Abstract
BackgroundB-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.ResultsIn 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.ConclusionsThese 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.
Highlights
B-cell translocation gene 2 (BTG2) belongs to antiproliferative (ARPO) gene family and the expression of BTG2, human ortholog of rat PC3 and mouse TPA-inducible sequences 21 (TIS21) gene, has been shown to render cancer cells more sensitive to doxorubicin treatment by upregulating manganese-containing superoxide dismutase (MnSOD) expression without regulating any other reactive oxygen species (ROS) scavenging enzymes
Degradation of IκBα was accelerated via activation of Akt1 in the cells with BTG2 over-expressed, suggesting the regulation of crosstalk between PI3K/Akt1 and NFκB pathways
Endogenous level of MnSOD expression in the TIS21−/− mouse embryo fibroblast (MEF) along with wt-MEF was much lower in the TIS21−/− MEF than the control (Figure 1D), suggesting that the effect of BTG2 on MnSOD expression was both endogenously and exogenously regulated in mouse fibroblasts and cancer cells, and that there is a possibility of MnSOD gene as a direct target of BTG2
Summary
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. The APRO gene, including TIS21 [4], PC3 [5] and BTG2 [6], has originally been reported as a primary response gene transiently expressed in the established cell lines in response to various stimulations, BTG2/TIS21/PC3 (BTG2) expression in mouse and human tissues has been shown to be rather constitutive [7], and it is found to be significantly reduced during carcinogenesis in the epithelial cells of thymus [8], prostate [9], kidney [10], breast [11], liver [12] and brain [13]. BTG2 strongly induces G2/M phase arrest in U937 myelomonocytic leukemia (p53 null) and Huh (p53 mutant) hepatoma cells [22], we earlier suggested BTG2 as a pan-cell cycle inhibitor independent of p53 and pRB activities via interaction with Pin in response to EGF stimulation [23]
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