Evidence that Igf2 down-regulation in postnatal tissues and up-regulation in malignancies is driven by transcription factor E2f3
Evidence that Igf2 down-regulation in postnatal tissues and up-regulation in malignancies is driven by transcription factor E2f3
复制标题
DOI：
10.1073/pnas.1219079110
复制
发表时间：
2013-04-09
影响因子：
11.1
通讯作者：
Baron, Jeffrey
中科院分区：
文献类型：
--
作者：
Lui, Julian C.;Baron, Jeffrey
胰岛素样生长因子2（IGF2）是一种重要的胎儿生长因子。它的表达在出生后的多个器官中显著下调，但在癌症中经常上调。驱动出生后组织中IGF2下调或恶性肿瘤中IGF2上调的机制尚不清楚。我们发现E2F转录因子3（E2F3）驱动这些表达变化的证据。E2f3 mRNA表达，蛋白质表达，并结合到Igf2启动子出生后随着年龄的增长，在多个小鼠器官。在晚期幼龄肝细胞中，E2f3高表达的恢复恢复了Igf2的高表达，表明存在因果关系，但这种诱导在胎肝细胞中未发生，胎肝细胞已经具有高E2f3和Igf2表达。E2f3在HEK293细胞和晚期幼龄肝细胞中的瞬时表达能够激活含有小鼠Igf2启动子P2的报告基因构建体，其中包括共有E2F结合位点。在人类中，微阵列数据显示E2F3和IGF2表达随年龄的下降与小鼠相似。此外，E2F3过表达的人前列腺癌和膀胱癌显示IGF2表达增加，并且这些癌症中E2F3和IGF2 mRNA的水平呈正相关。总之，研究结果表明，随着年龄的增长，E2f3的下调有助于推动出生后器官中Igf2表达的急剧下降，而人类癌症中E2F3的过度表达会诱导IGF2的过度表达。
Insulin-like growth factor 2 (IGF2) is an important fetal growth factor. Its expression is dramatically down-regulated in multiple organs after birth but is frequently up-regulated in cancers. The mechanisms that drive down-regulation of IGF2 in postnatal tissues or the up-regulation in malignancy are unclear. We found evidence that E2F transcription factor 3 (E2F3) drives these changes in expression. E2f3 mRNA expression, protein expression, and binding to the Igf2 promoter all decreased with age postnatally in multiple mouse organs. In late juvenile hepatocytes, restoration of high E2f3 expression restored high Igf2 expression, indicating a causal relationship, but this induction did not occur in fetal hepatocytes, which already have high E2f3 and Igf2 expression. Transient expression of E2f3 in both HEK293 cells and in late juvenile hepatocytes were able to activate reporter constructs containing the mouse Igf2 promoter P2, which includes consensus E2F-binding sites. In humans, microarray data revealed declines in E2F3 and IGF2 expression with age similar to the mouse. In addition, E2F3-overexpressing human prostate and bladder cancers showed increased IGF2 expression, and levels of E2F3 and IGF2 mRNA in these cancers were positively correlated. Taken together, the findings suggest that down-regulation of E2f3 with age helps drive the dramatic decline in Igf2 expression in postnatal organs, and E2F3 overexpression in human cancers induces IGF2 overexpression.