The inhibitor of apoptosis proteins (IAPs) are important regulators of cell death and inflammation. The cellular inhibitor of apoptosis protein 2 (cIAP2) contains three Baculovirus IAP repeat (BIR) domains, a Ubiquitin associated (UBA) domain, and a RING domain with E3 ligase activity. cIAP2 inhibits apoptosis through direct inhibition of the pro-apoptotic caspase-3. cIAP2 also regulates cell survival through its role in the tumor necrosis factor alpha (TNF-alpha) signaling pathway. TNF-alpha is an important cytokine that elicits a pro-inflammatory response through the activation of nuclear factor-kB (NF-kB). cIAP2 plays a crucial role downstream of the tumor necrosis factor receptor through the ubiquitylation of the effector protein RIP1 and by triggering the degradation of IkB alpha, a negative regulator of NF-kB, and allowing the activation of inflammatory and pro-survival genes. Similarly, cIAP2 has also been shown to be involved in innate immunity through its role in NOD1 and TLR4 signal propagation in response to bacterial infection. The dual roles of cIAPs in inhibiting apoptosis and eliciting a pro-inflammatory response mediates cellular decisions between cell death or cell survival and has made it an attractive therapeutic target to sensitize cancer cells to apoptosis.
Western Blot: cIAP2 Antibody [NBP1-27972] - HeLa whole cell lysate.
Dr. Gores at the Mayo Clinic examined the effect of TNF-related apoptosis-inducing ligand (TRAIL), a potential chemotherapeutic agent, on cIAP levels in liver cancer cells (1). They used the cIAP2 antibody to measure protein levels through immunoblotting following TRAIL treatment and found cIAP1 but not cIAP2 is specifically reduced and leads to cytotoxicity. In a separate study the same group used the cIAP2 antibody to show Hedgehog signaling regulates cIAP levels and that inhibition of Hedgehog can further sensitize cancer cells to apoptosis offering an alternative approach to TRAIL resistant cancers (2). Loeder et al. also looked at TRAIL induced cytotoxicity in combination with pharmacological inhibition of IAPs in a different type of cancer, chronic lymphoblastic leukemia (CLL) (3). They used the cIAP2 antibody to monitor levels of IAPs in CLL cells as well as in normal B cells. Their study showed inhibition of XIAP sensitized cells to apoptosis and proved to be an effective therapy in combination with TRAIL in primary CLL cell lines. In the journal Oncogene the same group examined TRAIL resistant cancers in order to design new therapeutic strategies (4). They used the cIAP2 antibody among others to examine the expression of apoptosis regulatory proteins in response to different drug treatments. They found that dual treatment with IFN-gamma and histone deactylase inhibitors restores caspase-8 expression and overcomes TRAIL resistance. The Grassman group discovered cIAP2 overexpression is an important factor in the immortalization of T cells by human T cell leukemia virus type 1 (HLVT1) (5). They used the cIAP2 antibody to demonstrate cIAP2 induction in response to viral infection. They also showed depletion of cIAP2 by RNA interference is able to inhibit cell growth and cause apoptosis in the virally infected cells.
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