Max F. Perutz Laboratories, Department of Medical Biochemistry, Medical University of Vienna, Vienna, Austria.
Oncogene. 2011 Jun 9;30(23):2679-90. doi: 10.1038/onc.2010.639. Epub 2011 Jan 24.
We previously identified and characterized E2F-associated phospho-protein (EAPP), a nuclear phosphoprotein that interacts with the activating members of the E2F transcription factor family. EAPP levels are frequently elevated in transformed human cells. To examine the biological relevance of EAPP, we studied its properties in stressed and unstressed cells. Overexpression of EAPP in U2OS cells increased the fraction of G1 cells and lead to heightened resistance against DNA damage- or E2F1-induced apoptosis in a p21-dependent manner. EAPP itself becomes upregulated in confluent cells and after DNA damage and stimulates the expression of p21 independently of p53. It binds to the p21 promoter and seems to be required for the assembly of the transcription initiation complex. RNAi-mediated knockdown of EAPP expression brought about increased sensitivity towards DNA damage and resulted in apoptosis even in the absence of stress. Our results indicate that the level of EAPP is critical for cellular homeostasis. Too much of it results in G1 arrest and resistance to apoptosis, which, paradoxically, might favor cellular transformation. Too little EAPP seems to retard the expression not only of the p21 gene, but also of a number of other genes and ultimately results in apoptosis.
我们之前鉴定和描述了 E2F 相关磷酸化蛋白（EAPP），这是一种与 E2F 转录因子家族激活成员相互作用的核磷酸化蛋白。EAPP 水平在转化的人类细胞中经常升高。为了研究 EAPP 的生物学相关性，我们研究了其在应激和非应激细胞中的特性。在 U2OS 细胞中过表达 EAPP 会增加 G1 期细胞的比例，并以依赖于 p21 的方式提高对 DNA 损伤或 E2F1 诱导的细胞凋亡的抵抗力。EAPP 自身在细胞汇合和 DNA 损伤后上调，并独立于 p53 刺激 p21 的表达。它与 p21 启动子结合，似乎是转录起始复合物组装所必需的。EAPP 表达的 RNAi 介导敲低导致对 DNA 损伤的敏感性增加，并导致细胞凋亡，即使在没有应激的情况下也是如此。我们的研究结果表明，EAPP 的水平对细胞稳态至关重要。过多的 EAPP 会导致 G1 期阻滞和对细胞凋亡的抵抗力，这反而可能有利于细胞转化。太少的 EAPP 似乎不仅会延迟 p21 基因的表达，还会延迟许多其他基因的表达，并最终导致细胞凋亡。
