BIRC2 (baculoviral IAP repeat-containing 2)

2009-06-01   Akiko Maeshima , Hitoshi Tsuda 

Clinical Laboratory Division, National Cancer Center Hospital, Tokyo, Japan




Atlas Image


31,436 bp, 9 exons.


3,753 bp mRNA.


Atlas Image


618 amino acids. The protein contains three motifs, i.e., BIR (Baculoviral Inhibitor of Apoptosis Repeat) domain, RING (Really Interesting New Gene)-finger domain, and CARD (Caspase Recruitment Domain).


Wide, highly expressed in large intestine, lung, endometrium, bladder and salivary gland.


Cytoplasmic and/or nucleus.


Inhibition of apoptosis by preventing the proteolytic processing of procaspase-3, procaspase-6, and procaspase-7, by inhibiting the cytochrome C-induced activation of procaspase-9; by binding to tumor necrosis factor receptor-associated factor II (TRAF2) and enhancing TRAF2-induced NF-kappaB activity that protects TRAF2 from ubiquitination in cells; by promoting the proteasome-dependent degradation of Smac/DIABLO through E3 ubiquitin ligase activity of their RING finger domains; and by direct ubiquitination of RIP1 in cancer cells and its association with the prosurvival kinase TAK1 (TGF-beta-activated kinase 1) (LaCasse et al., 2008).


Mouse, Rat.



Not found.

Implicated in

Entity name
Malignant lymphoma
All cIAP1/BIRC2, cIAP2 and XIAP were expressed in most of 240 non-Hodgkin lymphoma and all 40 Hodgkin lymphoma cell lines.
In non-Hodgkin lymphomas, cIAP1 was expressed in 73%, cIAP2 in 48% and XIAP in 15%. cIAP was positive in all precursor B-cell lymphoblastic lymphoma/leukemia and nodal marginal zone B-cell lymphoma, over 90% of follicular lymphoma and diffuse large B-cell lymphoma, and approximately 50 to 60% of myeloma, Burkitt lymphoma , lymphoplasmacytic lymphoma, small lymphocytic lymphoma/chronic lymphocytic leukemia, extranodal marginal zone B-cell lymphoma of mucosa associated lymphoid tissue (MALT-lymphoma), splenic marginal zone lymphoma, and mantle cell lymphoma.
In Hodgkin lymphomas, cIAP was positive in 75%, and were not correlated with histologic type (Akyurek et al., 2006). Treatment of diffuse large B-cell lymphoma cells with bortezomib caused apoptosis via involving the mitochondrial pathway and activation of caspases, and finally down-regulate the expression of cIAP1, XIAP and survivin (Uddin et al., 2008). Among multiple myeloma patients with increased multidrug-resistant (MDR) 1 expression after chemotherapy, those with a poor outcome exhibited significant increase in survivin, cIAP1, cIAP2, and XIAP expression by chemotherapy compared with those with a good prognosis. Similarly, in the lung resistance protein (LRP) expression-increased group, patients with a poor outcome showed significant increase of cIAP1 and cIAP2 expression compared with those with longer survival (Nakagawa et al., 2006). An integrated analysis of high-density oligonucleotide array CGH and gene expression profiling data from 155 multiple myeloma samples identified a promiscuous array of abnormalities contributing to the dysregulation of NF-KB in approximately 20% of patients. Mutations in 10 genes causing the inactivation of TRAF2, TRAF3, CYLD, cIAP1/cIAP2 and the activation of NF-kappaB1, NF-kappaB2, CD40, LTBR, TACI, and NIK that result primarily in constitutive activation of the noncanonical NF-KB pathway, with the single most common abnormality being inactivation of TRAF3 (Keats et al., 2007).
Entity name
Myelodysplastic syndrome
Overexpression of mRNA for survivin, cIAP1, NAIP and XIAP was significant in myelodysplastic syndrome bone marrow cells compared with control samples. However, the expression of mRNA for survivin, cIAP1 and cIAP2 exhibited a remarkable decrease after the development of overt leukemia (Yamamoto et al., 2004).
Entity name
Squamous cell carcinoma of head and neck (HNSCC)
Nuclear cIAP-1 expression was positive in 30% of HNSCC, was correlated with lymph node metastasis and advanced disease stage, and tend to be correlated with poor patient prognosis. Nuclear cIAP-1 expression was inversely correlated with caspase-3 expression, but was correlated with Smac/DIABLO expression. Nuclear cIAP-1 expression appears to be a useful marker for predicting poor patient prognosis in HNSCCs, and may play roles in HNSCC through the signaling pathway mediated by Smac/DIABLO and caspase-3 (Tanimoto et al., 2005). Nuclear, cytoplasmic and concurrent cIAP-1 immunoreactions were significantly correlated with lymph node metastasis in tongue SCCs. Concurrent cIAP-1 expression was inversely correlated with caspase-3, but was positively correlated with Ki-67 expression. Both nuclear and cytoplasmic patterns of cIAP-1 expression was useful markers for predicting cervical lymph node metastasis in tongue SCC (Qi et al., 2008).
Entity name
Squamous cell carcinoma (SCC) of esophagus
High copy-number amplification at 11q21-q23 was identified in cell lines derived from esophageal SCCs using comparative genomic hybridization. Only cIAP1 was consistently overexpressed in cell lines that showed amplification. cIAP1 protein was overexpressed in the primary tumors from which those cell lines had been established. cIAP1 is likely to be a target for 11q21-23 amplification and may be involved in the progression of esophageal SCC (Imoto et al., 2001).
Entity name
Squamous cell carcinoma (SCC) of uterine cervix
In the 2 of 9 cell lines of cervical SCC showed amplification and consistent overexpression of cIAP1, as well as significant resistance to radiation-induced cell death as compared with cell lines showing no cIAP1 amplification. Both overall survival and local recurrence-free survival rates were significantly lower among patients with tumors showing high levels of nuclear cIAP1 staining than among patients whose tumors revealed little or no nuclear cIAP1. Multivariate analyses showed nuclear cIAP1 staining to be an independent predictive factor for local recurrence-free survival after radiotherapy among patients with cervical SCC (Imoto et al., 2002).
Entity name
Adenoid cystic carcinoma of lacrymal gland
Expression of cIAP1, cIAP2, XIAP and survivin was higher in adenoid cystic carcinoma than in pleomorphic adenoma of the lacrymal gland (Liao et al., 2009).
Entity name
Nasopharyngeal carcinoma (NPC)
Among the IAPs family, only trancription of survivin, HIAP-1 and HIAP-2/BIRC2 was consistently up-regulated in nasopharyngeal carcinoma (NPC) and metastatic NPC tissues. Immunohistochemical staining showed that their proteins were more predominantly expressed in tumor cells nests. Survivin, HIAP-1 and HIAP-2 were upregulated by interleukin-1 alpha stimulation or EBV infection, and subsequently resulted in triggering rapid proliferation of NPC (Chua et al., 2008).
Entity name
Lung cancer
Amplification of chromosome 11q22 was detected in primary tumors and lung cancer cell lines of both non-small cell lung cancer and small cell lung cancer. Gene localized in this region included cIAP1 and cIAP2. Immunohistochemistry and western blot analysis identified cIAP1 and cIAP2 as potential oncogenes in this region as both were overexpressed in multiple lung cancers (Dai et al., 2003).
Entity name
Malignant pleural mesothelioma
IAP-1 was overexpressed in malignant pleural mesothelioma and is responsible for a large degree of the resistance of cultured mesothelioma cells to cisplatin. Levels of circulating TNF-alpha were significantly higher in mesothelioma patients prior to surgical tumor debulking compared with those after surgery. TNF-alpha could increase mRNA and protein levels of IAP-1, IAP-2 and XIAP. IAP gene expression levels were increased concomitantly with translocation to the nucleus of the TNF-responsive transcription factor NF-KB (Gordon et al., 2007).
Entity name
Renal cell carcinoma
Overexpression of cIAP1 and cIAP2 occurred in most renal cell carcinoma specimens, but 20% of the patients had lower cIAP levels in malignant than in normal tissue. The cIAP1 expression correlated with the tumor stage, levels being higher in pT1 tumors than in advanced pathological stages. Decreased cIAP1 expression in renal cell carcinoma relative to paired normal samples predicted an abbreviated time to recurrence and tumor-specific survival irrespectively of the tumor stage and grade. The prognostic effect of cIAP1 was most pronounced in patients with pT3 disease. The results of uni- and multivariate analyses suggested a prognostic value of cIAP1 expression for renal cell carcinoma patients, downregulation indicating an aggressive, potentially lethal phenotype (Kempkensteffen et al., 2007).
Entity name
Pancreatic neoplasms
cIAP1 expression was constantly high in non-neoplastic pancreatic tissues, in pancreatic intraepithelial neoplasia lesions, as well as in a subset of primary and metastatic pancreatic ductal adenocarcinomas, and a preferential cytoplasmic localisation was observed in the tumor tissues. cIAP expression was rare in a cystic tumors. Survival analyses revealed a shorter survival in patients with cIAP1/cIAP2-positive tumors (Esposito et al., 2007).
Entity name
Endometrial cancer
cIAP-1 expression was high in endometrial cancer cells expressing phospho-Akt. Akt phosphorylation decreased and apoptosis was strongly increased in PTEN-mutated endometrial cancer cells in the presence of phosphatidylinositol 3 kinase (PI3-K) inhibitor which was accompanied by a down-regulation of cIAP-1. Overexpression of Akt using a constitutively active Akt expression vector resulted in an up-regulation of cIAP-1 expression. Akt regulated endometrial cancer cell survival through the up-regulation of cIAP-1 (Gagnon et al., 2003).
Entity name
Various cancer cell lines
cIAP1 and XIAP were expressed in most cancer lines analised, with substantial variability in their relative levels. Higher levels of cIAP1 protein were associated with resistance to several anticancer drugs (Tamm et al., 2000). IAPs were induced by NF-KB or v-Rel in multiple cell lines and conversely, HIAP1 and HIAP2 activated NF-kappaB possibly forming a positive feed-back loop (LaCasse et al., 1998). cIAP1 and cIAP2 promoted cancer cell survival by functioning as E3 ubiquitin ligases that maintain constitutive ubiquitination of the RIP1 adaptor protein (Bertrand et al., 2008).


Pubmed IDLast YearTitleAuthors
169837042006Expression of inhibitor of apoptosis proteins in B-cell non-Hodgkin and Hodgkin lymphomas.Akyurek N et al
185708722008cIAP1 and cIAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination.Bertrand MJ et al
187983032008Regulation of IAPs gene family by interleukin-1 alpha and Epstein-Barr virus in nasopharyngeal carcinoma.Chua HH et al
126518742003A comprehensive search for DNA amplification in lung cancer identifies inhibitors of apoptosis cIAP1 and cIAP2 as candidate oncogenes.Dai Z et al
167751162007Overexpression of cellular inhibitor of apoptosis protein 2 is an early event in the progression of pancreatic cancer.Esposito I et al
128889212003Akt activity in endometrial cancer cells: regulation of cell survival through cIAP-1.Gagnon V et al
172535972007Inhibitor of apoptosis proteins are regulated by tumour necrosis factor-alpha in malignant pleural mesothelioma.Gordon GJ et al
122087312002Expression of cIAP1, a target for 11q22 amplification, correlates with resistance of cervical cancers to radiotherapy.Imoto I et al
115595252001Identification of cIAP1 as a candidate target gene within an amplicon at 11q22 in esophageal squamous cell carcinomas.Imoto I et al
176928052007Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma.Keats JJ et al
171541762007Expression parameters of the inhibitors of apoptosis cIAP1 and cIAP2 in renal cell carcinomas and their prognostic relevance.Kempkensteffen C et al
189316922008IAP-targeted therapies for cancer.LaCasse EC et al
189550462009Expression patterns and prognostic significance of inhibitor of apoptosis proteins in adenoid cystic carcinoma and pleomorphic adenoma of lachrymal gland.Liao Y et al
169295352006IAP family protein expression correlates with poor outcome of multiple myeloma patients in association with chemotherapy-induced overexpression of multidrug resistance genes.Nakagawa Y et al
186215062008Expression of cIAP-1 correlates with nodal metastasis in squamous cell carcinoma of the tongue.Qi S et al
108159002000Expression and prognostic significance of IAP-family genes in human cancers and myeloid leukemias.Tamm I et al
159111102005Nuclear expression of cIAP-1, an apoptosis inhibiting protein, predicts lymph node metastasis and poor patient prognosis in head and neck squamous cell carcinomas.Tanimoto T et al
188505832008S-phase kinase protein 2 is an attractive therapeutic target in a subset of diffuse large B-cell lymphoma.Uddin S et al
153803462004Expression of IAP family proteins in myelodysplastic syndromes transforming to overt leukemia.Yamamoto K et al

Other Information

Locus ID:

NCBI: 329
MIM: 601712
HGNC: 590
Ensembl: ENSG00000110330


dbSNP: 329
ClinVar: 329
TCGA: ENSG00000110330


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Ubiquitin mediated proteolysisKEGGko04120
Focal adhesionKEGGko04510
Small cell lung cancerKEGGko05222
Ubiquitin mediated proteolysisKEGGhsa04120
Focal adhesionKEGGhsa04510
Pathways in cancerKEGGhsa05200
Small cell lung cancerKEGGhsa05222
NOD-like receptor signaling pathwayKEGGko04621
NOD-like receptor signaling pathwayKEGGhsa04621
NF-kappa B signaling pathwayKEGGhsa04064
NF-kappa B signaling pathwayKEGGko04064
Hippo signaling pathwayKEGGhsa04390
Hippo signaling pathwayKEGGko04390
TNF signaling pathwayKEGGhsa04668
TNF signaling pathwayKEGGko04668
Metabolism of proteinsREACTOMER-HSA-392499
Post-translational protein modificationREACTOMER-HSA-597592
Immune SystemREACTOMER-HSA-168256
Innate Immune SystemREACTOMER-HSA-168249
Toll-Like Receptors CascadesREACTOMER-HSA-168898
Toll Like Receptor 3 (TLR3) CascadeREACTOMER-HSA-168164
MyD88-independent TLR3/TLR4 cascadeREACTOMER-HSA-166166
TRIF-mediated TLR3/TLR4 signalingREACTOMER-HSA-937061
IKK complex recruitment mediated by RIP1REACTOMER-HSA-937041
Toll Like Receptor 4 (TLR4) CascadeREACTOMER-HSA-166016
Activated TLR4 signallingREACTOMER-HSA-166054
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathwaysREACTOMER-HSA-168643
NOD1/2 Signaling PathwayREACTOMER-HSA-168638
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
TNFR2 non-canonical NF-kB pathwayREACTOMER-HSA-5668541
TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathwayREACTOMER-HSA-5676594
Signal TransductionREACTOMER-HSA-162582
Death Receptor SignallingREACTOMER-HSA-73887
TNF signalingREACTOMER-HSA-75893
Programmed Cell DeathREACTOMER-HSA-5357801
Apoptotic execution phaseREACTOMER-HSA-75153
Apoptotic cleavage of cellular proteinsREACTOMER-HSA-111465
Regulated NecrosisREACTOMER-HSA-5218859
RIPK1-mediated regulated necrosisREACTOMER-HSA-5213460
Regulation of necroptotic cell deathREACTOMER-HSA-5675482
TNFR1-induced NFkappaB signaling pathwayREACTOMER-HSA-5357956
Regulation of TNFR1 signalingREACTOMER-HSA-5357905
Apoptosis - multiple speciesKEGGko04215
Apoptosis - multiple speciesKEGGhsa04215
Platinum drug resistanceKEGGko01524
Platinum drug resistanceKEGGhsa01524
Ub-specific processing proteasesREACTOMER-HSA-5689880

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
185708722008cIAP1 and cIAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination.383
186217372008c-IAP1 and c-IAP2 are critical mediators of tumor necrosis factor alpha (TNFalpha)-induced NF-kappaB activation.200
211131352010c-IAP1 and UbcH5 promote K11-linked polyubiquitination of RIP1 in TNF signalling.125
163391512006The human anti-apoptotic proteins cIAP1 and cIAP2 bind but do not inhibit caspases.121
209324752010A cytoplasmic ATM-TRAF6-cIAP1 module links nuclear DNA damage signaling to ubiquitin-mediated NF-κB activation.106
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
178226772007A mutation of Keap1 found in breast cancer impairs its ability to repress Nrf2 activity.80
189316632008IAPs contain an evolutionarily conserved ubiquitin-binding domain that regulates NF-kappaB as well as cell survival and oncogenesis.79
125255022003Cellular inhibitor of apoptosis 1 and 2 are ubiquitin ligases for the apoptosis inducer Smac/DIABLO.70
126518742003A comprehensive search for DNA amplification in lung cancer identifies inhibitors of apoptosis cIAP1 and cIAP2 as candidate oncogenes.63


Akiko Maeshima ; Hitoshi Tsuda

BIRC2 (baculoviral IAP repeat-containing 2)

Atlas Genet Cytogenet Oncol Haematol. 2009-06-01

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