Burton Teralee R, Eisenstat David D, Gibson Spencer B
Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada R3E 0V9.
J Neurosci. 2009 Apr 1;29(13):4189-99. doi: 10.1523/JNEUROSCI.5747-08.2009.
The Bcl-2 19 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.
Bcl-2 19 kDa相互作用蛋白（BNIP3）是Bcl-2家族中仅含BH3结构域的促细胞死亡成员。我们之前发现，BNIP3在大多数多形性胶质母细胞瘤（GBM）肿瘤中定位于细胞核，且不能诱导细胞死亡。在此，我们发现细胞核中的BNIP3与凋亡诱导因子（AIF）基因的启动子结合并抑制其表达。BNIP3与PTB相关剪接因子（PSF）和组蛋白脱乙酰基酶1（HDAC1）结合，从而导致AIF基因的转录抑制。这种由BNIP3介导的AIF表达降低导致胶质瘤细胞中替莫唑胺诱导的凋亡减少。此外，GBM中细胞核BNIP3的表达与AIF表达降低相关。我们共同发现了BNIP3一种新的转录抑制功能，该功能导致AIF表达降低并增加对凋亡的抗性。因此，细胞核BNIP3可能赋予胶质瘤细胞生存优势，并部分解释了为什么BNIP3在实体瘤尤其是GBM中高表达。
