Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:6.3.2.19 (
ubiquitin-protein ligase
)
799
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
The Inhibitor of Apoptosis proteins (IAPs) are key repressors of apoptosis. Several IAP proteins contain a RING domain that functions as an E3 ubiquitin ligase involved in the ubiquitin-proteasome pathway. Here we investigated the interplay of ubiquitin-proteasome pathway and RING-mediated IAP turnover. We found that the CARD-RING domain of
cIAP1
(
cIAP1
-CR) is capable of down-regulating protein levels of RING-bearing IAPs such as
cIAP1
, cIAP2, XIAP, and Livin, while sparing NAIP and Survivin, which do not possess a RING domain. To determine whether polyubiquitination was required, we tested the ability of
cIAP1
-CR to degrade IAPs under conditions that impair ubiquitination modifications. Remarkably, although the ablation of E1
ubiquitin-activating enzyme
prevented
cIAP1
-CR-mediated down-regulation of
cIAP1
and cIAP2, there was no impact on degradation of XIAP and Livin. XIAP mutants that were not ubiquitinated in vivo were readily down-regulated by
cIAP1
-CR. Moreover, XIAP degradation in response to cisplatin and doxorubicin was largely prevented in
cIAP1
-silenced cells, despite cIAP2 up-regulation. The knockdown of
cIAP1
and cIAP2 partially blunted Fas ligand-mediated down-regulation of XIAP and protected cells from cell death. Together, these results show that the E3 ligase RING domain of
cIAP1
targets RING-bearing IAPs for proteasomal degradation by ubiquitin-dependent and -independent pathways.
...
PMID:The RING domain of cIAP1 mediates the degradation of RING-bearing inhibitor of apoptosis proteins by distinct pathways. 1843 93
