BNIP3 (Bcl-219 kDa Interacting Protein) Acts as Transcriptional Repressor of Apoptosis-Inducing Factor Expression Preventing Cell Death in Human Malignant Gliomas
BNIP3 (Bcl-219 kDa Interacting Protein) Acts as Transcriptional Repressor of Apoptosis-Inducing Factor Expression Preventing Cell Death in Human Malignant Gliomas
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DOI：
10.1523/jneurosci.5747-08.2009
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发表时间：
2009-04-01
影响因子：
5.3
通讯作者：
Gibson, Spencer B.
中科院分区：
文献类型：
--
作者：
Burton, Teralee R.;Eisenstat, David D.;Gibson, Spencer B.
Bcl-219 kDa相互作用蛋白（BNIP 3）是Bcl-2家族中仅促细胞死亡的BH 3成员。我们先前发现BNIP 3定位于大多数多形性胶质母细胞瘤（GBM）肿瘤的细胞核，并且不能诱导细胞死亡。在此，我们已经发现，核BNIP 3结合到凋亡诱导因子（AIF）基因的启动子，并抑制其表达。BNIP 3与PTB相关剪接因子（PSF）和HDAC 1（组蛋白脱乙酰酶1）相关，有助于AIF基因的转录抑制。这种BNIP 3介导的AIF表达减少导致神经胶质瘤细胞中替莫唑胺诱导的凋亡减少。此外，GBM中的核BNIP 3表达与AIF表达降低相关。总之，我们发现了BNIP 3的一种新的转录抑制功能，导致AIF表达减少和对凋亡的抗性增加。因此，核BNIP 3可能赋予胶质瘤细胞生存优势，并部分解释了为什么BNIP 3在实体瘤，特别是GBM中以高水平表达。
The Bcl-219 kDa interacting protein (BNIP3) is a pro-cell-death BH3-only member of the Bcl-2 family. We previously found that BNIP3 is localized to the nucleus in the majority of glioblastoma multiforme (GBM) tumors and fails to induce cell death. Herein, we have discovered that nuclear BNIP3 binds to the promoter of the apoptosis-inducing factor (AIF) gene and represses its expression. BNIP3 associates with PTB-associating splicing factor (PSF) and HDAC1 (histone deacetylase 1) contributing to transcriptional repression of the AIF gene. This BNIP3-mediated reduction in AIF expression leads to decreased temozolomide-induced apoptosis in glioma cells. Furthermore, nuclear BNIP3 expression in GBMs correlates with decreased AIF expression. Together, we have discovered a novel transcriptional repression function for BNIP3 causing reduced AIF expression and increased resistance to apoptosis. Thus, nuclear BNIP3 may confer a survival advantage to glioma cells and explain, in part, why BNIP3 is expressed at high levels in solid tumors, especially GBM.