The Oncoprotein BCL11A Binds to Orphan Nuclear Receptor TLX and Potentiates its Transrepressive Function
The Oncoprotein BCL11A Binds to Orphan Nuclear Receptor TLX and Potentiates its Transrepressive Function
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DOI：
10.1371/journal.pone.0037963
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发表时间：
2012-06-04
期刊：
影响因子：
3.7
通讯作者：
Estebanez-Perpina, Eva
中科院分区：
文献类型：
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作者：
Estruch, Sara B.;Buzon, Victor;Estebanez-Perpina, Eva
核孤儿受体TLX（NR 2 E1）主要作为转录抑制因子发挥功能，其在脑发育、胶质母细胞瘤、精神发育迟滞和视网膜病理学中的关键作用使其成为有吸引力的药物靶标。TLX在脑室下区和海马颗粒下区的神经干细胞（NSC）中表达，这些区域在成人脑中具有持续的神经发生，并且作为NSC维持和自我更新的重要调节剂发挥作用。很少有人知道的TLX社会网络的相互作用和只有少数TLX的coregulators的描述。为了鉴定和表征新的TLX结合剂和可能的辅助调节剂，我们使用不同的TLX构建体作为诱饵对人类成年脑cDNA文库进行酵母双杂交（Y2 H）筛选。我们的筛选鉴定了Atrophin-1（ATN 1）的多个克隆，ATN 1是先前描述的TLX相互作用物。此外，我们确定了与癌蛋白和锌指转录因子BCL 11 A（CTIP 1/Evi 9）的相互作用，BCL 11 A是造血系统和主要血液相关恶性肿瘤的关键参与者。这种相互作用通过人细胞中的表达和免疫共沉淀来验证。BCL 11 A在体外报告基因测定中增强TLX的反式阻遏功能。我们的工作表明，BCL 11 A是一种新的TLX辅助调节因子，可能参与大脑中TLX依赖的基因调控。
Nuclear orphan receptor TLX (NR2E1) functions primarily as a transcriptional repressor and its pivotal role in brain development, glioblastoma, mental retardation and retinopathologies make it an attractive drug target. TLX is expressed in the neural stem cells (NSCs) of the subventricular zone and the hippocampus subgranular zone, regions with persistent neurogenesis in the adult brain, and functions as an essential regulator of NSCs maintenance and self-renewal. Little is known about the TLX social network of interactors and only few TLX coregulators are described. To identify and characterize novel TLX-binders and possible coregulators, we performed yeast-two-hybrid (Y2H) screens of a human adult brain cDNA library using different TLX constructs as baits. Our screens identified multiple clones of Atrophin-1 (ATN1), a previously described TLX interactor. In addition, we identified an interaction with the oncoprotein and zinc finger transcription factor BCL11A (CTIP1/Evi9), a key player in the hematopoietic system and in major blood-related malignancies. This interaction was validated by expression and coimmunoprecipitation in human cells. BCL11A potentiated the transrepressive function of TLX in an in vitro reporter gene assay. Our work suggests that BCL11A is a novel TLX coregulator that might be involved in TLX-dependent gene regulation in the brain.