Besnard Antoine, Galan-Rodriguez Beatriz, Vanhoutte Peter, Caboche Jocelyne
Laboratoire de Physiopathologie des Maladies du Système Nerveux Central, UMR CNRS-7224 CNRS et UMRS-INSERM 952, Université Pierre et Marie Curie-Paris 6 Paris, France.
Front Neurosci. 2011 Mar 16;5:35. doi: 10.3389/fnins.2011.00035. eCollection 2011.
The ternary complex factor (TCF) Elk-1 is a transcription factor that regulates immediate early gene (IEG) expression via the serum response element (SRE) DNA consensus site. Elk-1 is associated with a dimer of serum response factor (SRF) at the SRE site, and its phosphorylation occurs at specific residues in response to mitogen-activated protein kinases (MAPKs), including c-Jun-N terminal kinase (JNK), p38/MAPK, and extracellular-signal regulated kinase (ERK). This phosphorylation event is critical for triggering SRE-dependent transcription. Although MAPKs are fundamental actors for the instatement and maintenance of memory, and much investigation of their downstream signaling partners have been conducted, no data yet clearly implicate Elk-1 in these processes. This is partly due to the complexity of Elk-1 sub-cellular localization, and hence functions, within neurons. Elk-1 is present in its resting state in the cytoplasm, where it colocalizes with mitochondrial proteins or microtubules. In this particular sub-cellular compartment, overexpression of Elk-1 is toxic for neuronal cells. When phosphorylated by the MAPK/ERK, Elk-1 translocates to the nucleus where it is implicated in regulating chromatin remodeling, SRE-dependent transcription, and neuronal differentiation. Another post-translational modification is the conjugation to SUMO (Small Ubiquitin-like MOdifier), which relocalizes Elk-1 in the cytoplasm. Thus, Elk-1 plays a dual role in neuronal functions: pro-apoptotic within the cytoplasm, and pro-differentiation within the nucleus. To address the role of Elk-1 in the brain, one must be aware of its multiple facets, and design molecular tools that will shut down Elk-1 expression, trafficking, or activation, in specific neuronal compartments. We summarize in this review the known molecular functions of Elk-1, its regulation in neuronal cells, and present evidence of its possible implication in model systems of synaptic plasticity, learning, but also in neurodegenerative diseases.
三元复合因子(TCF)Elk-1是一种转录因子,它通过血清反应元件(SRE)DNA共有序列位点调节即刻早期基因(IEG)的表达。Elk-1在SRE位点与血清反应因子(SRF)二聚体相关联,其磷酸化发生在特定残基上,以响应丝裂原活化蛋白激酶(MAPK),包括c-Jun氨基末端激酶(JNK)、p38/MAPK和细胞外信号调节激酶(ERK)。这一磷酸化事件对于触发SRE依赖的转录至关重要。尽管MAPK是记忆形成和维持的基本参与者,并且已经对其下游信号伙伴进行了大量研究,但尚无数据明确表明Elk-1参与这些过程。部分原因是Elk-1在神经元内的亚细胞定位及其功能的复杂性。Elk-1以静止状态存在于细胞质中,在那里它与线粒体蛋白或微管共定位。在这个特定的亚细胞区室中,Elk-1的过表达对神经元细胞有毒性。当被MAPK/ERK磷酸化时,Elk-1转移到细胞核,在那里它参与调节染色质重塑、SRE依赖的转录和神经元分化。另一种翻译后修饰是与SUMO(小泛素样修饰物)结合,这会使Elk-1重新定位到细胞质中。因此,Elk-1在神经元功能中发挥双重作用:在细胞质中具有促凋亡作用,在细胞核中具有促分化作用。为了阐明Elk-1在大脑中的作用,必须了解其多个方面,并设计能够在特定神经元区室中关闭Elk-1表达、运输或激活的分子工具。在本综述中,我们总结了Elk-1的已知分子功能、其在神经元细胞中的调节,并提供了其可能参与突触可塑性、学习模型系统以及神经退行性疾病的证据。