title: Signals regulating necrosis of cardiomyoblast by BTG2(/TIS21/PC3) via activation of GSK3β and opening of mitochondrial permeability transition pore in response to H2O2.
abstract: 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 30 min 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, BK21 Cell Transformation and Restoration Project, Ajou University School of Medicine, Suwon 443-721, Republic of Korea.
authors.forename: Yong Won
authors.initials: YW
authors.lastname: Choi
authors.forename: Tae Jun
authors.initials: TJ
authors.lastname: Park
authors.forename: Hyo Soo
authors.initials: HS
authors.lastname: Kim
authors.forename: In Kyoung
authors.initials: IK
authors.lastname: Lim
mesh_terms: D000818:Animals; D001483:Base Sequence; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000378:metabolism; D017931:DNA Primers; D004789:Enzyme Activation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D017874:Immediate-Early Proteins / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D032383:Myocytes, Cardiac / Q000378:metabolism*; D009336:Necrosis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: C521959:BTG2 protein, rat; D000081406:Peptidyl-Prolyl Isomerase F; D017931:DNA Primers; D017874:Immediate-Early Proteins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D025521:Tumor Suppressor Proteins; D006861:Hydrogen Peroxide; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D021983:Cyclophilins