Alazard Robert, Blaud Magali, Elbaz Shmouel, Vossen Christine, Icre Guillaume, Joseph Gérard, Nieto Laurence, Erard Monique
Institut de Pharmacologie et de Biologie Structurale UMR 5089, 205 Route de Narbonne, 31077 Toulouse Cedex 4, France.
Nucleic Acids Res. 2005 Mar 14;33(5):1513-23. doi: 10.1093/nar/gki284. Print 2005.
N-Oct-3 is a neuronal transcription factor widely expressed in the developing mammalian central nervous system, and necessary to maintain neural cell differentiation. The key role of N-Oct-3 in the transcriptional regulation of a multiplicity of genes is primarily due to the structural plasticity of its so-called 'POU' (acronym of Pit, Oct, Unc) DNA-binding domain. We have recently reported about the unusual dual neuro-specific transcriptional regulation displayed by N-Oct-3 [Blaud,M., Vossen,C., Joseph,G., Alazard,R., Erard,M. and Nieto,L. (2004) J. Mol. Biol., 339, 1049-1058]. To elucidate the underlying molecular mechanisms, we have now made use of molecular modeling, DNA footprinting and electrophoretic mobility shift assay techniques. This combined approach has allowed us to uncover a novel mode of homodimerization adopted by the N-Oct-3 POU domain bound to the neuronal aromatic amino acids de-carboxylase and corticotropin-releasing hormone gene promoters and to demonstrate that this pattern is induced by a structural motif that we have termed 'NORE' (N-Oct-3 responsive element), comprising the 14 bp sequence element TNNRTAAATAATRN. In addition, we have been able to explain how the same structural motif can also induce the formation of a heterodimer in association with hepatocyte nuclear factor 3beta(/Forkhead box a2). Finally, we discuss the possible role of the NORE motif in relation to neuroendocrine lung tumor formation, and in particular the development of small cell lung cancer.
N-Oct-3是一种神经元转录因子，在发育中的哺乳动物中枢神经系统中广泛表达，对维持神经细胞分化至关重要。N-Oct-3在多种基因转录调控中的关键作用主要归因于其所谓的“POU”（Pit、Oct、Unc的首字母缩写）DNA结合域的结构可塑性。我们最近报道了N-Oct-3表现出的不寻常的双重神经特异性转录调控[布劳德，M.，沃森，C.，约瑟夫，G.，阿拉扎德，R.，埃拉尔，M.和涅托，L.（2004年）《分子生物学杂志》，339，1049 - 1058]。为了阐明潜在的分子机制，我们现在利用了分子建模、DNA足迹分析和电泳迁移率变动分析技术。这种综合方法使我们能够揭示与神经元芳香族氨基酸脱羧酶和促肾上腺皮质激素释放激素基因启动子结合的N-Oct-3 POU结构域采用的一种新的同二聚化模式，并证明这种模式是由我们称为“NORE”（N-Oct-3反应元件）的结构基序诱导的，该基序由14个碱基对的序列元件TNNRTAAATAATRN组成。此外，我们还能够解释相同的结构基序如何也能诱导与肝细胞核因子3β（/叉头框a2）形成异二聚体。最后，我们讨论了NORE基序在神经内分泌性肺肿瘤形成，特别是小细胞肺癌发展中的可能作用。
