Demir Ozlem, Aysit Nese, Onder Zeynep, Turkel Nezaket, Ozturk Gurkan, Sharrocks Andrew D, Kurnaz Isil Aksan
Yeditepe University, Department of Genetics and Bioengineering, 26 Agustos Yerlesimi, 34755, Kayisdagi, Istanbul, Turkey.
Biochim Biophys Acta. 2011 Jun;1812(6):652-62. doi: 10.1016/j.bbadis.2011.02.012. Epub 2011 Mar 17.
Elk-1 belongs to the ternary complex factors (TCFs) subfamily of the ETS domain proteins, and plays a critical role in the expression of immediate-early genes (IEGs) upon mitogen stimulation and activation of the mitogen-activated protein kinase (MAPK) cascade. The association of TCFs with serum response elements (SREs) on IEG promoters has been widely studied and a role for Elk-1 in promoting cell cycle entry has been determined. However, the presence of the ETS domain transcription factor Elk-1 in axons and dendrites of post-mitotic adult brain neurons has implications for an alternative function for Elk-1 in neurons other than controlling proliferation. In this study, possible alternative roles for Elk-1 in neurons were investigated, and it was demonstrated that blocking TCF-mediated transactivation in neuronal cells leads to apoptosis through a caspase-dependent mechanism. Indeed RNAi-mediated depletion of endogenous Elk-1 results in increased caspase activity. Conversely, overexpression of either Elk-1 or Elk-VP16 fusion proteins was shown to rescue PC12 cells from chemically-induced apoptosis, and that higher levels of endogenous Elk-1 correlated with longer survival of DRGs in culture. It was shown that Elk-1 regulated the Mcl-1 gene expression required for survival, and that RNAi-mediated degradation of endogenous Elk-1 resulted in elimination of the mcl-1 message. We have further identified the survival-of-motor neuron-1 (SMN1) gene as a novel target of Elk-1, and show that the ets motifs in the SMN1 promoter are involved in this regulation.
Elk-1属于ETS结构域蛋白的三元复合因子（TCFs）亚家族，在有丝分裂原刺激和丝裂原活化蛋白激酶（MAPK）级联激活后，对即刻早期基因（IEGs）的表达起关键作用。TCFs与IEG启动子上的血清反应元件（SREs）的关联已得到广泛研究，并且已经确定了Elk-1在促进细胞周期进入中的作用。然而，有丝分裂后成年脑神经元的轴突和树突中存在ETS结构域转录因子Elk-1，这意味着Elk-1在神经元中可能具有除控制增殖以外的其他功能。在本研究中，研究了Elk-1在神经元中可能的其他作用，结果表明，阻断神经元细胞中TCF介导的反式激活会通过半胱天冬酶依赖性机制导致细胞凋亡。事实上，RNA干扰介导的内源性Elk-1缺失会导致半胱天冬酶活性增加。相反，Elk-1或Elk-VP16融合蛋白的过表达可使PC12细胞免受化学诱导的凋亡，并且内源性Elk-1水平越高，培养的背根神经节（DRGs）存活时间越长。研究表明，Elk-1调节生存所需的Mcl-1基因表达，RNA干扰介导的内源性Elk-1降解会导致mcl-1信息的消除。我们进一步确定运动神经元存活蛋白-1（SMN1）基因为Elk-1的一个新靶点，并表明SMN1启动子中的ets基序参与了这一调控。
