生物
E2F型
细胞周期
细胞生物学
细胞生长
转录因子
RNA干扰
基因沉默
分子生物学
基因
遗传学
核糖核酸
作者
Corinne Cayrol,Chrystelle Lacroix,Catherine Mathé,Vincent Ecochard,Michele Ceribelli,Emilie Loreau,Vladimir Lazar,Philippe Dessen,Roberto Mantovani,Luc Aguilar,Jean-Philippe Girard
出处
期刊:Blood
[American Society of Hematology]
日期:2006-09-26
卷期号:109 (2): 584-594
被引量:125
标识
DOI:10.1182/blood-2006-03-012013
摘要
Abstract We recently cloned a novel human nuclear factor (designated THAP1) from postcapillary venule endothelial cells (ECs) that contains a DNA-binding THAP domain, shared with zebrafish E2F6 and several Caenorhabditis elegans proteins interacting genetically with retinoblastoma gene product (pRB). Here, we show that THAP1 is a physiologic regulator of EC proliferation and cell-cycle progression, 2 essential processes for angiogenesis. Retroviral-mediated gene transfer of THAP1 into primary human ECs inhibited proliferation, and large-scale expression profiling with microarrays revealed that THAP1-mediated growth inhibition is due to coordinated repression of pRB/E2F cell-cycle target genes. Silencing of endogenous THAP1 through RNA interference similarly inhibited EC proliferation and G1/S cell-cycle progression, and resulted in down-regulation of several pRB/E2F cell-cycle target genes, including RRM1, a gene required for S-phase DNA synthesis. Chromatin immunoprecipitation assays in proliferating ECs showed that endogenous THAP1 associates in vivo with a consensus THAP1-binding site found in the RRM1 promoter, indicating that RRM1 is a direct transcriptional target of THAP1. The similar phenotypes observed after THAP1 overexpression and silencing suggest that an optimal range of THAP1 expression is essential for EC proliferation. Together, these data provide the first links in mammals among THAP proteins, cell proliferation, and pRB/E2F cell-cycle pathways.
科研通智能强力驱动
Strongly Powered by AbleSci AI