Department of Biochemistry and Molecular Biology, BK21 Cell Transformation and Restoration, Ajou University School of Medicine, Suwon 443-721, Republic of Korea.
Cell Commun Signal. 2013 Sep 18;11:69. doi: 10.1186/1478-811X-11-69.
B-cell translocation gene 2 (BTG2) belongs to antiproliferative (ARPO) gene family and the expression of BTG2, human ortholog of rat PC3 and mouse TIS21 gene, has been shown to render cancer cells more sensitive to doxorubicin treatment by upregulating MnSOD expression without regulating any other reactive oxygen species (ROS) scavenging enzymes.
In the present study, by employing exogenous and endogenous BTG2/TIS21/Pc3 expression by transfection and transduction analyses, and by knockdown of gene expression using RNA interference or using gene knockout cells, we observed that BTG2 increased the binding of activated NF-κB (p65/RelA) to the enhancer element of MnSOD gene in the 2nd intron, which was regulated by p-Akt1, and the induction of MnSOD by BTG2 was accompanied with subsequent downregulation of ROS level and cyclin B1 biosynthesis along with the increase of p21WAF1, resulting in the G2/M arrest independent of p53.
These results show for the first time that BTG2 mediates crosstalk between PI3K-Akt1 and NF-κB pathways, which regulates p53-independent induction of G2/M phase arrest both in normal and cancer cells.
B 细胞易位基因 2（BTG2）属于增殖抑制基因（ARPO）家族，BTG2 的表达，大鼠 PC3 和小鼠 TIS21 基因的人同源物，已被证明通过上调 MnSOD 的表达使癌细胞对阿霉素治疗更敏感，而不调节任何其他活性氧（ROS）清除酶。
在本研究中，通过转染和转导分析采用外源性和内源性 BTG2/TIS21/Pc3 表达，以及使用 RNA 干扰或基因敲除细胞降低基因表达，我们观察到 BTG2 增加了激活的 NF-κB（p65/RelA）与 MnSOD 基因第 2 内含子增强子元件的结合，这受 p-Akt1 调节，BTG2 诱导的 MnSOD 伴随着随后 ROS 水平和 cyclin B1 生物合成的降低以及 p21WAF1 的增加，导致 G2/M 期阻滞不依赖于 p53。
这些结果首次表明 BTG2 介导了 PI3K-Akt1 和 NF-κB 通路之间的串扰，调节了正常和癌细胞中 p53 非依赖性的 G2/M 期阻滞诱导。
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