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J. Biol. Chem., Vol. 276, Issue 39, 36071-36074, September 28, 2001
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From the Centre de recherche en cancérologie de
l'Université Laval, L'Hôtel-Dieu de Québec, 9 rue McMahon, Québec G1R 2J6, Canada
Ask1 (apoptosis
signal-regulating kinase 1) is
activated as a consequence of cell exposure to a variety of stresses
and can then initiate apoptosis. A known pathway of apoptosis
downstream of Ask1 involves the activation of the stress-activated
protein kinases, the release of cytochrome c from
mitochondria, the activation of caspases, and the fragmentation of
nuclei. Here, we characterized a novel mechanism of Ask1-mediated cell
killing that is triggered by the interaction with Daxx. Co-transfection
of Ask1 and Daxx induced a caspase-independent cell-death process
characterized at the morphological level by distinctive crumpled nuclei
easily distinguishable from the condensed and fragmented nuclei seen during classical caspase-dependent apoptosis. The
kinase activity of Ask1 was not involved in this process, because
mutants lacking kinase activity were as efficient as wild type Ask1 in
mediating Daxx-induced cell death. Ask1N, a deletant that lacks the
C-terminal half including the kinase domain of Ask1, was constitutively
active in producing crumpled nuclei. In contrast, Ask1
N, the
reciprocal deletant that possesses constitutive kinase activity,
produced fragmented nuclei typical of caspase-dependent
death processes. We conclude that in addition to a
caspase-dependent pro-apoptotic function that depends on
its kinase activity, Ask1 possesses a caspase-independent killing
function that is independent on its kinase activity and is activable by
interaction with Daxx. In the physiological situation, such an activity
is induced as a consequence of the translocation of Daxx from the
nucleus to the cytoplasm, a condition that occurs following activation
of the death receptor Fas.
To whom correspondence should be addressed. Tel.: 418-525-4444 (ext. 5555); Fax: 418-691-5439; E-mail:
jacques.landry@med.ulaval.ca.
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