Kim Hong-Gyum, Shi Chengcheng, Bode Ann M, Dong Zigang
The Hormel Institute, University of Minnesota, Austin, Minnesota.
The First Affiliated Hospital, Zhengzhou University, Zhengzhou, China.
Mol Carcinog. 2016 May;55(5):910-7. doi: 10.1002/mc.22331. Epub 2015 May 12.
Arsenic exposure has been reported to cause neoplastic transformation through the activation of PcG proteins. In the present study, we show that activation of p38α mitogen-activated protein kinase (MAPK) is required for arsenic-induced neoplastic transformation. Exposure of cells to 0.5 μM arsenic increased CRE and c-Fos promoter activities that were accompanied by increases in p38α MAPK and CREB phosphorylation and expression levels concurrently with AP-1 activation. Introduction of short hairpin (sh) RNA-p38α into BALB/c 3T3 cells markedly suppressed arsenic-induced colony formation compared with wildtype cells. CREB phosphorylation and AP-1 activation were decreased in p38α knockdown cells after arsenic treatment. Arsenic-induced AP-1 activation, measured as c-Fos and CRE promoter activities, and CREB phosphorylation were attenuated by p38 inhibition in BALB/c 3T3 cells. Thus, p38α MAPK activation is required for arsenic-induced neoplastic transformation mediated through CREB phosphorylation and AP-1 activation.
据报道，砷暴露可通过激活多梳蛋白（PcG）导致肿瘤转化。在本研究中，我们发现p38α丝裂原活化蛋白激酶（MAPK）的激活是砷诱导肿瘤转化所必需的。将细胞暴露于0.5μM砷会增加CRE和c-Fos启动子活性，同时伴随着p38α MAPK和CREB磷酸化及表达水平的增加，同时AP-1也被激活。与野生型细胞相比，将短发夹（sh）RNA-p38α导入BALB/c 3T3细胞可显著抑制砷诱导的集落形成。砷处理后，p38α基因敲低的细胞中CREB磷酸化和AP-1激活减少。在BALB/c 3T3细胞中，通过抑制p38可减弱以c-Fos和CRE启动子活性衡量的砷诱导的AP-1激活以及CREB磷酸化。因此，p38α MAPK激活是通过CREB磷酸化和AP-1激活介导的砷诱导肿瘤转化所必需的。
