Down-Regulated CUEDC2 Increases GDNF Expression by Stabilizing CREB Through Reducing Its Ubiquitination in Glioma
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ORIGINAL PAPER
Down‑Regulated CUEDC2 Increases GDNF Expression by Stabilizing CREB Through Reducing Its Ubiquitination in Glioma Xin‑Feng Liu1,2 · Chuan‑Xi Tang1 · Lin Zhang1 · Shu‑Yan Tong1 · Yue Wang1 · Ayanlaja Abiola Abdulrahman1 · Guang‑Quan Ji1 · Yue Gao1 · Dian‑shuai Gao1 · Bao‑Le Zhang1 Received: 1 December 2019 / Revised: 28 September 2020 / Accepted: 1 October 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract 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 ubiquitinregulated 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. Keywords CUEDC2 · GDNF · CREB · TRIM21 · Glioma · Ubiquitination Abbreviations GDNF Glial cell line-derived neurotrophic factor CUEDC2 CUE domain-containing protein 2 TRIM21 Tripartite motif-containing 21
CREB CAMP response element-binding protein ChIP-PCR Chromatin immunoprecipitation-polymerase chain reaction HA Human astrocytes
Xin-Feng Liu and Chuan-Xi Tang have contributed equally to this work.
Introduction
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11064-020-03140-w) contains supplementary material, which is available to authorized users. * Dian‑shuai Gao [email protected] * Bao‑Le Zhang [email protected] 1
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
2
Glial cell line-derived neurotrophic factor (GDNF), a member of the transforming growth factor-β (TGF-β) superfamily, was first isolate
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