The inhibitor of apoptosis (IAP) family protects cells from self-execution by blocking the relentless caspase death cascade. IAPs bind to and inhibit activated caspases through their BIR domains. Some IAPs such as Livin also contain a RING domain that has E3 ubiquitin ligase activity and promotes the degradation of Smac/DIABLO through ubiquitination. Since Smac/DIABLO promotes apoptosis by inhibiting IAP-caspase interactions, degradation of Smac/DIABLO allows IAPs to more effectively block caspase activity thereby promoting cell survival.
In general, members of the IAP family are highly expressed in several types of cancer. However, Survivin, an IAP that lacks a RING domain, definitely stands out among the family for its clear association with cancer. Abundantly expressed during development but scarce in normal adult tissues, Survivin is upregulated during tumorigenesis and associated with chemotherapy resistance and poor patient survival.
IAPs are fast emerging as targets for potential diagnostics and therapeutics. For example, patients suffering from diverse cancers develop antibodies against Livin suggesting that Livin may be a novel diagnostic or prognostic tumor marker. Additionally, preclinical studies indicate that down-regulation of Survivin can sensitize tumor cells to chemotherapy, thereby increasing apoptosis and overall treatment response.
Key Publications 1.Crnkovic-Mertens, J Semzow, F Hoppe-Seyler and K Butz. 2006. Isoform-specific silencing of the Livin gene by RNA interference defines Livin B as key mediator of apoptosis inhibition in HeLa cells. J Mol Med 84:232-240.View Abstract 2.Wright CW and CS Duckett. 2005. Reawakening the cellular death program in neoplasia through the therapeutic blockade of IAP function. J Clin Investigation. 115:2673-2678.View Abstract 3.Zaffaroni N, M Pennati and MG Daidone. 2005. Survivin as a target for new anticancer interventions. J Cell Mol Med. 9:360-372.View Abstract 4. Fukuda S and LM Pelus. 2006. Survivin, a cancer target with an emerging role in normal adult tissues. Mol Cancer Ther. 5:1087-1094. View Abstract
IAPs Inhibit Apoptosis Pathways FIGURE 1.IAP proteins inhibit apoptosis by binding to activated caspases. They inhibit signals generated through both the two major pathways of apoptosis: the Extrinsic (death receptor mediated) and the Intrinsic (mitochondrial mediated) pathways.
Livin (IMG-347A)
Survivin (IMG-5754)
FIGURE 2.Western blot analysis of Liivin cells transiently transfected with human Livin cDNA using IMG-347A at 2 ug/ml.
FIGURE 3.Immunohistochemical analysis of Survivin in formalin-fixed, paraffin-embedded human breast cancer using IMG-5754 at 1:2000.
