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.

源自神经胶质瘤细胞的神经胶质细胞系神经营养因子（GDNF）的异常高表达对神经胶质瘤的发生和发展具有重要影响，但神经胶质瘤细胞中GDNF表达增加的分子基础仍不清楚。这项工作旨在研究可能解释神经胶质瘤中GDNF积累的分子机制。首先，我们观察到cAMP反应元件结合蛋白（CREB），即与GDNF启动子区域结合的重要转录因子，被高度表达，并在胶质瘤细胞核中明显积累，这可能有助于GDNF的转录。 。其次，含有CUE域的蛋白2（CUEDC2）是一种遍在蛋白调节的蛋白，可能会增加含E3连接酶的三方基序21（TRIM21）与CREB之间的结合量，并影响CREB水平。像我们以前的研究一样，它表明神经胶质瘤中的CUEDC2明显下调。最后，我们的数据表明，GDNF表达受转录因子泛素化间接调控。实际上，CUEDC2的下调减少了CREB的泛素化和降解，这与高水平的GDNF有关。此外，参与与GDNF启动子区域结合的大量CREB有助于GDNF在神经胶质瘤细胞中的高表达。共同地，证实了GDNF表达受CUEDC2水平调节的CREB泛素化影响。我们的数据表明，GDNF表达受转录因子泛素化间接调控。确实，CUEDC2的下调减少了CREB的泛素化和降解，这与高水平的GDNF有关。此外，参与与GDNF启动子区域结合的大量CREB有助于GDNF在神经胶质瘤细胞中的高表达。共同地，证实了GDNF表达受CUEDC2水平调节的CREB泛素化影响。我们的数据表明，GDNF表达受转录因子泛素化间接调控。实际上，CUEDC2的下调减少了CREB的泛素化和降解，这与高水平的GDNF有关。此外，参与与GDNF启动子区域结合的大量CREB有助于GDNF在神经胶质瘤细胞中的高表达。共同地，证实了GDNF表达受CUEDC2水平调节的CREB泛素化影响。