Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China.
Cell Signal. 2011 Jan;23(1):193-200. doi: 10.1016/j.cellsig.2010.09.003. Epub 2010 Sep 17.
MDM2 expression is down-regulated upon E2F1 over-expression, but the mechanism is not well defined. In the current study, we found that E2F1 inhibits MDM2 expression by suppressing its promoter activity. Although E2F1 binds to the MDM2 promoter, the inhibitory effect of E2F1 on the MDM2 promoter does not require the direct binding. We demonstrate that E2F1 inhibits MDM2 promoter activity in a p53-dependent manner. Knockdown of p53 in U2OS cells impairs the inhibitory effect of E2F1 on the MDM2 promoter. Consistent with this observation, E2F1 does not inhibit MDM2 promoter activity in p53-deficient H1299 cells, and the inhibition is restored when p53 is expressed exogenously. Both E2F1 and p53 are up-regulated after DNA damage stimulation. We show that such stimulation induces E2F1 to inhibit MDM2 promoter activity and promote p53 accumulation. Furthermore, inhibition of MDM2 by E2F1 promotes E2F1 induced apoptosis. These data suggest that E2F1 regulates the MDM2-p53 pathway by inhibiting p53 induced up-regulation of MDM2.
E2F1 过表达会下调 MDM2 的表达，但具体机制尚不清楚。本研究发现，E2F1 通过抑制 MDM2 启动子活性来抑制 MDM2 的表达。虽然 E2F1 结合到 MDM2 启动子上，但 E2F1 对 MDM2 启动子的抑制作用不需要直接结合。我们证明 E2F1 以 p53 依赖性方式抑制 MDM2 启动子活性。在 U2OS 细胞中敲低 p53 会损害 E2F1 对 MDM2 启动子的抑制作用。与这一观察结果一致，E2F1 不会抑制 p53 缺失的 H1299 细胞中的 MDM2 启动子活性，并且当外源性表达 p53 时，抑制作用得到恢复。E2F1 和 p53 在 DNA 损伤刺激后均上调。我们表明，这种刺激诱导 E2F1 抑制 MDM2 启动子活性并促进 p53 积累。此外，E2F1 对 MDM2 的抑制作用促进了 E2F1 诱导的细胞凋亡。这些数据表明，E2F1 通过抑制 p53 诱导的 MDM2 上调来调节 MDM2-p53 通路。
