7 research outputs found
Family and Province: a Contribution To the Knowledge of Family Structures in Early Modern France
Caspase-7 Is Directly Activated by the âŒ700-kDa Apoptosome Complex and Is Released as a Stable XIAP-Caspase-7 âŒ200-kDa Complex
Elevated p21-Activated Kinase 2 Activity Results in Anchorage-Independent Growth and Resistance to Anticancer DrugâInduced Cell Death
The E3 Ubiquitin Ligase cIAP1 Binds and Ubiquitinates Caspase-3 and -7 via Unique Mechanisms at Distinct Steps in Their Processing*Sâ
Inhibitor of apoptosis (IAP) proteins are widely expressed throughout
nature and suppress cell death under a variety of circumstances. X-linked IAP,
the prototypical IAP in mammals, inhibits apoptosis largely through direct
inhibition of the initiator caspase-9 and the effector caspase-3 and -7. Two
additional IAP family members, cellular IAP1 (cIAP1) and cIAP2, were once
thought to also inhibit caspases, but more recent studies have suggested
otherwise. Here we demonstrate that cIAP1 does not significantly inhibit the
proteolytic activities of effector caspases on fluorogenic or endogenous
substrates. However, cIAP1 does bind to caspase-3 and -7 and does so,
remarkably, at distinct steps prior to or following the removal of their
prodomains, respectively. Indeed, cIAP1 bound to an exposed IAP-binding motif,
AKPD, on the N terminus of the large subunit of fully mature caspase-7,
whereas cIAP1 bound to partially processed caspase-3 in a manner that required
its prodomain and cleavage between its large and small subunits but did not
involve a classical IAP-binding motif. As a ubiquitin-protein isopeptide
ligase, cIAP1 ubiquitinated caspase-3 and -7, concomitant with binding, in a
reaction catalyzed by members of the UbcH5 subfamily (ubiquitin carrier
protein/ubiquitin-conjugating enzymes), and in the case of caspase-3,
differentially by UbcH8. Moreover, wild-type caspase-7 and a chimeric
caspase-3 (bearing the AKPD motif) were degraded in vivo in a
proteasome-dependent manner. Thus, cIAPs likely suppress apoptosis, at least
in part, by facilitating the ubiquitination and turnover of active effector
caspases in cells