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

András Balogh, Mária Németh, Ibolya Koloszár, Lajos Markó, Lukasz Przybyl, Kazushi Jinno, Csilla Szigeti, Marija Heffer, Matthias Gebhardt, József Szeberényi, Dominik N. Müller, György Sétáló, Marianna Pap

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11 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1080-1098
Number of pages19
JournalApoptosis
Volume19
Issue number7
DOIs
Publication statusPublished - Jul 2014

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Keywords

  • Apoptosis
  • CREB
  • ER stress
  • PC12 cells
  • Tunicamycin
  • Unfolded protein response

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science
  • Clinical Biochemistry
  • Cell Biology
  • Biochemistry, medical
  • Cancer Research

Cite this

Balogh, A., Németh, M., Koloszár, I., Markó, L., Przybyl, L., Jinno, K., Szigeti, C., Heffer, M., Gebhardt, M., Szeberényi, J., Müller, D. N., Sétáló, G., & Pap, M. (2014). Overexpression of CREB protein protects from tunicamycin-induced apoptosis in various rat cell types. Apoptosis, 19(7), 1080-1098. https://doi.org/10.1007/s10495-014-0986-z