Involvement of caspase family proteases in transforming growth factor-beta-induced apoptosis.
Transforming growth factor-beta (TGF-beta) is a potent inducer of programmed cell death in liver as well as some hepatoma cell lines. To explore the mechanism by which TGF-beta induces apoptosis, we investigated the role of caspase family proteases in the apoptotic death of a human hepatoma cell line, Hep3B. We showed that TGF-beta-induced apoptosis was blocked by expression of the cowpox virus protein CrmA, a serpin-like pseudosubstrate for some of the caspase family proteases. CrmA expression, however, did not affect TGF-beta-induced regulation of promoter activities of the cyclin A and plasminogen activator inhibitor type I genes. These results indicate that CrmA inhibits a step specific for the apoptotic effect of TGF-beta. In addition to CrmA, a tripeptide caspase-protease inhibitor, z-Val-Ala-Asp-fluoromethylketone could also suppress TGF-beta-induced apoptosis in a dose-dependent manner. In TGF-beta-treated Hep3B cells, we observed a specific degradation of the catalytic subunit of DNA-dependent protein kinase, which was previously shown to be a substrate of caspase-3 but not several other members of the caspase family. This degradation was not seen in Hep3B cells transfected with CrmA nor in Hep3B cells pretreated with the tripeptide caspase inhibitor. Our study indicates a requirement of caspase family proteases in TGF-beta-induced apoptosis.
Chen
R H
RH
Dr. H.L. Tsai Memorial Laboratory, Institute of Molecular Medicine, College of Medicine, Taipei, Taiwan.
Chang
T Y
TY
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology*; D006528:Carcinoma, Hepatocellular; D053148:Caspase 3; D020169:Caspases; D015608:Cowpox virus; D016213:Cyclins / Q000235:genetics; D003546:Cysteine Endopeptidases / Q000502:physiology*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins; D006801:Humans; D008113:Liver Neoplasms; D009687:Nuclear Proteins; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000032:analysis; D015843:Serpins / Q000235:genetics / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014764:Viral Proteins
D000590:Amino Acid Chloromethyl Ketones; D016213:Cyclins; D015853:Cysteine Proteinase Inhibitors; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D017395:Plasminogen Activator Inhibitor 1; D018125:Receptors, Transforming Growth Factor beta; D015843:Serpins; D016212:Transforming Growth Factor beta; D014764:Viral Proteins; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C074641:interleukin-1beta-converting enzyme inhibitor; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D017346:Protein Serine-Threonine Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases