Determination of Cell Survival by RING-Mediated Regulation of Inhibitor of Apoptosis (IAP) Protein Abundance

Inhibitor of apoptosis (IAP) proteins, which bind to caspases via their baculoviral IAP repeat domains, also bear RING domains that enable them to promote ubiquitylation of themselves and other interacting proteins. Here we show that the RING domain of cIAP1 allows it to bind directly to the RING of...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2005-11, Vol.102 (45), p.16182-16187
Main Authors: Silke, John, Tobias Kratina, Diep Chu, Ekert, Paul G., Day, Catherine L., Pakusch, Miha, David C. S. Huang, Vaux, David L.
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Amino acids
Antibodies
Apoptosis
Biochemistry
Biological Sciences
Caspases - physiology
Cell death
Cell Line
Cell lines
Cell Survival
Cisplatin - therapeutic use
Drug therapy
Gels
Homeostasis
Inhibitor drugs
Inhibitor of Apoptosis Proteins - metabolism
Medical research
Melanoma
Melanoma - drug therapy
Melanoma - pathology
Molecular Sequence Data
Physiological regulation
Proteasome Endopeptidase Complex - physiology
Protein Structure, Tertiary
Proteins
Ubiquitin-Protein Ligases - physiology
X-Linked Inhibitor of Apoptosis Protein - metabolism
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Summary:Inhibitor of apoptosis (IAP) proteins, which bind to caspases via their baculoviral IAP repeat domains, also bear RING domains that enable them to promote ubiquitylation of themselves and other interacting proteins. Here we show that the RING domain of cIAP1 allows it to bind directly to the RING of X-linked IAP, causing its ubiquitylation and degradation by the proteasome, thus revealing a mechanism by which IAPs can regulate their abundance. Expression of a construct containing the RING of cellular IAP1 was able to deplete melanoma cells of endogenous X-linked IAP, promoted apoptosis, and also markedly reduced their clonogenicity when treated with cisplatin. Cross control of protein levels by RING domains may therefore enable their levels to be manipulated therapeutically.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0502828102