Signals regulating necrosis of cardiomyoblast by BTG2/TIS21/PC3 via activation of GSK3β and opening of mitochondrial permeability transition pore in response to H2O2

• Published in: Biochemical and biophysical research communications 2013-05, Vol.434 (3), p.559-565
• Main Authors: Choi, Yong Won, Park, Tae Jun, Kim, Hyo Soo, Lim, In Kyoung
• Format: Article
• Language: English
• Subjects: Akt; BTG2/TIS21/PC3 gene; Cyclophilin D; Erk; H9c2 cardiomyoblast; Necrosis
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2013.03.114

•Induction of BTG2 expression in heart and H9c2 cardiomyoblasts in response to ROS.•Aggravation of ROS-initiated necrosis by expression of BTG2 in H9c2 cells.•Translocation of BTG2 protein from nuclei to mitochondria in response to H2O2.•Activation of GSK3β by BTG2 via downregulation of Erk1/2 and Akt activities.•Regulation of mPTP opening by BTG2 via activating cyclophilin D in mitochondria. To investigate signal transduction pathway of cell death regulated by a tumor suppressor after oxidative stress, cardiomyoblasts were virally transfected with BTG2/TIS21/PC3 (BTG2) and subsequently treated with H2O2. Heart muscle rarely expresses BTG2 unless oxidative stress occurs, however, ischemia induced BTG2 expression and necrosis, not apoptosis, of cardiomyoblasts. BTG2-expressioning cardiomyblasts showed impaired recoveries of survival kinases, Akt and Erk, thus sustaining GSK-3β activity in 30min of H2O2 exposure, in contrast to their rapid recoveries in LacZ control. The phenomenon was accompanied by the failure of ATP regeneration and the sustained activation of AMPK in the BTG2 expresser. Furthermore, H2O2 treatment markedly induced BTG2 translocation from nuclei to mitochondria along with cell death by cyclophilin D activation and mPTP opening. Exogenous and endogenous effect of BTG2 was confirmed by chemical inhibitors and BTG2-KO-MEF, respectively. Here, we suggest tumor suppressor, BTG2, as one of the regulators of necrosis in myocardium via inhibiting Akt/Erk, but activating GSK3β and cyclophilin D, which resulted in mPTP opening in response to H2O2.