Determination of cell survival by RING-mediated regulation of inhibitor of apoptosis (IAP) protein abundance

John Silke(Walter and Eliza Hall Institute of Medical Research), Tobias Kratina(Walter and Eliza Hall Institute of Medical Research), Diep Chu(Walter and Eliza Hall Institute of Medical Research), Paul G. Ekert(Walter and Eliza Hall Institute of Medical Research), Catherine L. Day(Walter and Eliza Hall Institute of Medical Research), Miha Pakusch(Walter and Eliza Hall Institute of Medical Research), David C.S. Huang(Walter and Eliza Hall Institute of Medical Research), David L. Vaux(Walter and Eliza Hall Institute of Medical Research)
Proceedings of the National Academy of Sciences
November 1, 2005
10.1073/pnas.0502828102
Cited by 148Open Access
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Abstract

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.

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