Activation of a caspase-dependent oxidative damage response mediates TGFbeta1 apoptosis in rat hepatocytes.
Activation of transforming growth factor-beta type 1- (TGFbeta1) mediated signaling occurs in response to cell injury affecting stem-type cells and hepatocytes in liver. In this work we used WB stemlike liver epithelial cells and p53-defective CWSV-1 nontumorigenic rat hepatocytes to investigate the possible roles of caspases and oxidative stress in TGFbeta1 signaling. TGFbeta1 significantly increased the level of 4-hydroxy-2-nonenal (4-HNE), a stable product of lipid peroxidation. In addition, TGFbeta1-treated cells exhibited activation of caspases that accompanied by enhanced cleavage of the caspase substrate poly(ADP)-ribose polymerase (PARP) and induction of apoptosis. WB cells were twice as sensitive as sensitive as CWSV-1 cells to induction of TGFbeta1 apoptosis. TGFbeta1-apoptosis was significantly reduced when cells were treated with TGFbeta1 in the presence of inhibitors of caspase-1, -3, -8, and -9. Importantly, in addition to suppression of apoptosis, treatment of cells with the caspase-3 inhibitor Z-DEVD-FMK in the presence of TGFbeta1 suppressed the formation 4-HNE and restored mitotic activity. Together, these data suggest TGFbeta1 induces activation of a caspase signaling cascade that includes an oxidative damage response, PARP cleavage, and apoptosis that do not require intact p53 in rat hepatocytes.
Albright
Craig D
CD
Department of Nutrition, School of Public Health and School of Medicine, University of North Carolina, Chapel Hill 27599-7461, USA. cdalbrig@email.unc.edu
Borgman
Crystal
C
Craciunescu
Corneliu N
CN
D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D002452:Cell Count; D002455:Cell Division; D002460:Cell Line; D002472:Cell Transformation, Viral; D004791:Enzyme Inhibitors / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D020287:In Situ Nick-End Labeling; D009842:Oligopeptides / Q000494:pharmacology; D018384:Oxidative Stress; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology; D053773:Transforming Growth Factor beta1; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency
D000447:Aldehydes; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D009842:Oligopeptides; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D016159:Tumor Suppressor Protein p53; C110772:benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; D011065:Poly(ADP-ribose) Polymerases; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; C027576:4-hydroxy-2-nonenal