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Activation of caspases occurs downstream from radical oxygen species production, Bcl-xL down-regulation, and early cytochrome C release in apoptosis induced by transforming growth factor beta in rat fetal hepatocytes.

Abstract

Most of the morphologic changes that are observed in apoptotic cells are caused by a set of cysteine proteases (caspases) that are activated during this process. In previous works from our group we found that treatment of rat fetal hepatocytes with transforming growth factor beta1 (TGF-beta1) is followed by apoptotic cell death. TGF-beta1 mediates radical oxygen species (ROS) production that precedes bcl-xL down-regulation, loss of mitochondrial transmembrane potential, release of cytochrome c, and activation of caspase-3 (Herrera et al., FASEB J 2001;15:741-751). In this work, we have analyzed how TGF-beta1 activates the caspase cascade and whether or not caspase activation precedes the oxidative stress induced by this factor. Our results show that TGF-beta1 activates at least caspase-3, -8, and -9 in rat fetal hepatocytes, which are not required for ROS production, glutathione depletion, bcl-xL down-regulation, and initial cytochrome c release. However, caspase activation mediates cleavage of Bid and Bcl-xL that could originate an amplification loop on the mitochondrial events. An interesting result is that transmembrane potential disruption occurs later than the initial cytochrome c release and is mostly blocked by the pan-caspase inhibitor Z-VAD.fmk, indicating that the decrease in mitochondrial transmembrane potential (Delta(Psi)m) may be a consequence of caspase activity rather than the mechanism by which TGF-beta induces cytochrome c efflux. Finally, although Z-VAD.fmk completely blocks nucleosomal DNA fragmentation, it only delays cell death, which suggests that activation of the apoptotic program by TGF-beta in fetal hepatocytes inevitably leads to death, with or without caspases.

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  • Authors+Show Affiliations

    ,

    Departamento de Bioquímica y Biología Molecular, Instituto de Bioquímica, Centro Mixto CSIC/UCM, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain.

    , , , , ,

    Source

    Hepatology (Baltimore, Md.) 34:3 2001 Sep pg 548-56

    MeSH

    Animals
    Apoptosis
    Caspases
    Cells, Cultured
    Cytochrome c Group
    Down-Regulation
    Enzyme Activation
    Fetus
    Hepatocytes
    Humans
    Mitochondria, Liver
    Proto-Oncogene Proteins c-bcl-2
    Rats
    Rats, Wistar
    Reactive Oxygen Species
    Recombinant Proteins
    Time Factors
    Transforming Growth Factor beta
    bcl-X Protein

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    11526541

    Citation

    Herrera, B, et al. "Activation of Caspases Occurs Downstream From Radical Oxygen Species Production, Bcl-xL Down-regulation, and Early Cytochrome C Release in Apoptosis Induced By Transforming Growth Factor Beta in Rat Fetal Hepatocytes." Hepatology (Baltimore, Md.), vol. 34, no. 3, 2001, pp. 548-56.
    Herrera B, Fernández M, Alvarez AM, et al. Activation of caspases occurs downstream from radical oxygen species production, Bcl-xL down-regulation, and early cytochrome C release in apoptosis induced by transforming growth factor beta in rat fetal hepatocytes. Hepatology. 2001;34(3):548-56.
    Herrera, B., Fernández, M., Alvarez, A. M., Roncero, C., Benito, M., Gil, J., & Fabregat, I. (2001). Activation of caspases occurs downstream from radical oxygen species production, Bcl-xL down-regulation, and early cytochrome C release in apoptosis induced by transforming growth factor beta in rat fetal hepatocytes. Hepatology (Baltimore, Md.), 34(3), pp. 548-56.
    Herrera B, et al. Activation of Caspases Occurs Downstream From Radical Oxygen Species Production, Bcl-xL Down-regulation, and Early Cytochrome C Release in Apoptosis Induced By Transforming Growth Factor Beta in Rat Fetal Hepatocytes. Hepatology. 2001;34(3):548-56. PubMed PMID: 11526541.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Activation of caspases occurs downstream from radical oxygen species production, Bcl-xL down-regulation, and early cytochrome C release in apoptosis induced by transforming growth factor beta in rat fetal hepatocytes. AU - Herrera,B, AU - Fernández,M, AU - Alvarez,A M, AU - Roncero,C, AU - Benito,M, AU - Gil,J, AU - Fabregat,I, PY - 2001/8/30/pubmed PY - 2001/9/21/medline PY - 2001/8/30/entrez SP - 548 EP - 56 JF - Hepatology (Baltimore, Md.) JO - Hepatology VL - 34 IS - 3 N2 - Most of the morphologic changes that are observed in apoptotic cells are caused by a set of cysteine proteases (caspases) that are activated during this process. In previous works from our group we found that treatment of rat fetal hepatocytes with transforming growth factor beta1 (TGF-beta1) is followed by apoptotic cell death. TGF-beta1 mediates radical oxygen species (ROS) production that precedes bcl-xL down-regulation, loss of mitochondrial transmembrane potential, release of cytochrome c, and activation of caspase-3 (Herrera et al., FASEB J 2001;15:741-751). In this work, we have analyzed how TGF-beta1 activates the caspase cascade and whether or not caspase activation precedes the oxidative stress induced by this factor. Our results show that TGF-beta1 activates at least caspase-3, -8, and -9 in rat fetal hepatocytes, which are not required for ROS production, glutathione depletion, bcl-xL down-regulation, and initial cytochrome c release. However, caspase activation mediates cleavage of Bid and Bcl-xL that could originate an amplification loop on the mitochondrial events. An interesting result is that transmembrane potential disruption occurs later than the initial cytochrome c release and is mostly blocked by the pan-caspase inhibitor Z-VAD.fmk, indicating that the decrease in mitochondrial transmembrane potential (Delta(Psi)m) may be a consequence of caspase activity rather than the mechanism by which TGF-beta induces cytochrome c efflux. Finally, although Z-VAD.fmk completely blocks nucleosomal DNA fragmentation, it only delays cell death, which suggests that activation of the apoptotic program by TGF-beta in fetal hepatocytes inevitably leads to death, with or without caspases. SN - 0270-9139 UR - https://www.unboundmedicine.com/medline/citation/11526541/Activation_of_caspases_occurs_downstream_from_radical_oxygen_species_production_Bcl_xL_down_regulation_and_early_cytochrome_C_release_in_apoptosis_induced_by_transforming_growth_factor_beta_in_rat_fetal_hepatocytes_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0270-9139(01)87457-7 DB - PRIME DP - Unbound Medicine ER -