清華大學(xué)生物膜與膜工程國(guó)家重點(diǎn)實(shí)驗(yàn)室的陳曄光研究組以斑馬魚(yú)模型為基礎(chǔ)，發(fā)現(xiàn)Dpr1作用Wnt信號(hào)途徑的又一新機(jī)制：Dpr1能同時(shí)調(diào)控細(xì)胞質(zhì)和細(xì)胞核中的Wnt信號(hào)途徑,。
Dapper (Dpr)是近期發(fā)現(xiàn)的信號(hào)調(diào)控分子,，目前研究結(jié)果表明，爪蟾和斑馬魚(yú)等低等動(dòng)物的Dpr在早期胚胎發(fā)育的多個(gè)過(guò)程中起重要作用,，這些作用主要通過(guò)對(duì) Wnt 和 Nodal/TGF-β 信號(hào)通路的負(fù)調(diào)控來(lái)完成,。Wnt和TGF-β 信號(hào)通路在胚胎發(fā)育和疾病發(fā)生過(guò)程中起著非常重要的作用，因而 Dpr 可能是通過(guò)影響這些信號(hào)通路而參與生理,、病理過(guò)程,。
研究人員利用報(bào)告基因分析和體內(nèi)斑馬魚(yú)胚胎分析，證明被迫定位于細(xì)胞核的Dpr1能對(duì)抗Wnt信號(hào)途徑：與β-catenin,，以及LEF1相互作用,，擾亂復(fù)合物的形成，而且Dpr1能與組蛋白去乙?；?相互作用,，增強(qiáng)LEF1與去乙酰化酶1之間的作用,。因此研究人員認(rèn)為這說(shuō)明Dpr1通過(guò)LEF1負(fù)調(diào)控了細(xì)胞核中Wnt信號(hào)途徑的基本活性,，從而得出結(jié)論：Dpr1能同時(shí)調(diào)控細(xì)胞質(zhì)和細(xì)胞核中的Wnt信號(hào)途徑。（生物谷Bioon.com）
生物谷推薦原始出處：
J. Biol. Chem., Vol. 283, Issue 51, 35679-35688, December 19, 2008
Dapper1 Is a Nucleocytoplasmic Shuttling Protein That Negatively Modulates Wnt Signaling in the Nucleus*
Xia Gao, Jun Wen, Long Zhang, Xiang Li, Yuanheng Ning, Anming Meng, and Ye-Guang Chen1
From the State Key Laboratory of Biomembrane and Membrane Biotechnology, Department of Biological Sciences and Biotechnology, Tsinghua University, Beijing 100084, China
Wnt signaling, via the activation of the canonical β-catenin and lymphoid enhancer factor (LEF)/T-cell factor pathway, plays an important role in embryogenesis and cancer development by regulating the expression of genes involved in cell proliferation, differentiation, and survival. Dapper (Dpr), as a Dishevelled interactor, has been suggested to modulate Wnt signaling by promoting Dishevelled degradation. Here, we provide evidence that Dpr1 shuttles between the cytoplasm and the nucleus. Although overexpressed Dpr1 was mainly found in the cytoplasm, endogenous Dpr1 was localized over the cell, and Wnt1 induced its nuclear export. Treatment with leptomycin B induced nuclear accumulation of both endogenous and overexpressed Dpr1. We further identified the nuclear localization signal and the nuclear export signal within Dpr1. Using reporter assay and in vivo zebrafish embryo assay, we demonstrated that the forced nuclearly localized Dpr1 possessed the ability to antagonize Wnt signaling. Dpr1 interacted with β-catenin and LEF1 and disrupted their complex formation. Furthermore, Dpr1 could associate with histone deacetylase 1 (HDAC1) and enhance the LEF1-HDAC1 interaction. Together, our findings suggest that Dpr1 negatively modulates the basal activity of Wnt/β-catenin signaling in the nucleus by keeping LEF1 in the repressive state. Thus, Dpr1 controls Wnt/β-catenin signaling in both the cytoplasm and the nucleus.
