HMGA2 regulates transcription of the Imp2 gene via an intronic regulatory element in cooperation with nuclear factor-κB
HMGA2 regulates transcription of the Imp2 gene via an intronic regulatory element in cooperation with nuclear factor-κB
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DOI：
10.1158/1541-7786.mcr-06-0331
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发表时间：
2007-04-01
影响因子：
5.2
通讯作者：
Petit, Marleen M. R.
中科院分区：
文献类型：
--
作者：
Cleynen, Isabelle;Brants, Jan R.;Petit, Marleen M. R.
IMP2(胰岛素样生长因子-II mRNA结合蛋白2)是一种癌胎儿蛋白，在多种类型的癌症中异常表达。我们最近发现Imp2基因是建筑转录因子HMGA2(高迁移率族A2)及其肿瘤特异性截短形式HMGA2Tr的靶基因。在本研究中，我们研究了HMGA2调控Imp2基因表达的机制。我们发现HMGA2和HMGA2Tr通过与位于第一内含子的富含AT的调节区结合，直接调控Imp2基因的转录。在记者实验中，我们证明了这个富含AT的调控区模仿了内源Imp2基因对HMGA2和HMGA2Tr的反应。此外，我们还发现，位于富含AT的调控区附近的一个共识的核因子-kappa B(NF-kappa B)结合位点与NF-kappa B结合，并且NF-kappa B和HMGA2协同调节Imp2基因的表达。最后，我们提供的证据表明，在人类脂肪肉瘤中，HMGA2和IMP2基因的表达有很强的统计学意义上的相关性。
IMP2 (insulin-like growth factor-II mRNA binding protein 2) is an oncofetal protein that is aberrantly expressed in several types of cancer. We recently identified the Imp2 gene as a target gene of the architectural transcription factor HMGA2 (high mobility group A2) and its tumor-specific truncated form HMGA2Tr. In this study, we investigated the mechanism via which HMGA2 regulates Imp2 gene expression. We show that HMGA2 and HMGA2Tr directly regulate transcription of the Imp2 gene by binding to an AT-rich regulatory region located in the first intron. In reporter experiments, we show that this AT-rich regulatory region mimics the response of the endogenous Imp2 gene to HMGA2 and HMGA2Tr. Furthermore, we show that a consensus nuclear factor-kappa B (NF-kappa B) binding site located immediately adjacent to the AT-rich regulatory region binds NF-kappa B and that NF-kappa B and HMGA2 cooperate to regulate Imp2 gene expression. Finally, we provide evidence that there is a strong and statistically significant correlation between HMGA2 and IMP2 gene expression in human liposarcomas.