Ishii Hideshi, Mimori Koshi, Vecchione Andrea, Sutheesophon Krittaya, Fujiwara Toshiyoshi, Mori Masaki, Furukawa Yusuke
Center for Molecular Medicine, Jichi Medical School, Tochigi 329-0498, Japan.
Biochem Biophys Res Commun. 2004 Apr 16;316(4):1088-93. doi: 10.1016/j.bbrc.2004.02.159.
The expression of two tumor suppressor genes, fragile histidine triad (FHIT) and WW domain containing oxidoreductase (WWOX), encompassing common chromosome fragile regions, FRA3B at 3p14.2 and FRA16D at 16q23, is altered in many epithelial tumors. Since DNA sequence search shows that the FHIT gene has the E2F-1 recognition site in 5'] region, which regulates cell cycle, we tested the effect of E2F-1 overexpression in tumor cells. Ectopic E2F-1 expression led to an increase of Fhit and Wwox expression in allele remaining tumor cells and resulted in induction of apoptosis. Reporter assay showed that the E2F-1 site in FHIT 5' region was involved in the down-stream transcription after exogenous E2F-1 introduction. Chromatin immunoprecipitation detected exogenous E2F-1 binding to the recognition site in FHIT 5' region. The data suggest that E2F-1 overexpression plays a role in suppression of tumor, at least in part trough transcriptional regulation of FHIT and relevant activation of WWOX.
两个肿瘤抑制基因，脆性组氨酸三联体（FHIT）和含WW结构域的氧化还原酶（WWOX），其表达在许多上皮肿瘤中发生改变，这两个基因包含常见的染色体脆性区域，即位于3p14.2的FRA3B和位于16q23的FRA16D。由于DNA序列搜索显示FHIT基因在5'区域有E2F-1识别位点，该位点调控细胞周期，我们测试了E2F-1在肿瘤细胞中过表达的影响。异位表达E2F-1导致等位基因保留的肿瘤细胞中Fhit和Wwox表达增加，并诱导细胞凋亡。报告基因检测表明，在外源引入E2F-1后，FHIT 5'区域的E2F-1位点参与下游转录。染色质免疫沉淀检测到外源E2F-1与FHIT 5'区域的识别位点结合。数据表明，E2F-1过表达至少部分通过对FHIT的转录调控和WWOX的相关激活在肿瘤抑制中发挥作用。
