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Overexpression of CREB protein protects from tunicamycin-induced apoptosis in various rat cell types

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Abstract

Endoplasmic reticulum (ER) stress plays an essential role in unfolded protein response induced apoptosis contributing to several pathological conditions. Glycogen synthase kinase-3β (GSK-3β) plays a central role in several apoptotic signaling, including ER stress, as the active form of GSK-3β induces apoptosis. The phosphorylation of cAMP responsive element (CRE) binding protein (CREB) Ser-133 (S133) residue is the end-point of various signaling pathways, like growth factor signaling, while the Ser-129 (S129) residue is phosphorylated by GSK-3β. The significance of the ubiquitously expressed transcription factor CREB is demonstrated in prolonged, tunicamycin (TM)-induced ER stress in this study. In the experiments wild-type (wt) CREB, S129Ala, S133Ala or S129Ala–S133Ala mutant CREB expressing PC12 rat pheochromocytoma cell lines showed increased survival under TM-evoked prolonged ER stress compared to wtPC12 cells. After TM treatment ER stress was activated in all PC12 cell types. Lithium and SB-216763, the selective, well-known inhibitors of GSK-3β, decreased TM-induced apoptosis and promoted cell survival. The proapoptotic BH3-only Bcl-2 family member Bcl-2-interacting mediator of cell death (Bim) level was decreased in the different CREB overexpressing PC12 cells as a result of TM treatment. CREB overexpression also inhibited the sequestration of Bim protein from tubulin molecules, as it was demonstrated in wtPC12 cells. Transient expression of wtCREB diminished TM-induced apoptosis in wtPC12, Rat-1 and primary rat vascular smooth muscle cells. These findings demonstrate a novel role of CREB in different cell types as a potent protector against ER stress.

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Acknowledgments

This work was supported by Grants from the Hungarian National Research Fund to József Szeberényi (OTKA T037528) and from Pécs University to Marianna Pap (PTE AOK KA 34039-13/2009). The purchase of the Olympus FV-1000 laser scanning confocal system was supported by Grant GVOP-3.2.1-2004-04-0172/3.0 to Pécs University. The authors would like to thank Gabriele N’diaye for the outstanding technical assistance.

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  1. Department of Medical Biology, University of Pécs Medical School, Szigeti 12, Pecs, 7624, Hungary

    András Balogh, Mária Németh, Ibolya Koloszár, Kazushi Jinno, Csilla Szigeti, József Szeberényi, György Sétáló Jr. & Marianna Pap

  2. Signal Transduction Research Group, University of Pécs János Szentágothai Research Centre, Ifjúság útja 20, Pecs, 7624, Hungary

    András Balogh, Mária Németh, Ibolya Koloszár, Kazushi Jinno, Csilla Szigeti, József Szeberényi, György Sétáló Jr. & Marianna Pap

  3. Experimental and Clinical Research Center, Charité Medical Faculty and Max-Delbrück Center for Molecular Medicine, Berlin, Germany

    Lajos Markó, Lukasz Przybyl, Matthias Gebhardt & Dominik N. Müller

  4. Department of Medical Biology, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia

    Marija Heffer

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Balogh, A., Németh, M., Koloszár, I. et al. Overexpression of CREB protein protects from tunicamycin-induced apoptosis in various rat cell types. Apoptosis 19, 1080–1098 (2014). https://doi.org/10.1007/s10495-014-0986-z

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