Abstract
Transcription factor cAMP response element-binding protein (CREB) plays a critical role in memory formation. Ubiquitin-proteasome system-dependent protein degradation affects the upstream signaling pathways which regulate CREB activity. However, the molecular mechanisms of proteasome inhibition on reductive CREB activity are still unclear. The current study demonstrated that MG132-inhibited proteasome activity resulted in a dose dependence of CREB dephosphorylation at Ser133 as well as decreased phosphorylation of N-methyl-d-aspartate (NMDA) receptor subunit NR2B (Tyr1472) and its tyrosine protein kinase Fyn (Tyr416). These dephosphorylations are probably caused by disturbance of expression and post-translational modifications of tau protein since tau siRNA decreased the activity of Fyn, NR2B, and CREB. To further confirm this perspective, HEK293 cells stably expressing human tau441 protein were treated with MG132 and dephosphorylations of CREB and NR2B were observed. The current research provides an alternative pathway, tau/Fyn/NR2B signaling, regulating CREB activity.
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Acknowledgments
We thank Professor Wang Jianzhi at Tongji Medical College of Huazhong University of Sciences and Technology, Wuhan, China, for providing N2a, HEK293/wt, and HEK293/tau441 cells used in these studies. This work was financially supported by the Nature Science Foundation of Hubei Province (No. 2016CFB561) and the Project of Hubei Key Laboratory of Genetic Regulation and Integrative Biology (No. GRIB201604).
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Xie, M., Li, Y., Wang, Sh. et al. The Involvement of NR2B and tau Protein in MG132-Induced CREB Dephosphorylation. J Mol Neurosci 62, 154–162 (2017). https://doi.org/10.1007/s12031-017-0919-8
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DOI: https://doi.org/10.1007/s12031-017-0919-8