Ooe Norihisa, Saito Koichi, Mikami Nobuyoshi, Nakatuka Iwao, Kaneko Hideo
Environmental Health Science Laboratory, Sumitomo Chemical Co. Ltd., Konohana-ku, Osaka 554-8558, Japan.
Mol Cell Biol. 2004 Jan;24(2):608-16. doi: 10.1128/MCB.24.2.608-616.2004.
Sim2, a basic helix-loop-helix (bHLH)-PAS transcriptional repressor, is thought to be involved in some symptoms of Down's syndrome. In the course of searching for hypothetical Sim2 relatives, we isolated another bHLH-PAS factor, NXF. NXF was a novel gene and was selectively expressed in neuronal tissues. While no striking homolog of NXF was found in vertebrates, a Caenorhabditis elegans putative transcription factor, C15C8.2, showed similarity in the bHLH-PAS domain. NXF had an activation domain as a transcription activator, and Arnt-type bHLH-PAS subfamily members were identified as the heterodimer partners of NXF. The NXF/Arnt heterodimer was capable of binding and activating a subset of Sim2/Arnt target DNA variants, and Sim2 could compete with the NXF activity on the elements. We showed that Drebrin had several such NXF/Arnt binding elements on the promoter, which could be direct or indirect cross talking points between NXF (activation) and Sim2 (repression) action. Drebrin has been reported to be engaged in dendritic-cytoskeleton modulation at synapses, and such a novel NXF signaling system on neural gene promoter may be a molecular target of the adverse effects of Sim2 in the mental retardation of Down's syndrome.
Sim2是一种碱性螺旋-环-螺旋（bHLH）-PAS转录抑制因子，被认为与唐氏综合征的某些症状有关。在寻找假定的Sim2相关因子的过程中，我们分离出了另一个bHLH-PAS因子NXF。NXF是一个新基因，在神经组织中选择性表达。虽然在脊椎动物中未发现NXF的显著同源物，但秀丽隐杆线虫的一个假定转录因子C15C8.2在bHLH-PAS结构域显示出相似性。NXF作为转录激活因子具有一个激活结构域，并且Arnt型bHLH-PAS亚家族成员被鉴定为NXF的异二聚体伙伴。NXF/Arnt异二聚体能够结合并激活Sim2/Arnt靶DNA变体的一个子集，并且Sim2可以在这些元件上与NXF的活性竞争。我们发现Drebrin在启动子上有几个这样的NXF/Arnt结合元件，它们可能是NXF（激活）和Sim2（抑制）作用之间的直接或间接相互作用点。据报道，Drebrin参与突触处的树突细胞骨架调节，并且神经基因启动子上这样一个新的NXF信号系统可能是Sim2在唐氏综合征智力迟钝中产生不利影响的分子靶点。
