the inhibitor of apoptosis proteins ( iaps ) are potent suppressors of apoptosis and the human family is comprised of eight members : cellular iap 1 ( ciap1 ) , cellular iap 2 ( ciap2 ) , x - linked iap ( xiap ) , neuronal apoptosis inhibitory protein ( naip ) , melanoma iap ( ml - iap ) , survivin , apollon , and iap like protein 2 ( ilp2 ) . all iap proteins are characterized by the presence of one to three baculovirus iap repeat ( bir ) domains , which are zinc - binding regions of approximately 70 amino acids that mediate protein - protein interactions . a number of iaps also contain a ring ( really interesting new gene ) domain that confers ubiquitin protein ligase ( e3 ) activity and are capable of auto - ubiquitination , as well as ubiquitination of proteins involved in apoptosis and signaling . instead , they exert their antiapoptotic effects through protein - protein interactions and by modulating the levels of other proteins through their function as ubiquitin ligases . firstly , ciap1/2 can bind to smac and sequester it from xiap , allowing xiap to inhibit caspases and suppress apoptosis . furthermore , the ciaps can target caspases and smac for degradation by mediating their ubiquitination [ 5 , 6 ] . the ubiquitin ligase activity of the ciaps is conferred by the presence of the ring domain in their carboxy terminus and their substrates include themselves and proteins involved in signaling , including multiple substrates in the tumour necrosis factor receptor ( tnfr ) complex [ 8 , 9 ] . activation of nf-b signaling regulates a large number of genes involved in a wide range of biological functions including cytokines , adhesion molecules , chemokines , and a number of genes that contribute to survival by promoting proliferation and inhibiting apoptosis . the ciaps can regulate the canonical and noncanonical nf-b pathways in contrasting ways ( figure 1 ) . ciap1/2 plays a critical role in tnf receptor ( tnfr ) signaling to canonical nf-b . binding of tnf- to tnfr induces the formation of complex i , consisting of tradd ( tnf receptor - associated death domain ) , traf2 ( tnf receptor - associated factor 2 ) , and rip1 ( receptor interacting protein 1 ) . traf2 recruits ciap1/2 to the complex , where they are required for tnfr - induced activation of nf-b signaling . the ring domains of ciap1/2 catalyze the activating k63-linked polyubiquitination of rip1 , which activates the tak1 ( transforming growth factor--activated kinase 1 ) kinase complex . this complex mediates the phosphorylation of ikk , which in turn phosphorylates ib to signal its degradation and activates canonical nf-b . the k63-linked polyubiquitination of rip1 also suppresses the activation of caspase-8 and formation of the proapoptotic complex ii , thereby preventing apoptosis . the expression of prosurvival genes stimulated by tnf- activation of nf-b signaling is believed to play a major role in the protection against tnf--induced cell death . as previously mentioned , ciap1/2 participate in a multi - subunit ubiquitin ligase complex that includes traf2 and traf3 . this complex targets nik and tonically represses it to limit the activation of both the canonical and noncanonical nf-b signaling [ 1719 ] . mutations in the constituents of this complex , including ciap1/2 , lead to constitutive activation of nf-b [ 20 , 21 ] .   thus , the ciaps can both positively and negative regulate the nf-b pathway . while ciaps participate in the activating ubiquitination of rip to result in activation of the canonical pathway in response to tnf / death ligands , they conversely ubiquitinate nik in an inhibitory manner to suppress the both the canonical and noncanonical pathways . true to its name , the ciaps play an important role in the inhibition of apoptosis . they are induced to promote survival during cellular stresses such as detachment from extracellular matrix   and er stress . they are also induced by pro - survival signaling such as nuclear factor ( nf)-b [ 24 , 25 ] . not surprisingly , their antiapoptotic activity is exploited for tumour cell survival , and their expression is induced by potent oncogenes such as ras   and e6 . many members of the iap family , including the ciaps , are overexpressed in a number of human cancers and are associated with poor prognosis . chromosomal amplification of the 11q2123 region , which encompasses both ciap1 and ciap2 , is observed in a variety of cancers , including renal cell carcinomas , glioblastomas , gastric carcinomas , and nonsmall cell lung carcinomas [ 2931 ] . approximately 50% of surveyed cases displayed a t(11,18 ) ( q21 ; q21 ) translocation , which results in a fusion of the bir domains of ciap2 with the carboxy terminus of the paracaspase domain of malt1 [ 32 , 33 ] . the resulting fusion protein promotes constitutive activation of nf-b , leading to increased prosurvival signaling . the anti - apoptotic function of iaps and their overexpression in a wide variety of cancers make them attractive therapeutic targets . as such , a number of strategies to target iap proteins in cancer are currently under investigation . one focus has been on the generation of molecules that mimic the aminoterminus of mature smac . these smac mimetics disrupt iap  :  caspase and iap  :  smac interactions and can stimulate cell death . originally designed to target xiap , following treatment with an iap antagonist , it is speculated that the downregulation of ciaps result in the accumulation of nik , which activates noncanonical nf-b signaling and leads to autocrine tnf- production [ 3537 ] . in the absence of ciaps , tnf- instead triggers the formation of the pro - apoptotic complex ii , consisting of fadd , caspase-8 , and deubiquitinated rip1 , resulting in apoptosis . while treatment with iap antagonists as a single agent has shown some success in a limited number of human cancer cell lines , their cytotoxicity is often augmented when used in combination with other agents such as tnf- and tumour necrosis factor - related apoptosis - inducing ligand ( trail ) [ 30 , 40 ] . while overexpression of ciaps likely promote tumourigenesis by inhibiting apoptosis through their interactions with components of the apoptotic machinery ( i.e. , smac / diablo ) , the loss of ciaps in a number of blood malignancies is associated with pro - survival activation of nf-b signaling . recent studies have shown that mutations or translocations resulting in the loss of ciaps are , in part , responsible for constitutive activation of nf-b signaling in several cancers . two independent groups reported that constitutive activation of nf-b signaling in multiple myeloma may be attributable to alterations in ciap2 or components of the nik - regulating complex including ciap1 , traf2 , and/or traf3 [ 20 , 21 ] . the resulting nik - mediated activation of both canonical and noncanonical nf-b signaling is essential for promoting tumour cell survival in multiple myeloma . aberrant activation of nf-b is also detected in a majority ( ~60% ) of splenic marginal zone lymphomas ( smzl ) . investigation into possible molecular lesions in the nf-b pathway revealed disruption of ciap2 as a contributor to constitutive nf-b activation . out of 101 smzl cases analyzed , 11% of cases harboured abnormalities in ciap2 by inactivating mutations , missense mutations and gene deletions . these mutations were all monoallelic , suggesting that genetic lesions in ciap2 may have a dominant negative effect . all of the smzl primary cases displaying ciap2 mutations showed constitutive activation of nf-b signaling , including accumulation of nik . rossi et al . recently showed that genetic disruption of ciap2 in chronic lymphocytic leukemia is associated with fludarabine resistance and a poor outcome similar to that attributed to tp53 abnormalities . additionally , progressive but fludarabine - sensitive disease was devoid of ciap2 mutations / loss , indicating that the genetic lesions are specifically associated with a chemoresistant phenotype . the loss of ciap2 in these lesions was found to be associated with constitutive activation of nf-b , consistent with its role as a negative regulator of nik . interestingly , disruption of ciap2 through inactivating mutations and/or gene deletions was found to be mutually exclusive with tp53 abnormalities . since nf-b is a known negative regulator of p53 , it is possible that the loss of ciap2 in these cells results in reduced p53 function , thus obviating the requirement for inactivating mutations in tp53 . in line with this , our lab has shown that in breast mammary epithelial cells , the downregulation of ciap2 results in reduction of wild - type p53 protein ( unpublished data ) . this may also explain why cll patients lacking functional ciap2 display a similar outcome as patients with tp53 abnormalities . transient activation of nf-b signaling is utilized by normal b - lymphocytes to promote cell survival and differentiation as a response to antigens . however , aberrant activation of nf-b is a major contributor to the oncogenesis . the loss of ciaps in a number of lymphoid malignancies results in constitutive activation of both canonical and non - canonical nf-b signaling , leading to increased survival and proliferative signals . in contrast to the oncogenic role typically attributed to iaps , these recent studies have shown a tumour - suppressing role for the ciaps in limiting nf-b activity . these studies underscore the importance of the cellular context under which ciaps are therapeutically targeted since overexpression and loss can both contribute to cancer cell progression .
cellular inhibitors of apoptosis proteins 1 and 2 ( ciap1/2 ) are members of the inhibitor of apoptosis protein ( iap ) family that has been implicated in the pathology of human cancers due to their overexpression and function as blockers of cell death in various cancers . as a result , small molecule iap antagonists have been developed and are currently under clinical evaluation for potential therapeutic use . in contrast 
 , recent evidence has indicated a tumour - suppressing role for the ciaps . 
 mutations in or loss of ciaps have been identified as molecular lesions that contribute to constitutive activation of nf-b in hematopoietic malignancies . 
 these studies reveal a context - dependent role for the ciaps wherein both their overexpression and loss may contribute to tumourigenesis .