Department of Neurobiology and Anatomy, Xuzhou Key Laboratory of Neurobiology, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China.
Department of Emergency Surgery, Xuzhou First People's Hospital, The Affiliated Xuzhou Municipal Hospital of Xuzhou Medical University, Xuzhou, 221000, Jiangsu, China.
Neurochem Res. 2020 Dec;45(12):2915-2925. doi: 10.1007/s11064-020-03140-w. Epub 2020 Oct 30.
Abnormally high expression of glial cell line-derived neurotrophic factor (GDNF) derived from glioma cells has essential impacts on gliomagenesis and development, but the molecular basis underlying increased GDNF expression in glioma cells remain unclear. This work aimed to study the molecular mechanisms that may explain the accumulation of GDNF in glioma. Firstly, we observed that cAMP response element-binding protein (CREB), known as an important transcription factor for binding of GDNF promoter region, was highly expressed with an apparent accumulation into the nucleus of glioma cells, which may contribute to the transcription of GDNF. Secondly, CUE domain-containing protein 2 (CUEDC2), a ubiquitin-regulated protein, could increase the amount of binding between the E3 ligase tripartite motif-containing 21 (TRIM21) and CREB and affect the CREB level. Like our previous study, it showed that there was a significantly down-regulation of CUEDC2 in glioma. Finally, our data suggest that GDNF expression is indirectly regulated by transcription factor ubiquitination. Indeed, down-regulation of CUEDC2, decreased the ubiquitination and degradation of CREB, which was associated to high levels of GDNF. Furthermore, abundant CREB involved in the binding to the GDNF promoter region contributes to GDNF high expression in glioma cells. Collectively, it was verified the GDNF expression was affected by CREB ubiquitination regulated by CUEDC2 level.
神经胶质细胞系衍生神经营养因子（GDNF）在神经胶质瘤细胞中的异常高表达对神经胶质瘤的发生和发展有重要影响，但导致神经胶质瘤细胞中 GDNF 表达增加的分子基础尚不清楚。本研究旨在探讨可能解释 GDNF 在神经胶质瘤中积累的分子机制。首先，我们观察到环磷酸腺苷反应元件结合蛋白（CREB）作为 GDNF 启动子区域结合的重要转录因子，在神经胶质瘤细胞中高度表达，并明显积累到细胞核中，这可能有助于 GDNF 的转录。其次，CUE 结构域包含蛋白 2（CUEDC2）是一种受泛素调控的蛋白，可增加 E3 连接酶三部分基序包含蛋白 21（TRIM21）和 CREB 之间的结合，并影响 CREB 水平。与我们之前的研究一样，结果表明神经胶质瘤中 CUEDC2 的表达明显下调。最后，我们的数据表明，GDNF 的表达受到转录因子泛素化的间接调节。实际上，CUEDC2 的下调减少了 CREB 的泛素化和降解，这与 GDNF 的高水平有关。此外，大量参与与 GDNF 启动子区域结合的 CREB 有助于神经胶质瘤细胞中 GDNF 的高表达。总之，证实了 GDNF 的表达受到 CUEDC2 水平调节的 CREB 泛素化的影响。
