Overexpression of CREB protein protects from tunicamycin-induced apoptosis in various rat cell types.
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.
Department of Medical Biology, University of Pécs Medical School, Szigeti 12, Pecs, 7624, Hungary.
András
A
Balogh
Mária
M
Németh
Ibolya
I
Koloszár
Lajos
L
Markó
Lukasz
L
Przybyl
Kazushi
K
Jinno
Csilla
C
Szigeti
Marija
M
Heffer
Matthias
M
Gebhardt
József
J
Szeberényi
Dominik N
DN
Müller
György
G
Sétáló
Marianna
M
Pap
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D002470:Cell Survival; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D008870:Microtubules / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009154:Mutation; D009928:Organ Specificity; D016716:PC12 Cells; D051381:Rats; D014415:Tunicamycin / Q000494:pharmacology*
D000970:Antineoplastic Agents; D017362:Cyclic AMP Response Element-Binding Protein; D014415:Tunicamycin; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3