Cell cycle transactivation factor E2F-4 is associate with the ganstrointestinal carcinogenesis and/or acquisition of chemoresistance

E2 F是一个转录因子家族，参与调控G1-S转换所需的基因表达。我们以前在散发性结直肠癌的一个亚组中检测到E2 F-4基因三核苷酸重复编码序列的肿瘤特异性突变。本研究的目的是调查这些E2 F-4突变的潜在功能后果。我们用含有野生型以及突变型E2 F-4 cDNA的表达构建体转染NIH 3 T3成纤维细胞，并检查E2 F-4突变对增殖的影响。通过将E2 F-4与DP-2构建体瞬时共转染到培养的人细胞中，也检查了E2 F共有启动子序列反式激活的改变。过表达突变体E2 F-4的转染细胞克隆生长更迅速，增殖细胞核抗原（PCNA）的免疫组化染色增加，表现出更高的增殖活性。E2 F-4的所有三种突变形式均显示E2 F共有启动子序列的反式激活升高。因此，突变体E2 F-4s的表达赋予体内生长优势，并且这种效应可能与获得肿瘤表型有关。

E2F is a family of transcription factors implicated in the regulation of gene expression required for progression through the G1-S transition. We have previously detected tumor-specific mutations at a trinucleotide repeat coding sequence of E2F-4 gene in a subset of human sporadic colorectal cancers. The purpose of this study was to investigate the potential functional consequences of these E2F-4 mutations. We transfected NIH3T3 fibroblasts with expression constructs containing wild type as well as mutant E2F-4 cDNA and the effect of the E2F-4 mutations on proliferation was examined. Alteration in transactivation of the E2F consensus promoter sequence was also examined by transient cotransfection of a E2F-4 with a DP-2 construct into cultured human cells. Transfected cell clones overexpressing mutant E2F-4 grew more rapidly and showed higher proliferative activity by increased immunohistochemical staining for proliferating cell nuclear antigen (PCNA). All three mutant forms of E2F-4 showed elevated transactivation of the E2F consensus promoter sequence. Thus, expression of mutant E2F-4s confers a growth advantage in vivo, and this effect may be related to the acquisition of a neoplastic phenotype.