Research: The iaps are a family of genes that are highly conserved across species as diverse as insects, birds and mammals. Certain members of this protein family have been shown to bind to and inhibit the activity of caspases, the principle executioners of apoptotic cell death. hILP, also known as human X-linked IAP protein (XIAP), blocks apoptosis induced by a wide variety of stimuli including Fas, TNF, UV irradiation and chemotoxic drugs. Recent data have shown that the BIR domains of XIAP/hILP are required for caspase-binding and inhibition. We have found that XIAP/hILP is a multi-functional protein which, in addition to inhibiting apoptosis, also binds to the type I transforming growth factor-beta (TGF-beta) receptor, and enhances TGF-beta-mediated gene expression. Interestingly, our data suggest that XIAP/hILP signals in a SMAD-dependent, but JNK-independent manner. Furthermore, we have found that the signaling properties of XIAP/hILP can be separated from caspase-binding in that signaling by XIAP/hILP requires the RING and linker domains of the protein, but not the BIR domains. Interestingly, we have found that cells which respond to TGF-beta by undergoing apoptosis exhibit a rapid degradation of XIAP/hILP prior to the onset of cell death, while TGF-beta-resistant cells retain high levels of XIAP/hILP. We speculate that the stability of XIAP/hILP may be a determining factor in the cellular response to TGF-beta. Given the frequent inactivation of the TGF-beta pathway in neoplastic tranformation, we are exploring the possibility that pharmacologic disruption of XIAP/hILP may lower the apoptotic threshold of tumor cells.
