Daxx deletion mutant (amino acids 501–625)‐induced apoptosis occurs through the JNK/p38‐Bax‐dependent mitochondrial pathway

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Abstract
Death‐associated protein (Daxx) deletion mutant (aa 501–625) has been known to be an inducer of apoptosis. In this study, we observed that the Bax‐dependent mitochondrial death signaling pathway plays an important role in Daxx501–625‐induced apoptosis. Daxx fragment‐induced activation of caspase‐9 and ‐3 was mediated through the apoptosis signal‐regulating kinase 1 (ASK1)–MEK–c‐Jun‐N‐terminal kinase (JNK)/p38–Bax pathway. By overexpressing JNK‐binding domain (JBD) of JIP1, a JNK‐inhibitory protein, and treatment with SB203580, a specific p38 inhibitor, DU‐145 cells were made resistant to Daxx501–625‐induced apoptosis. Capase‐3 deficiency, Bax deficiency, or overexpression of a dominant‐negative caspase‐9 mutant prevented apoptosis, even though the Daxx501–625 fragment still activated the ASK1–MEK–MAPK pathway. Interestingly, Daxx501–625‐induced Bcl‐2 interacting domain (Bid) cleavage was suppressed in the dominant‐negative caspase‐9 mutant cells, whereas Bim was still phosphorylated in these cells. These results suggest that cleavage of Bid occurs downstream of caspase‐9 activation. In contrast, phosphorylation of Bim is upstream of caspase‐9 activation. Taken together, our results suggest that Daxx501–625‐induced apoptosis is mediated through the ASK1–MEK–JNK/p38–Bim–Bax‐dependent caspase pathway.