The pro-cell death Bcl-2 family member, BNIP3, is localized to the nucleus of human glial cells: Implications for glioblastoma multiforme tumor cell survival under hypoxia
The pro-cell death Bcl-2 family member, BNIP3, is localized to the nucleus of human glial cells: Implications for glioblastoma multiforme tumor cell survival under hypoxia
复制标题
DOI：
10.1002/ijc.21547
复制
发表时间：
2006-04-01
影响因子：
6.4
通讯作者：
Gibson, SB
中科院分区：
文献类型：
--
作者：
Burton, TR;Henson, ES;Gibson, SB
Bcl-2 19千道尔顿相互作用蛋白3（BNIP 3）是Bcl-2家族的缺氧诱导的促凋亡成员，其通过与线粒体结合来诱导细胞死亡。在正常情况下，BNIP 3在骨骼肌和大脑中以低水平表达。在许多人实体瘤中，BNIP 3在缺氧区域上调，但矛盾的是，这种BNIP 3表达不能诱导细胞死亡。在此，我们已经确定BNIP 3主要定位于正常人脑的神经胶质细胞的细胞核，以及恶性神经胶质瘤细胞系U251中。当U251细胞暴露于缺氧时，细胞质中的BNIP 3表达增加并定位于线粒体，有助于诱导细胞死亡。相反，当BNIP 3在细胞核中强制过表达时，它不能诱导细胞死亡。在U251细胞中表达N-末端BNIP 3（缺乏跨膜和保守结构域）通过与野生型BNIP 3结合并阻断其与线粒体的结合来阻断作为显性负性蛋白的缺氧诱导的细胞死亡。在多形性胶质母细胞瘤（GBM）肿瘤中，BNIP 3表达在肿瘤的缺氧区域中增加，并且在类似于80%的肿瘤中主要定位于细胞核。因此，BNIP 3被隔离在脑内的细胞核中，但在缺氧条件下，BNIP 3主要变成细胞质，促进细胞死亡。在GBM中，BNIP 3表达增加，但它仍然被隔离在缺氧区域的细胞核中，从而阻断BNIP 3与线粒体结合的能力，为肿瘤细胞提供可能的生存优势。(c)2005 Wiley-Liss，Inc.
The Bcl-2 nineteen kilodalton interacting protein 3 (BNIP3) is a hypoxia-inducible proapoptotic member of the Bcl-2 family that induces cell death by associating with the mitochondria. Under normal conditions, BNIP3 is expressed in skeletal muscle and in the brain at low levels. In many human solid tumors, BNIP3 is upregulated in hypoxic regions but paradoxically, this BNIP3 expression fails to induce cell death. Herein, we have determined that BNIP3 is primarily localized to the nucleus of glial cells of the normal human brain, as well as in the malignant glioma cell line U251. Upon exposure of U251 cells to hypoxia, BNIP3 expression in the cytoplasm increases and localizes with the mitochondria, contributing to induction of cell death. In contrast, when BNIP3 is forcibly over expressed in the nucleus, it fails to induce cell death. Expression of N-terminal BNIP3 (lacking the transmembrane and conserved domains) in U251 cells blocks hypoxia-induced cell death acting as a dominant negative protein by binding to wildtype BNIP3 and blocking its association with the mitochondria. In glioblastoma multiforme (GBM) tumors, BNIP3 expression is increased in hypoxic regions of the tumor and is primarily localized to the nucleus in similar to 80% of tumors. Hence, BNIP3 is sequestered in the nucleus within the brain but under hypoxic conditions, BNIP3 becomes primarily cytoplasmic, promoting cell death. In GBMs, BNIP3 expression is increased but it remains sequestered in the nucleus in hypoxic regions, thereby blocking BNIP3's ability to associate with the mitochondria, providing tumor cells with a possible survival advantage. (c) 2005 Wiley-Liss, Inc.