The University of Texas MD Anderson Cancer Center, Science Park Research Division, Smithville, Texas 78957, USA.
Mol Carcinog. 2010 Feb;49(2):152-6. doi: 10.1002/mc.20584.
Deregulation of E2F transcriptional activity as a result of alterations in the p16-cyclin D-Rb pathway is a hallmark of cancer. However, the roles of the different E2F family members in the process of tumorigenesis are still being elucidated. Studies in mice and humans suggest that E2F2 functions as a tumor suppressor. Here we demonstrate that E2f2 inactivation cooperates with transgenic expression of Myc to enhance tumor development in the skin and oral cavity. In fact, hemizygosity at the E2f2 locus was sufficient to increase tumor incidence in this model. Loss of E2F2 enhanced proliferation in Myc transgenic tissue but did not affect Myc-induced apoptosis. E2F2 did not behave as a simple activator of transcription in epidermal keratinocytes but instead appeared to differentially regulate gene expression dependent on the individual target. E2f2 inactivation also altered the changes in gene expression in Myc transgenic cells by enhancing the increase of some genes, such as cyclin E, and reversing the repression of other genes. These findings demonstrate that E2F2 can function as a tumor suppressor in epithelial tissues, perhaps by limiting proliferation in response to Myc.
E2F 转录活性的失调是癌症的一个标志，这是由于 p16-cyclin D-Rb 通路的改变所致。然而，不同 E2F 家族成员在肿瘤发生过程中的作用仍在阐明之中。在小鼠和人类中的研究表明，E2F2 作为一种肿瘤抑制因子发挥作用。在这里，我们证明 E2f2 的失活与 Myc 的转基因表达协同作用，增强了皮肤和口腔的肿瘤发生。事实上，E2f2 基因座的杂合性缺失足以增加该模型中的肿瘤发生率。E2F2 的缺失增强了 Myc 转基因组织中的增殖，但不影响 Myc 诱导的细胞凋亡。E2F2 在表皮角质形成细胞中并不表现为转录的简单激活因子，而是似乎根据单个靶标差异调节基因表达。E2f2 的失活还通过增强某些基因（如 cyclin E）的增加并逆转其他基因的抑制，改变了 Myc 转基因细胞中的基因表达变化。这些发现表明，E2F2 可以在上皮组织中作为一种肿瘤抑制因子发挥作用，可能是通过限制对 Myc 的增殖反应。
