BIRC6 (Baculoviral IAP repeat-containing 6)

2014-10-01   Sze Ue Iris Luk , Yuzhuo Wang 




The BIRC6 gene (BRUCE\/APOLLON) encodes the cytoplasmic protein BIRC6 in mammals, consisting of a single N-terminal baculoviral IAP repeat (BIR) domain and a C-terminal ubiquitin-conjugating (UBC) domain. Of the huge protein size at 528 kDa, BIRC6 demonstrated pleiotropic functions including inhibition of apoptosis, cytoprotection, regulation of cytokinesis, mitosis, autophagy and neutrophil differentiation. With the BIR domain, BIRC6 is defined as a member of the Inhibitor of Apoptosis (IAP) family. Through its BIR domain, BIRC6 binds to active caspases, including caspases-3, 6, 7 and 9 and accounts for its ability to inhibit the caspase cascade and ultimately apoptosis. The UBC domain has chimeric E2\/E3 ubiquitin ligase activity where it facilitates proteosomal degradation of various proteins, including pro-apoptotic proteins p53, caspases, Smac and mitotic regulator cyclin A. More importantly, the UBC domain plays an indispensable role in embryonic development in mammals and spermatogenesis in Drosophila. Increasing evidence supports the cancer promoting role of BIRC6. Elevated BIRC6 expression has been found in a variety of cancers and was shown to contribute to treatment resistance.



The BIRC6 gene comprises 75 exons resulting in a transcript of 16066 bps. The ATG is in the first exon.


Only one variant of BIRC6 has been found so far which comprises 14490 bps. There are several synonymous and nonsynonymous SNPs reported for BIRC6 (E589K, L1742F, R2187T, T2646S, T3708N, E3864K, Q4323H, N4324Y, S4325C, N4326T, P4329R).


Not known. There is evidence for a processed pseudogene in M. musculus.


Atlas Image
BIRC6 is a component of the apoptosis regulatory network. Multiple protein-protein interactions allow a switch from apoptosis inhibition to inactivation in later steps in apoptosis. BIRC6s action on activated caspases and other pro-apoptotic molecules might be restricted to the trans-Golgi network and the vesicular system.


BIRC6 contains two functionally validated domains: A N-terminal BIR repeat (SMART SM00238, aa: 256-332) and a C-terminal UBC domain (SMART SM00212, aa: 4548 - 4712). The BIR repeat is needed for interactions with caspases and IAP-binding motif (IBM) containing proteins (HtrA2, Smac). The UBC domain can form a thiolester linkage with ubiquitin transferred by E1.
Between aa 1589-1633 a coiled-coil region can be found.


BIRC6 is highly expressed in brain, testis, lymphatic cells and secretory organs and also found in any other tissues (Hauser et al., 1998). It is highly expressed in the mouse embryos up to E11 and then transcript levels drop. Single-cell RNA cytometry analysis revealed a bi-modal distributed Birc6 mRNA expression heterogeneity within mouse hematopoietic stem cell (HSC) population. Upon ageing, BIRC6-high expressing HSC cells were shown to out-compete Birc6-low cells (Dimov et al., 2014). BIRC6 is frequently elevated in various cancer tissues.


Localized to membranes of the trans Golgi network (TGN) and the endosomal system (Hauser et al., 1998). BIRC6 relocalizes considerably during the cell cycle. It concentrates in a pericentriolar compartment in interphase, moves partially to spindle poles in metaphase, and finally localizes to the spindle midzone and the midbody in telophase and during cytokinesis (Pohl and Jentsch, 2008).


Inhibitor of apoptosis. BIRC6 is a peripheral membrane protein of the trans-Golgi network that protects cells from apoptosis by functioning as an inhibitor of apoptosis protein (IAP). BIRC6 can bind and inhibit activated caspases CASP-3, CASP-6, CASP-7, CASP-8 and CASP-9. Furthermore it ubiquitylates caspase-9, HtrA2 (a pro-apoptotic serine protease) and DIABLO/Smac (a competitor for caspase-IAP interactions) thereby targeting them for proteasomal degradation. The ubiquityltion reactions do not require an ubiquitin E3 ligase making BIRC6 a chimeric E2/E3 ubiquitin ligase (Bartke et al., 2004; Hao et al., 2004). More importantly, distinct from other IAP members, BIRC6 is able to antagonize both precursor and mature forms of Smac and caspase-9. The ability to antagonize precursor apoptotic molecules represents an important mechanism for the prevention of apoptosis under normal conditions (Qiu and Goldberg, 2005). On the other hand, BIRC6 also inhibits apoptosis via negatively regulating p53 protein levels by facilitating its degradation via ubiquitination (Ren et al., 2005; Tang et al., 2014).
BIRC6 and treatment resistance. Silencing of BIRC6 has been shown to sensitize cancer cells to various anticancer agents, including 5-fluorouracil (in cervical, fibrosarcoma and breast cancer cells) (Chu et al., 2008), oxaliplatin and cisplatin (in colonospheres) (Van Houdt et al., 2011), MEK inhibitor, BRAFV600E-specific inhibitor and soluble or membrane-bound TRAIL (in melanoma cells) (Tassi et al., 2012), cisplatin (in non-small cell lung cancer and glioma) (Dong et al., 2013; Chen et al., 1999), camptothecin (glioma) (Chen et al., 1999) and sorafenib (in hepatoma) (Tang et al., 2014).
Essential in embryonic development. Targeted disruption of BIRC6 in mice caused embryonic and neonatal lethality. BIRC6 homozygous-mutant embryos which did not express BIRC6 all died immediately after birth. At E18.5, viable mutant embryos had normal appearance, but were significantly smaller (10-20% less body weight) than control littermates. Macroscopic analysis of mutant embryos at E15.5 revealed that more than half of them had severely defective angiogenesis that often coincided with severe oedema (Hao et al., 2004). Consistantly, BIRC6 knock-out mice showed retarded growth and poor vascularization from E13.5 and perinatal lethality (Lotz et al., 2004). BIRC6 mutant mice were embryonic lethal (Hitz et al., 2000; Ren et al., 2005).
Regulator of cytokinesis. BIRC6 is a major regulator of abscission, the final stage of cytokinesis. During cytokinesis, BIRC6 moves from the vesicular system to the midbody ring and serves as a platform for the membrane delivery machinery and mitotic regulators. Depletion of BIRC6 in cell cultures causes defective abscission and cytokinesis-associated apoptosis, accompanied by a block of vesicular targeting and defective formation of the midbody and the midbody ring. BIRC6 coordinates multiple steps required for abscission including the relocalization of ubiquitin from midbody microtubules to the midbody ring during cytokinesis (Pohl and Jentsch, 2008).
Novel regulator of mitosis. BIRC6 interacts with cyclin A and promotes its degradation in early mitosis. BIRC6 also interacts with APC/C, and it facilitates cyclin A ubiquitylation. The elimination of cyclin A and cyclin B are essential for entry into mitosis. BIRC6 -deficient MEF cells exhibit earlier replicative senescence, large nuclei with excess centrosome, and mitotic delay. BIRC6 facilitates the ubiquitylation of CYCLIN A by recruiting it to APC/C without the need of a functional UBC domain, suggesting its role as a substrate recognition subunit in a complex of ubiquitin ligase (Kikuchi et al., 2014).
BIRC6 and autophagy. Functional BIRC6 is required to inhibit autophagy under nutrient-rich conditions in D. melanogaster oogenesis. Lack of BIRC6 function in BIR-domain deleted flies resulted in an increase in both autophagic punctate and TUNEL staining in germaria and degenerating midstage egg chambers (Hou et al., 2008). On the contrary, recent evidence suggested that BIRC6 may promote autophagy in prostate cancer cells. Silencing of BIRC6 was showed to decrease Beclin-1 protein, LC3 cleavage and reduce LC3 punctate formation (Low et al., 2013).

Regulation of BIRC6
Despite the ability of BIRC6 to target caspases, Smac and HtrA2, BIRC6 is also negatively regulated by these pro-apoptotic molecules. Caspase-3 and HtrA2 are capable of cleaving BIRC6 and inhibit its anti-apoptotic function. Smac inhibits the IAP function of BIRC6 by its ability to block BIRC6-caspase binding (Bartke et al., 2004; Sekine et al., 2005). Nrdp1, a RING finger containing ubiquitin ligase, promotes proteasomal degradation of BIRC6 (Qiu et al., 2004).
Epstein-Barr Virus (EBV) microRNAs (miRNAs) processed from the BHRF1 and BamHI A rightward (BART) transcript, miR-BART15-3p, targets the 3 untranslated region (UTR) of BIRC6. miR-BART15-3p inhibits the translation of BIRC6 protein in EBV-infected gastric carcinoma cells and contributes to host cells apoptosis induction (Choi et al., 2013). In muscle, prostaglandin F2a upregulates BIRC6 which promotes muscle cell survival and growth (Jansen and Pavlath, 2008).

Atlas Image
Summary of the pleiotropic functions of BIRC6.


- ubc-17 (C. elegans)
- IAP6 (A. gambiae)
- Bruce (D. melanogaster)
- BIRC6 (X. tropicalis)
- Birc6 (M. musculus)



There are several synonymous and nonsynonymous SNPs reported for BIRC6 (E589K, L1742F, R2187T, T2646S, T3708N, E3864K, Q4323H, N4324Y, S4325C, N4326T, P4329R).

Implicated in

Entity name
Myelodysplastic syndromes
Bone marrow cells of myelodysplastic syndromes exhibit significant expression of BIRC6 (Abe et al., 2005).
Entity name
Childhood acute myeloid leukemia
BIRC6 elevation associated with poor prognosis in childhood de novo Acute Myeloid Leukemia: BIRC6 overexpression (>median expression) was associated with an unfavorable day 7 response to induction chemotherapy and also associated with a poorer 3-year relapse-free survival rate (Sung et al., 2007).
BIRC6 mRNA expression was associated with the differentiation status of AML cells.
BIRC6 mRNA expression was induced upon neutrophil differentiation of AML cells, whereas knocking-down BIRC6 attenuates neutrophil differentiation of APL cells without altering cell survival.
AML patient samples with the t(8;21), the t(15;17) or a complex karyotype express BIRC6 significantly lower than normal human granulocytes (Schläfli et al., 2012).
Entity name
Colorectal cancer
BIRC6 expression increased in colorectal cancer tissue and stem-like cells enriched colonosphere.
BIRC6 mRNA expression was significantly up-regulated in primary colorectal cancer tissues compared with normal mucosa (Bianchini et al., 2006). Moreover, BIRC6 protein highly up-regulated in patient derived colonosphere compared with differentiated counterpart. Knockdown of BIRC6 sensitized colonosphere against the chemotherapeutic drugs oxaliplatin and cisplatin in vitro. (Van Houdt et al, 2011).
Entity name
Brain cancers
Elevated expression in brain cancers.
BIRC6 knockdown induces apoptosis in neuroblastoma cells and associated with increased DIABLO protein expression in cytoplasm (Lamers et al., 2012). It is also overexpressed in glioma cell lines (SF-268, SNB-78) (Chen et al., 1999).
Frequent gain of the BIRC6 gene on chromosome 2 neuroblastoma tumors, which resulted in increased BIRC6 mRNA expression (Lamers et al., 2012).
Entity name
BIRC6 is constitutively expressed in melanoma and promote resistance to antitumor agents.
BIRC6 was constitutively expressed by melanoma cells, in vitro and in patient samples, and at higher levels than in benign melanocytic lesions. Melanoma susceptibility to apoptosis by cytotoxic drugs fotemustine and target-specific inhibitors (MEK inhibitor and BRAFV600E-specific inhibitor) correlated with down-modulation of BIRC6 protein. The antitumor agents promoted BIRC6 downmodulation, is caspase independent and proteasome dependent. Moreover, targeting of BIRC6, by siRNA, significantly enhanced caspase-dependent melanoma apoptosis in response to cytotoxic drugs, MEK, and BRAFV600E inhibitors and soluble or membrane-bound TRAIL (Tassi et al., 2012).
Entity name
Non-small cell lung cancer (NSCLC)
Elevated expression in non-small cell lung cancer (NSCLC).
BIRC6 down-regulation inhibited growth of the NSCLC cells and sensitized the cells to cisplatin in vitro.
Elevated BIRC6 protein expression in NSCLC tissues was associated with poor 3-year relapse-free patient survival, regional lymph node metastasis, and advanced pathological tumor, node, metastasis stage. (Dong et al., 2013).
Entity name
Prostate cancer
BIRC6 is elevated in advanced prostate cancer and important in promoting growth and suppressing apoptosis.
Elevated BIRC6 protein expression was found in prostate cancer cell lines and clinical specimens compared to benign tissue. In particular, increased BIRC6 expression was associated with Gleason 6-8 cancers, castration resistance, higher clinical T stages and correlates with the presence of poor prognostic factors including PSA recurrence, lymph node metastasis and prostatic capsule invasion (Low et al., 2013; Luk et al., 2014).
Entity name
Epithelial ovarian cancer
Elevated expression and poor prognostic factor in epithelial ovarian cancer.
BIRC6 expression was higher in the epithelial ovarian cancer (EOC) tissue than in normal control tissue at protein level.
BIRC6 was an independent significant predictor for overall survival and disease-free survival. Cytoplasmic BIRC6 expression is associated with EOC differentiation (Wang et al., 2014).
Entity name
Hepatocellular carcinoma (HCC)
BIRC6 promotes hepatocellular carcinogenesis and associates with poor patient survival and prognosis.
BIRC6 knockdown suppressed hepatoma cell proliferation, caused G1/S arrest and sensitized hepatoma cells to sorafenib-induced apoptosis in vitro and in vivo.
BIRC6 overexpression was significantly correlated with serum alanine aminotransferase level and HCC vascular invasion in patient samples. Patients with BIRC6 positive expression in tumor tissue had a poor survival and a high rate of recurrence (Tang et al., 2014).
Entity name
Breast cancer
BIRC6 promotes cell growth and inhibiting apoptosis in breast cancer cells with wild type p53.
BIRC6 knockdown resulted in a marked decline of cell growth and an increased rate of apoptosis in wild-type p53 ZR75.1 cells, which was associated with p53 stabilisation and activation of the mitochondrial-dependent apoptotic pathway. A less pronounced anti-proliferative and pro-apoptotic effects were observed in mutant p53 breast cancer cells (Lopergolo et al., 2009).
Entity name
Pseudoexfoliative glaucoma (PEXG)
Polymorphism in the BIRC6 Gene plays a protective role in Pseudoexfoliative Glaucoma.
TT allele of the rs2754511 in the BIRC6 gene plays a protective role in PEXG patients of the Pakistani population (Ayub et al., 2014).


Pubmed IDLast YearTitleAuthors
160387382005Bone marrow cells of myelodysplastic syndromes exhibit significant expression of apollon, livin and ILP-2 with reduction after transformation to overt leukemia.Abe S et al
251187082014Association of a polymorphism in the BIRC6 gene with pseudoexfoliative glaucoma.Ayub H et al
152009572004Dual role of BRUCE as an antiapoptotic IAP and a chimeric E2/E3 ubiquitin ligase.Bartke T et al
167731882006Comparative study of gene expression by cDNA microarray in human colorectal cancer tissues and normal mucosa.Bianchini M et al
105440191999A human IAP-family gene, apollon, expressed in human brain cancer cells.Chen Z et al
236781702013Epstein-Barr virus-encoded microRNA BART15-3p promotes cell apoptosis partially by targeting BRUCE.Choi H et al
182396052008Oncolytic adenovirus-mediated shRNA against Apollon inhibits tumor cell growth and enhances antitumor effect of 5-fluorouracil.Chu L et al
246679952014Discriminating cellular heterogeneity using microwell-based RNA cytometry.Dimov IK et al
232878532013Elevated expression of BIRC6 protein in non-small-cell lung cancers is associated with cancer recurrence and chemoresistance.Dong X et al
153002552004Apollon ubiquitinates SMAC and caspase-9, and has an essential cytoprotection function.Hao Y et al
96288971998A giant ubiquitin-conjugating enzyme related to IAP apoptosis inhibitors.Hauser HP et al
158872672005Progressive loss of the spongiotrophoblast layer of Birc6/Bruce mutants results in embryonic lethality.Hitz C et al
187943302008Effector caspase Dcp-1 and IAP protein Bruce regulate starvation-induced autophagy during Drosophila melanogaster oogenesis.Hou YC et al
185666032008Prostaglandin F2alpha promotes muscle cell survival and growth through upregulation of the inhibitor of apoptosis protein BRUCE.Jansen KM et al
243027282014APOLLON protein promotes early mitotic CYCLIN A degradation independent of the spindle assembly checkpoint.Kikuchi R et al
227889202012Identification of BIRC6 as a novel intervention target for neuroblastoma therapy.Lamers F et al
192239052009Apollon gene silencing induces apoptosis in breast cancer cells through p53 stabilisation and caspase-3 activation.Lopergolo A et al
154859032004BRUCE, a giant E2/E3 ubiquitin ligase and inhibitor of apoptosis protein of the trans-Golgi network, is required for normal placenta development and mouse survival.Lotz K et al
234090572013BIRC6 protein, an inhibitor of apoptosis: role in survival of human prostate cancer cells.Low CG et al
250710092014The BIRC6 gene as a novel target for therapy of prostate cancer: dual targeting of inhibitors of apoptosis.Luk SU et al
153404452004An Apollon vista of death and destruction.Martin SJ et al
183293692008Final stages of cytokinesis and midbody ring formation are controlled by BRUCE.Pohl C et al
155074512005The membrane-associated inhibitor of apoptosis protein, BRUCE/Apollon, antagonizes both the precursor and mature forms of Smac and caspase-9.Qiu XB et al
147651252004Nrdp1-mediated degradation of the gigantic IAP, BRUCE, is a novel pathway for triggering apoptosis.Qiu XB et al
156403522005The Birc6 (Bruce) gene regulates p53 and the mitochondrial pathway of apoptosis and is essential for mouse embryonic development.Ren J et al
232111882012BIRC6 (APOLLON) is down-regulated in acute myeloid leukemia and its knockdown attenuates neutrophil differentiation.Schläfli AM et al
157812612005HtrA2 cleaves Apollon and induces cell death by IAP-binding motif in Apollon-deficient cells.Sekine K et al
162362532005Bruce/apollon promotes hippocampal neuron survival and is downregulated by kainic acid.Sokka AL et al
177855652007Overexpression of Apollon, an antiapoptotic protein, is associated with poor prognosis in childhood de novo acute myeloid leukemia.Sung KW et al
251962172015BIRC6 promotes hepatocellular carcinogenesis: interaction of BIRC6 with p53 facilitating p53 degradation.Tang W et al
225533422012Role of Apollon in human melanoma resistance to antitumor agents that activate the intrinsic or the extrinsic apoptosis pathways.Tassi E et al
217884032011Comparative proteomics of colon cancer stem cells and differentiated tumor cells identifies BIRC6 as a potential therapeutic target.Van Houdt WJ et al
115163432001Inhibitor of apoptosis proteins and their relatives: IAPs and other BIRPs.Verhagen AM et al
121216272002Drosophila Bruce can potently suppress Rpr- and Grim-dependent but not Hid-dependent cell death.Vernooy SY et al
244530322014Expression and clinical significance of BIRC6 in human epithelial ovarian cancer.Wang L et al

Other Information

Locus ID:

NCBI: 57448
MIM: 605638
HGNC: 13516
Ensembl: ENSG00000115760


dbSNP: 57448
ClinVar: 57448
TCGA: ENSG00000115760


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Ubiquitin mediated proteolysisKEGGko04120
Ubiquitin mediated proteolysisKEGGhsa04120
Apoptosis - multiple speciesKEGGko04215
Apoptosis - multiple speciesKEGGhsa04215


Pubmed IDYearTitleCitations
183293692008Final stages of cytokinesis and midbody ring formation are controlled by BRUCE.77
153002552004Apollon ubiquitinates SMAC and caspase-9, and has an essential cytoprotection function.73
290748492017The circular RNA circBIRC6 participates in the molecular circuitry controlling human pluripotency.54
147651252004Nrdp1-mediated degradation of the gigantic IAP, BRUCE, is a novel pathway for triggering apoptosis.45
217884032011Comparative proteomics of colon cancer stem cells and differentiated tumor cells identifies BIRC6 as a potential therapeutic target.31
155074512005The membrane-associated inhibitor of apoptosis protein, BRUCE/Apollon, antagonizes both the precursor and mature forms of Smac and caspase-9.28
208197782010MicroRNA-related genetic variations as predictors for risk of second primary tumor and/or recurrence in patients with early-stage head and neck cancer.21
192239052009Apollon gene silencing induces apoptosis in breast cancer cells through p53 stabilisation and caspase-3 activation.19
257338712015BRUCE regulates DNA double-strand break response by promoting USP8 deubiquitination of BRIT1.17
251962172015BIRC6 promotes hepatocellular carcinogenesis: interaction of BIRC6 with p53 facilitating p53 degradation.16


Sze Ue Iris Luk ; Yuzhuo Wang

BIRC6 (Baculoviral IAP repeat-containing 6)

Atlas Genet Cytogenet Oncol Haematol. 2014-10-01

Online version:

Historical Card

2006-11-01 BIRC6 (Baculoviral IAP repeat-containing 6) by  Christian Pohl,Stefan Jentsch 

Department of Molecular Cell Biology, Max-Planck-Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried\\\/Munich, Germany