNIP3會造成內質網壓力和粒線體的損傷,進而調控細胞走向細胞凋亡死亡。
BNIP3 is a BH3-only pro-apoptotic member of the Bcl-2 family with a C-terminal transmembrane (TM) domain, which mediates cell death by membrane insertion through TM domain that directs the protein to mitochondrial and endoplasmic reticular (ER) membranes. Previous studies have demonstrated that calcium ionophore can activate protein kinase C (PKC) to phosphorylate BNIP3 and to promote BNIP3 accumulation in cell. In this study, BNIP3 involved in A23187-induced death in Neuro2a cells. A23187, a calcium ionophore, can result in ER stress and apoptosis in Neuro2a cells. Treatment of Neuro2a cells with A23187 up-regulated BNIP3, and overexpression of BNIP3ΔTM blocked the A23187-induced cell death, showing that A23187-induced apoptosis may be through BNIP3. While overexpressed BNIP3, BNIP3 colocalized with MitoCapture in mitochondrial outer membrane and resulted in mitochondrial dysfunction. Furthermore, A23187 induced the expression of GRP78 protein, which is a maker protein of endoplasmic reticulum (ER) stress, and the expression is suppressed by BNIP3ΔTM. Our finding showed that A23187-induced ER stress mediated by BNIP3. Pre-treated chelerythrine (PKC inhibitor) reduces A23187-induced cell death and also decreased GRP78 expression. These results showed that A23187 causes BNIP3 accumulation via the activation of PKC and BNIP3 mediated A23187-induced cell death by inducing ER stress and mitochondrial dysfunction in Neuro2a cells.
URI: http://ethesys.lib.ntou.edu.tw/cdrfb3/record/#G0M97360018
http://ntour.ntou.edu.tw/ir/handle/987654321/17881
Appears in Collections:[生命科學暨生物科技學系] 博碩士論文

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