ICE-like protease (caspase) is involved in transforming growth factor β1-mediated apoptosis in FaO rat hepatoma cell line

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Abstract
Transforming growth factor-β1 (TGF-β1) arrests growth and/or stimulates apoptosis of a variety of cells. The biochemical pathways involved in the apoptotic processes, however, remain poorly defined. TGF-β1 induces DNA fragmentation together with morphological changes, which are characteristic of apoptosis in the FaO rat hepatoma cell line. Histones were remarkably enriched in lysates of these cells during TGF β1-induced apoptosis. We identified U1-70 kd as a death substrate which is cleaved following TGF-β1 treatment. The tetrapeptide caspase inhibitor carbobenzoxy-valyl-alanly-aspartyl-(β-O-methyl)-fluoromethyl ketone (ZVAD-FMK) prevented TGF β1-induced apoptotic DNA fragmentation and cleavage of the U1-70 kd protein, showing that caspase(s) are involved in TGF β1-mediated apoptosis. To identify specific caspases involved in apoptosis induced by TGF-β1 in FaO cells, proteolytic activation of several of these caspases and their substrates were studied as a function of time following TGF β1-treatment. TGF β1-treatment induced the progressive proteolytic processing of caspase-2 (ICH-1L/Nedd-2), whereas caspase-1 itself did not show any cleavage from the precursor. Pre-treatment with ZVAD-FMK abrogated the maturation of caspase-2 and blocked the apoptotic progress. These results suggest that caspase-2, but not caspase-1, may play a crucial role in TGF β1-induced apoptosis in these cells.

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