Introduction

Apoptosis is of crucial importance for the development and homeostasis of the immune system. Hematopoietic progenitor cells that do not receive appropriate survival signals from the microenvironment are removed by apoptosis.¹ In lymph nodes, the development of the immune repertoire occurs through the elimination of cells with nonfunctional or self-reactive receptors. The activation and expansion of lymphocytes after an encounter with antigen is also tightly regulated by pro- and antiapoptotic mechanisms.^{2, 3} Failure of lymphocytes to undergo apoptosis can promote malignant transformation and the development of lymphomas.² This is illustrated by the observation that the antiapoptotic gene Bcl-2 is involved in the t(14;18) translocation in follicular Non-Hodgkin's lymphoma.⁴ More recently, it was shown that another antiapoptotic gene, c-IAP2, is targeted by the t(11;18) translocation in MALT lymphoma.⁵ Both Bcl-2 and c-IAP2 are members of protein families with distinct roles in apoptosis regulation.

Cellular survival is an intricate balance between factors that either promote or inhibit apoptosis. Several pathways and protein families together set a threshold for apoptosis to assure that apoptosis only takes place in response to an appropriate death signal, whereas cell death is prevented when cellular survival is required. Two pathways act as sensors for death signals and can activate the cellular cell death program of apoptosis (Figure 1a). The extrinsic or receptor-mediated pathway involves members of the TNF receptor (TNFR) superfamily and is engaged in response to cytokines and extracellular signals.^{6, 7} The intrinsic pathway is activated in response to intracellular signals and cytotoxic insults and is mediated by members of the Bcl-2 family at the level of mitochondria.^{8, 9} These two pathways control the activation of caspases. Caspases are the executioners of apoptosis, whose proteolytic activity leads to cleavage of cellular substrates and disassembly of the cell (Figure 1a). Recently, a new category of regulators of apoptosis has been identified by the discovery of inhibitor of apoptosis (IAP) family proteins. IAPs are endogenous inhibitors of caspases which allows them to set the threshold for apoptosis-induction in both the extrinsic and intrinsic pathways.

Figure 1.

(a) Cell death signals can activate apoptosis through the extrinsic receptor pathway or the intrinsic mitochondrial pathway. Both pathways result in the formation of adaptor complexes that lead to activation of caspases and subsequent disassembly of the cell. The IAP family can inhibit caspase activation and plays a key role in the regulation of apoptosis. Apaf-1, apoptosis protease activating factor-1; Cyt c, cytochrome c; DISC, death-inducing signaling complex. (b) Schematic representation of eight human IAPs with indicated functional domains. The C-terminal RING finger in some IAPs is a Zn-binding domain with supposed ubiquitin ligase activity. The CARD motif has a proposed function in protein interactions. BIR, baculoviral IAP repeat containing; NAIP, neuronal apoptosis inhibitory protein; Ts-IAP, testis-specific IAP; UBC, ubiquitin-conjugating domain; XIAP, X-linked IAP.

Full figure and legend (80K)

IAPs were first identified in baculoviruses^{10, 11} and since then many more IAPs have been discovered.^{12, 13, 14, 15, 16, 17, 18, 19, 20, 21} They belong to a family of homologous proteins characterized by the presence of one or more baculoviral IAP repeat (BIR) domains, together with an ability to suppress apoptosis. So far, eight human IAPs have been identified with different structural domains that can modulate apoptosis pathways in several ways (Figure 1b).^{22, 23, 24}

Caspase inhibition

Through their BIR domains IAPs can bind to and inhibit caspases. Specific interactions between IAPs and caspases can be mapped to various BIR domains. In IAPs with three BIR domains, the third BIR mediates binding and inhibition of caspase-9. Caspase-9 is an initiator caspase, which is particularly capable of processing and activating other caspases. To fulfill this initiator function, caspase-9 needs to be activated, which requires its homodimerization. Interaction with the third BIR domain of IAPs prevents the homodimerization and activation of caspase-9 (Figure 2a).^{25, 26, 27} The second BIR domain and the preceding linker region mediate the interaction of IAPs with caspase-3 and -7. Caspase-3 and -7 are effector caspases that are activated by initiator caspases. These effector caspases can proteolytically process cellular substrates with which they interact. Binding of IAPs to caspases prevents caspase interaction with cellular substrates and thus inhibits the proteolytic degradation of the cell that marks the final execution stage of apoptosis (Figure 2b).^{28, 29, 30, 31, 32} IAPs with one single BIR domain can inhibit caspase-3 and -7 or caspase-9.^{17, 21, 33} Of all IAPs, XIAP appears to be the most potent inhibitor of caspases.^{31, 34, 35}

Figure 2.

Mechanisms of caspase inhibition by IAPs. (a) Caspase-9 is inhibited through interaction with the third BIR domain of XIAP, which prevents homodimerization of caspase-9 and keeps caspase-9 in an inactive monomeric state. B, XIAP inhibits caspase-3 (and caspase-7) by interaction of BIR2 and the preceding linker region with active caspase-3 dimer, which prevents the interaction of caspase-3 dimers with their substrates.

Full figure and legend (52K)

Protein degradation

Several IAPs contain a RING finger, which is a domain that often possesses ubiquitin ligase activity (Figure 1b).²³ Ubiquitin ligases can target specific proteins for ubiquitination and subsequent degradation by the proteasome.³⁶ IAPs are also involved in protein degradation. Target proteins of IAPs include caspase-3 and -7^{37, 38} and the proapoptotic protein SMAC (second mitochondria-derived activator of caspases),^{39, 40} whose degradation may contribute to repression of caspase activity and apoptosis by IAPs (Figure 3). In addition, IAPs can promote their own degradation by targeting themselves for ubiquitination in response to apoptotic stimuli (Figure 4).⁴¹ It therefore remains to be investigated whether the ubiquitin ligase activity of IAPs enhances or represses their antiapoptotic function. IAPs may initially serve to inhibit caspases and promote their degradation to prevent a complete apoptotic response by low amounts of active caspases, induced in the absence of a true apoptotic stimulus.²⁴ Apoptotic stimuli may shift the balance from target ubiquitination to autoubiquitination of IAPs (eg through binding of dimeric substrates, which brings IAP molecules in close proximity to each other). This could lead to depletion of intracellular IAP stores, thus releasing caspases from IAP repression and allowing caspases to fulfill their apoptotic function. IAPs may thus set the threshold for apoptosis induction.

Figure 3.

IAPs control the threshold for apoptosis-induction through different mechanisms. IAPs interfere with apoptosis by direct inhibition of caspases (a). IAPs also promote ubiquitination and proteasomal degradation of proapoptotic molecules (indicated by arrow with 'ub') like caspases and SMAC (b). In addition, several IAPs can induce NF-B and other signaling pathways that promote survival by transcriptional regulation of survival genes, including IAPs (c).

Full figure and legend (62K)

Figure 4.

Regulatory mechanisms that control IAPs; regulating the regulators of apoptosis. IAPs can target themselves for proteasomal degradation (indicated by arrow with 'ub') in an autoregulatory negative feedback loop (a). IAPs also serve as substrates for caspases and are proteolytically processed during apoptosis (b). Proteins released from mitochondria during apoptosis, like SMAC (c) and Omi/HtrA2 (d) can interact with IAPs, which releases caspases from inhibition by IAPs. In addition, Omi/HtrA2 has serine protease activity, which may promote degradation of IAPs (d). XAF1 may antagonize IAP inhibition of apoptosis by sequestering XIAP in the nucleus (e).

Full figure and legend (55K)

Apart from autoubiquitination, turnover of IAPs may be enhanced through proteolytic processing by caspases during apoptosis (Figure 4). Both XIAP and c-IAP1 can be cleaved by caspases in vitro,^{42, 43, 44} but the physiological significance is unknown. The proteolytic fragments of IAPs that are yielded by caspase processing may have retained or reduced caspase-inhibitory capacities, or may even have shifted toward proapoptotic activity in case of c-IAP1.^{45, 46}

IAP-regulating proteins

In addition to the mechanisms that control the IAP turnover, a number of proteins have been identified that regulate IAP activity. SMAC^{47, 48} and Omi/HtrA2^{49, 50, 51, 52} are proteins that reside in the mitochondrial intermembrane space and translocate to the cytosol during apoptosis. Subsequent processing of SMAC and Omi/HtrA2 exposes an IAP-binding motif, which mediates interactions with IAPs. These interactions promote apoptosis, because SMAC and Omi/HtrA2 compete with caspases for binding to IAPs and can liberate caspases from IAP repression (Figure 4). SMAC can interact with several IAPs, including XIAP, c-IAP1, c-IAP2, Survivin and Livin^{47, 53} and thereby interferes with inhibition of caspase-3, -7 and -9.^{54, 55, 56} Omi/HtrA2 interferes with XIAP inhibition of caspases and may also promote cell death through a mechanism that involves the serine protease activity of Omi/HtrA2^{49, 50, 57} and degradation of IAPs.^{58, 59, 60, 61}

XIAP-associated factor 1 (XAF1) is a nuclear protein with IAP-regulating capacity that was identified by virtue of its interaction with XIAP.⁶² XAF1 is shown to antagonize XIAP inhibition of caspases and subsequent apoptosis. XAF1 also triggers the translocation of XIAP from the cytosol to the nucleus.⁶³ The sequestration of IAPs within the nucleus could prevent their inhibitory interaction with cytosolic caspases and may represent an additional mechanism by which IAPs are controlled (Figure 4).

Signaling

The antiapoptotic activity of some IAPs may be enhanced by their involvement in intracellular signaling pathways (Figure 5). Several members of the IAP family have been implicated in the NF-B (nuclear factor B) signaling pathway. NF-B is a transcription factor that is kept in an inactive state in the cytosol through interaction with I-B (inhibitor of B). Phosphorylation of I-B by kinases leads to ubiquitination and subsequent proteasomal degradation of I-B. This releases NF-B from the inhibitory interaction with I-B and allows translocation of NF-B to the nucleus, where it induces transcription of NF-B responsive genes (Figures 3 and 5).^{64, 65} Activation of the NF-B pathway constitutes an important survival signal,^{66, 67} which is probably mediated by transcriptional regulation of prosurvival genes. These include several antiapoptotic Bcl-2 homologues (Bcl-2, Bcl-xL, A1/Bfl-1),^{68, 69, 70, 71, 72} the caspase-inhibitor FLIP (FLICE-inhibitory protein)⁷³ and decoy death receptor DcR1.⁷⁴ Signaling through the NF-B pathway is particularly important for the regulation of immune and inflammatory responses⁶⁴ and survival of lymphocytes.^{75, 76}

Figure 5.

IAPs are involved in several signaling pathways with mutual interactions. Interaction of c-IAP1 and c-IAP2 with TRAFs on the cytoplasmic tail of TNF receptors can activate nuclear factor-B (NF-B) signaling and induces the expression of prosurvival genes, including IAPs. IAPs are also implicated in other signaling pathways, such as JNK1 and PI-3K/Akt.

Full figure and legend (55K)

c-IAP1 and c-IAP2 have been identified as proteins that interact with TRAFs in signaling complexes on the cytoplasmic tail of TNF receptors.^{13, 14} c-IAP1 and cIAP2 activate NF-B signaling through TRAFs (Figure 5). Inhibition of TNF-induced apoptosis is mediated through NF-B and requires interactions of c-IAP1, c-IAP2 and TRAFs.^{77, 78} XIAP may also induce NF-B signaling through activation of mitogen-activated protein kinases (Figure 5).^{44, 79} Activation of NF-B signaling induces expression of c-IAP1, c-IAP2 and XIAP.^{77, 78, 80} This provides evidence for a positive feedback mechanism by which induction of IAPs can lead to further NF-B activation and enhancement of the antiapoptotic signal by induction of additional survival genes (Figures 3 and 5).

Other signaling pathways that can be activated by IAPs include the JNK1 signaling cascade, which is required for suppression of apoptosis by XIAP, NAIP and Livin⁸¹ and the PI-3K/Akt signaling pathway, implicated in XIAP-mediated survival (Figure 5).^{82, 83}

IAPs and cancer

Acquired resistance to apoptosis is a hallmark of most types of cancer^{84, 85} as it provides the opportunity for malignant cells to escape cellular checkpoints that detect abnormalities within the cell or its direct surroundings. Furthermore, deregulated apoptosis pathways are critically involved in therapy resistance of many tumors, since chemo- and radiotherapy largely depend on the induction of apoptosis.⁸⁶ Since the discovery of IAPs in the 1990 s, many studies have revealed links between members of the IAP family and cancer. Several members of the IAP family have been discovered based on their expression in cancer cells, like Apollon in brain cancer cells²⁰ and Livin in melanoma.¹⁸

Survivin is not expressed in most adult differentiated tissues, but is prominently expressed in many tumors.¹⁶ The cancer-specific expression of Survivin has been validated by many studies in tumors originating from many different tissues,⁸⁷ including Non-Hodgkin's lymphoma^{88, 89, 90} and leukemia.^{91, 92, 93, 94} Furthermore, Survivin expression is correlated with unfavorable cancer characteristics such as aggressive behavior, shortened survival, resistance to therapy and increased risk for recurrences.⁸⁷ Deregulated expression of Survivin has been found in neuroblastoma and ovarian cancer.^{95, 96} Survivin has also been identified as one of the genes whose expression is repressed by p53,^{97, 98, 99} a tumor suppressor gene that is mutated in many human cancers.¹⁰⁰

This widespread involvement of Survivin in cancer may be explained by its involvement in both apoptosis and cell replication; two mechanisms critical for malignant transformation. Survivin appears to preferentially inhibit the intrinsic mitochondrial pathway of apoptosis through inhibition of caspase-9.^{101, 102, 103} In addition, Survivin plays an essential role in mitosis, demonstrated by the lethal phenotype of Survivin knockout mouse embryos with severe cell division defects¹⁰⁴ and the involvement of Survivin in microtubule stability.^{105, 106}

XIAP is expressed in many cancer cell lines and XIAP expression inversely correlates with survival and remission in acute myeloid leukemia.¹⁰⁷ High levels of XIAP expression are found in Hodgkin's lymphoma B cells.¹⁰⁸ XIAP expression is associated with resistance to chemotherapy in many malignancies,^{109, 110, 111, 112} including myeloid leukemia.¹¹³ Although the evidence for the involvement of XIAP in the development of cancer is largely circumstantial, studies on XIAP-antagonist XAF1 (Figure 4) have provided new insights. XAF1 is ubiquitously expressed in normal tissues, but its expression in cancer cell lines is very low, possibly due to allelic loss of the Xaf1 gene.^{62, 63} Furthermore, recent studies in human gastric tumors have shown that aberrant methylation of the Xaf1 promotor leads to reduced XAF1 levels.¹¹⁴ These data suggest that XAF1 may be a tumor suppressor gene that is involved in XIAP-mediated apoptosis resistance in cancer.

The chromosome region 11q21–q23 where c-IAP1 and c-IAP2 genes are localized, is a region of chromosomal amplification in many malignancies.²⁴ c-IAP1 and c-IAP2 have recently been identified as candidate oncogenes that are overexpressed in lung cancer.¹¹⁵ c-IAP1 is also a candidate target gene in oesophageal squamous cell carcinoma.¹¹⁶ A correlation between c-IAP1 expression and chemoresistance is found in leukemia, endometrial and cervical cancer.^{117, 118, 119} In a recent study, we have shown that several lymphoid malignancies could be distinguished from other lymphoid malignancies and control samples, based on their expression of three IAP genes c-IAP2, Survivin and c-IAP1.¹²⁰ This indicates a differential expression of these IAP genes and a possible role in lymphomagenesis. Overexpression of c-IAP2 has been reported in neutrophilic leukemia¹²¹ and bladder cancer.¹²² Evidence for direct involvement of c-IAP2 in lymphomagenesis comes from studies in MALT lymphoma. The translocation t(11;18), which occurs in approximately 50% of cases of MALT lymphoma, results in fusion of c-IAP2 to the Mlt locus, encoding a novel protein MALT1 with distant homology to caspases.^{5, 123} The fusion product encompasses a truncated c-IAP2 with intact BIR domains 1–3, but without the C-terminal RING and in most cases also the CARD domain.^{5, 123, 124, 125} The c-IAP2 fusion product may have retained apoptosis-repressing capacity through its BIR domains. Truncation of the RING motif may abrogate autoubiquitination and disable the negative feedback loop of c-IAP2. The fusion protein is also thought to contribute to lymphomagenesis through its enhanced ability to activate NF-B signaling.¹²³ The t(11;18) translocation is associated with advanced stages of MALT lymphoma and nuclear expression of Bcl-10.¹²⁶ Bcl-10 is also capable of activating NF-B signaling and is able to bind to MALT1 and the c-IAP2/MALT1 fusion product.^{123, 127} These data suggest that the c-IAP2/MALT1 fusion protein and Bcl-10 cooperate in MALT lymphoma oncogenesis by enhancing NF-B activation.

There are more examples besides MALT lymphoma of the involvement of signaling pathways that can be mediated by IAPs in cancer. Many genetic alterations in the NF-B pathway are observed in leukemias and lymphomas.¹²⁸ Activation of the NF-B pathway is implicated in malignant transformation of multiple myeloma,¹²⁹ mantle cell lymphoma¹³⁰ and diffuse large B-cell lymphoma of the activated B-cell subtype.¹³¹ In leukemia, c-IAP1, c-IAP2, XIAP and Survivin expression is associated with the PI-3K/Akt pathway and therapy resistance.^{83, 103, 132} Furthermore, transformation of myeloid cells is accompanied by PI-3K/Akt-mediated induction of NF-B and c-IAP2.¹³³

IAPs as targets for cancer therapy

The emerging role of IAPs in cancer has prompted investigations into the use of IAPs as targets for cancer therapy. Several approaches are currently under investigation. The promising results of antisense Bcl-2 in clinical trials involving several hematological malignancies^{134, 135, 136} have prompted studies addressing the use of antisense oligonucleotides to target other apoptosis-regulating genes, including IAPs. Antisense XIAP has been shown to induce apoptosis and to sensitize primary acute myeloid leukemia blasts to chemotherapy.⁸³ Antagonizing Survivin by antisense approaches also showed promising results both in vitro by apoptosis-induction in leukemia and lymphoma cells^{99, 137} and in vivo by reducing lymphoma development and growth in murine xenograft models.^{137, 138} Furthermore, the cancer-specific expression of Survivin has elicited studies investigating the therapeutic use of siRNA and dominant-negative mutant Survivin to antagonize Survivin function.^{87, 139} Other strategies aim to elicit an immune response against malignant cells expressing Survivin. Immunoreactivity against Survivin has been found in several cancers.^{140, 141, 142} Survivin-specific cytotoxic T-cell responses could be generated against human acute myeloid leukemia blasts and against murine lymphoma in an engraftment model.^{143, 144} The potential of Livin for immunotherapy is investigated in melanoma.¹⁴⁵ Of the IAP-regulating proteins, SMAC is investigated for its therapeutic potential in cancer. Strategies to enhance SMAC expression or the use of SMAC peptides have shown to increase chemosensitivity of several cancers in vitro and in xenograft models.^{146, 147, 148, 149}

The involvement of the NF-B pathway in many cancers suggests that inhibition of this pathway might provide new tools to fight cancer. Several in vitro studies have shown that inhibition of the NF-B pathway could induce apoptosis in myeloma, lymphoma and leukemia patient cells and may be beneficial for the treatment of these malignancies.^{150, 151, 152, 153, 154} Of particular interest are the clinical trials using the proteasome inhibitor PS-341 (VELCADE/bortezomib). Proteasome inhibition downregulates the NF-B pathway and decreases the expression of IAPs and other antiapoptotic genes.^{153, 155, 156} Members of the IAP family may be important targets for proteasome inhibitors like PS-341, because these inhibitors can interfere with IAPs in two ways: through their effect on NF-B signaling, which may alter IAP expression and through inhibition of proteasomal activity, which may affect IAP function. It was shown that the proteasome inhibitor PS-341 can enhance the sensitivity of cancer cells to chemotherapy and is involved in overcoming multiple drug resistance.¹⁵⁷ Furthermore, PS-341 appears to be clinically effective against multiple myeloma, Non-Hodgkin's lymphomas, refractory chronic lymphocytic leukemia and Hodgkin's lymphoma.^{157, 158} Studies with PS-341 in other malignancies are on the way.

Together these data suggest that members of the IAP family may play critical roles in the development of lymphomas and leukemias. Therapies that target IAPs may therefore prove to be beneficial for several types of cancer and could improve the efficiency of current treatment strategies.

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