Ghosh Asish K, Majumder Mainak, Steele Robert, Liu Ta-Jen, Ray Ratna B
Department of Pathology, Saint Louis University, St. Louis, Missouri, MO 63104, USA.
Oncogene. 2002 Apr 25;21(18):2775-84. doi: 10.1038/sj.onc.1205384.
MBP-1, a cellular factor, appears to be involved in multiple functions, including transcriptional modulation, apoptosis and cell growth regulation. In this study, we have investigated the signaling pathway involved in MBP-1 mediated apoptotic cell death. Human carcinoma cells infected with a replication deficient adenovirus expressing MBP-1 (AdMBP-1) induced apoptosis, when compared with cells infected by replication-defective adenovirus (dl312) as a negative control. Transduction of MBP-1 in carcinoma cells releases cytochrome c from mitochondria into the cytosol leading to activation of procaspase-9, procaspase-3 and PARP cleavage. We previously observed that MBP-1 mediated apoptosis can be protected by Bcl-2, although MBP-1 does not share a homology with the BH domain of the Bcl-2 family member of proteins. To further understand the mechanism of MBP-1 mediated apoptosis, we examined whether MBP-1 modulates the Bcl-2 gene family. Our results demonstrated that human breast carcinoma cells infected with AdMBP-1 selectively reduced Bcl-xL mRNA and protein expression when compared with dl312 infected negative control cells. An in vitro transient reporter assay also suggested repression of the Bcl-x promoter activity by MBP-1. Additional studies indicated that MBP-1 modulates Ets family protein function, thereby downregulating Bcl-xL expression. Taken together, our results suggest that MBP-1 selectively represses Bcl-xL expression in MCF-7 cells and induces mitochondrial involvement in the apoptotic process.
MBP-1是一种细胞因子，似乎参与多种功能，包括转录调节、细胞凋亡和细胞生长调控。在本研究中，我们调查了MBP-1介导的凋亡性细胞死亡所涉及的信号通路。与感染复制缺陷型腺病毒（dl312）作为阴性对照的细胞相比，感染表达MBP-1的复制缺陷型腺病毒（AdMBP-1）的人癌细胞诱导了凋亡。癌细胞中MBP-1的转导使细胞色素c从线粒体释放到细胞质中，导致procaspase-9、procaspase-3的激活以及PARP的裂解。我们之前观察到，尽管MBP-1与Bcl-2家族蛋白的BH结构域没有同源性，但MBP-1介导的凋亡可被Bcl-2保护。为了进一步了解MBP-1介导凋亡的机制，我们检测了MBP-1是否调节Bcl-2基因家族。我们的结果表明，与感染dl312的阴性对照细胞相比，感染AdMBP-1的人乳腺癌细胞选择性地降低了Bcl-xL mRNA和蛋白表达。体外瞬时报告基因检测也表明MBP-1抑制了Bcl-x启动子活性。进一步的研究表明，MBP-1调节Ets家族蛋白功能，从而下调Bcl-xL表达。综上所述，我们的结果表明，MBP-1在MCF-7细胞中选择性抑制Bcl-xL表达，并诱导线粒体参与凋亡过程。
