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J Biol Chem ; 276(10): 7602-8, 2001 Mar 09.
Article in English | MEDLINE | ID: mdl-11106668

ABSTRACT

Although human c-IAP1 and c-IAP2 have been reported to possess antiapoptotic activity against a variety of stimuli in several mammalian cell types, we observed that full-length c-IAP1 and c-IAP2 failed to protect cells from apoptosis induced by Bax overexpression, tumor necrosis factor alpha treatment or Sindbis virus infection. However, deletion of the C-terminal RING domains of c-IAP1 and c-IAP2 restored antiapoptotic activity, indicating that this region negatively regulates the antiapoptotic function of the N-terminal BIR domain. This finding is consistent with the observation by others that the spacer region and RING domain of c-IAP1 functions as an E3 ligase, promoting autoubiquitination and degradation of c-IAP1. In addition, we found that c-IAP1 is cleaved during apoptosis to 52- and 35-kDa fragments. Both fragments contain the C-terminal end of c-IAP1 including the RING finger. In vitro cleavage of c-IAP1 with apoptotic cell extracts or with purified recombinant caspase-3 produced similar fragments. Furthermore, transfection of cells with the spacer-RING domain alone suppressed the antiapoptotic function of the N-terminal BIR domain of c-IAP1 and induced apoptosis. Optimal death-inducing activity of the spacer-RING required both the spacer region and the zinc-binding RING domain of c-IAP1 but did not require the caspase recruitment domain located within the spacer region. To the contrary, deletion of the caspase recruitment domain increased proapoptotic activity, apparently by stabilizing the C-terminal fragment.


Subject(s)
Apoptosis , Caspases/metabolism , Viral Proteins/chemistry , Viral Proteins/metabolism , Animals , Binding Sites , CHO Cells , Caspase 3 , Cell Line , Cricetinae , Gene Deletion , Humans , Immunoblotting , Inhibitor of Apoptosis Proteins , Models, Genetic , Mutagenesis, Site-Directed , Plasmids/metabolism , Protein Binding , Protein Structure, Tertiary , Sindbis Virus/genetics , Transfection , Zinc/metabolism
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