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BIRC8 (baculoviral IAP repeat containing 8)

Written2019-07Paola Cristina Branco, Paula Christine Jimenez, João Agostinho Machado-Neto, Let´cia Veras Costa-Lotufo
Department of Pharmacology, Institute of Biomedical Sciences of the University of São Paulo, São Paulo, (PCB); (JAM-N); (LVC-L) Brazil; Department of Marine Sciences, Federal University of Sao Paulo, Santos, (PCJ), Brazil.

Abstract BIRC8, also known as ILP-2, is a homologous protein of BIRC4, however, its function has seldom been addressed. Despite the similarity with other Inhibitory Apoptosis Proteins (IAPs), there is evidence that BIRC8 acts in a peculiar manner, by impeding apoptosis induced by BAX without directly inhibiting the activity of caspases. BIRC8 expression has been detected in testis and lymphoblastic normal cells and, furthermore, it has been reported in different cancers, including breast carcinoma, hematological neoplasms, hepatocellular carcinoma, nasopharyngeal carcinoma, and neuroblastoma. However, the specific implications of such protein for treatment and prognosis must be further evaluated. In this review, current data on RNA, DNA, protein and the association of BIRC8 in cancer are presented.

Keywords BIRC8; apoptosis; Inhibitory Apoptosis Proteins; cancer

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Alias (NCBI)Baculoviral IAP Repeat Containing 8
Inhibitor of Apoptosis-Like Protein 2
IAP-Like Protein 2
Baculoviral IAP Repeat-Containing Protein 8
Testis-Specific Inhibitor of Apoptosis
HGNC Alias symbILP-2
HGNC Alias nameIAP-like protein 2
 inhibitor of apoptosis-like protein 2
HGNC Previous namebaculoviral IAP repeat-containing 8
LocusID (NCBI) 112401
Atlas_Id 43169
Location 19q13.42  [Link to chromosome band 19q13]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)


  Figure 1. BIRC8 structure. BIRC8 (also kwon as ILP-2) protein structure presents 236 aa and is composed of a Baculovirus IAP Repeat (BIR) domain, an Ubiquitin-associated (UBA) domain, and a RING finger domain.
Description The entire BIRC8 gene is approximately 2 kb (start: 53289601 and end: 53291622 bp; orientation: Minus strand). The BIRC8 cDNA contains 1 exon, 2022 bases and generates a protein with 236 amino acids. Two additional transcripts are deposited in Ensembl ( one processed transcript (1826 bases) and one transcribed processed pseudogene (1468), however, neither generated protein.


Description The BIRC8 protein contains a BIR3 domain, which is conserved among other Inhibitory Apoptosis Proteins (IAPs) members. Also, it contains an UBA domain, for ubiquitin binding, and a RING domain, with E3 ligase function. This protein presents a total of 236 amino acids and a molecular weight of 27 kDa.
The coding sequence of ILP-2 (BIRC8) is very similar to that of XIAP (ILP-1 or BIRC4), with 80% identity (95% homology) at the amino acid level (Richter et al., 2001). When analyzing the genomic organization of the BIRC4 locus, Lagacé et al. (2001) identified a cross-reactive band that encodes a gene that expressed a 2 kb novel transcript, homologous to BIRC4, called BIRC8. The same study demonstrated that overexpression of this gene protects cells against BAX-induced apoptosis. Additionally, it contains a putative open reading frame (ORF) that is homologous to the carboxy-terminal end of BIRC4 (Lagacé et al., 2001). However, such similarity does not follow the biochemical interaction with caspases, supported by the fact that the putative caspase 9 interaction domain is a weak inhibitor and conformationally unstable, thus leading to an inability of BIRC8 to independently inhibit CASP9 (caspase 9) (Shih et al., 2005).
Expression In normal tissues, BIRC8 (ILP-2) expression has only been detected in the cytoplasm of testis and lymphoblastoid cells (Richter et al., 2001; Lagacé et al., 2001). On the other hand, when assessed in cancer cells, BIRC8 was shown to be aberrantly expressed.
Function BIRC8 is known to protect cells against intrinsic apoptosis induced by BAX and caspase 9, however, the function of this IAP has not been completely elucidated. Nevertheless, it has been shown that BIRC8 may not operate independently and requires cooperation with yet unidentified cellular proteins (Shin et al, 2005). Moreover, BIRC8 seems to play a role in immune-related functions due to its multiple leukocyte Ig-like receptors, natural killer cells, ICAMs and Fc receptors (FcRs) (Saleem et al., 2013).
Furthermore, BIRC8 undertakes a role in transformation and progression of different cancers, by protecting cells from BAX-mediated apoptosis (Chuturgoon et al., 2015; Glodkowska-Mrowka et al., 2013; Zhu et al., 2018).
Homology At the amino acid sequence level, BIRC8 presents 80% identity and 95% homology with BIRC4. There are only a few data deposited on BIRC8 homology among different species. Still, it has been shown that there is 98.3% and 98.6% identity in BIRC8 protein and DNA, respectively, between Homo sapiens and Pan troglodytes (


Somatic Among the 148 mutations reported in COSMIC (Catalogue of Somatic Mutations in Cancer; for BIRC8, 77.03% are missense substitutions, 17.57% synonymous substitutions, and 8.11% nonsense substitutions. Similar findings are reported in cBioPortal ( among the 52666 cancer samples accessed, somatic mutations in BIRC8 occur in 0.3% of the tested samples (corresponding to 145 mutations, of which 127 are missense substitutions, 17 truncated genes, and 1 other mutation).

Implicated in

Entity Breast cancer
Note BIRC8 expression was evaluated in serum samples from patients with breast cancer and compared to that of either healthy women, women bearing galactophore hyperplasia, patients, with other types of cancer, or to post-breast cancer surgery patients. Increased expression was observed in patients with breast cancer when compared to those bearing other cancers or other breast pathologies, indicating that serum levels of BIRC8 may be a biomarker for breast cancer (Xiang et al., 2012).
BIRC8 overexpression was also observed in 59 tissue paraffin-embedded blocks, which including 35 breast cancer tissues and 24 galactophore hyperplasia tissues and in the breast cancer cell lines HCC-1937, MX-1 and MCF-7. Still, to verify the precise role of BIRC8, silencing experiments revealed that inhibition of BIRC8 induced apoptosis, corroborating to its pro-survival function in breast cancer cells. Additionally, BIRC8 depletion led to reduced breast cell migration, demonstrating that this gene is not only involved in sustaining breast cancer, but also in supporting the cell's migratory capacity (Zhu et al., 2018).
Entity Chronic myeloid leukemia
Note BIRC8 expression was evaluated in chronic myeloid leukemia (CML) patients and, opposite to what is expected for BIRC genes in tumor progression, a significant decrease in BIRC8 expression was observed following the development of tyrosine kinase inhibitor resistance in chronic phase CML patients. Such observation allows for speculation that BIRC8 does not display a classical apoptosis inhibition function in leukemia cells (Glodkowska-Mrowka et al., 2013).
Entity Hepatocellular carcinoma
Note Liver cancer induced by the mycotoxin fumonisin B1 (FB1), produced by Fusarium sp., leads to apoptosis resistance in the HepG2 cell line. A panel of 84 apoptosis-associated genes was evaluated after HepG2 cell exposure to FB1 and increased BIRC8 mRNA (5.7 fold) and protein (2.3 fold) expressions were detected, implying that BIRC8 contributes to liver tumorigenesis (Chuturgoon et al., 2015).
Entity Myelodysplastic syndrome
Note BIRC8 levels, along with Apallon and BIRC7, were significantly increased in bone marrow cells of myelodysplastic syndromes, even when compared to leukemia cells. Such feature may suggest that these BIRC proteins are transiently overexpressed at the very early stage of leukemia transformation, acting as a trigger for the expression of other IAPs members, like BIRC5 and BIRC4 (Abe et al., 2005).
Entity Nasopharyngeal Carcinoma
Note BIRC8 expression mediated by an up-regulation of the Rho-guanine nucleotide exchange factor 3 gene, ARHGEF3, contributed to the onset and progression of nasopharyngeal carcinoma. The factor ARHGEF3 plays a key role in the growth of such cancer. It has been demonstrated that depletion of ARHGEF3, using siRNA, induced apoptosis by a 5-fold down-regulation of BIRC8 expression in nasopharyngeal carcinoma cell lines (Liu et al., 2016).
Entity Neuroblastoma
Note BIRC8 was inhibited in neuroblastoma xenograft models after treatment with Azadirachta indica extract, contributing to radiosensitization and leading to cell death. This action was caused through the activation of pro-apoptotic signaling and inhibition of antiapoptotic genes, including the IAP members NAIP, BIRC6, and BIRC8 (Veeraraghavan et al., 2011).

To be noted

Acknowledgments: The authors wish to acknowledge the financial support provided by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) under the following processes: 2017/09022-8; 2015/17177-6 and 2017/24993-0.


Bone marrow cells of myelodysplastic syndromes exhibit significant expression of apollon, livin and ILP-2 with reduction after transformation to overt leukemia
Abe S, Yamamoto K, Hasegawa M, Inoue M, Kurata M, Hirokawa K, Kitagawa M, Nakagawa Y, Suzuki K
Leuk Res 2005 Sep;29(9):1095-6
PMID 16038738
Fumonisin B inhibits apoptosis in HepG2 cells by inducing Birc-8/ILP-2
Chuturgoon AA, Phulukdaree A, Moodley D
Toxicol Lett 2015 Jun 1;235(2):67-74
PMID 25800559
Differential expression of BIRC family genes in chronic myeloid leukaemia--BIRC3 and BIRC8 as potential new candidates to identify disease progression
Glodkowska-Mrowka E, Solarska I, Mrowka P, Bajorek K, Niesiobedzka-Krezel J, Seferynska I, Borg K, Stoklosa T
Br J Haematol 2014 Mar;164(5):740-2
PMID 24266799
Genomic organization of the X-linked inhibitor of apoptosis and identification of a novel testis-specific transcript
Lagacé M, Xuan JY, Young SS, McRoberts C, Maier J, Rajcan-Separovic E, Korneluk RG
Genomics 2001 Oct;77(3):181-8
PMID 11597143
The putative tumor activator ARHGEF3 promotes nasopharyngeal carcinoma cell pathogenesis by inhibiting cellular apoptosis
Liu TH, Zheng F, Cai MY, Guo L, Lin HX, Chen JW, Liao YJ, Kung HF, Zeng YX, Xie D
Oncotarget 2016 May 3;7(18):25836-48
PMID 27028992
Molecular cloning of ILP-2, a novel member of the inhibitor of apoptosis protein family
Richter BW, Mir SS, Eiben LJ, Lewis J, Reffey SB, Frattini A, Tian L, Frank S, Youle RJ, Nelson DL, Notarangelo LD, Vezzoni P, Fearnhead HO, Duckett CS
Mol Cell Biol 2001 Jul;21(13):4292-301
PMID 11390657
Inhibitors of apoptotic proteins: new targets for anticancer therapy
Saleem M, Qadir MI, Perveen N, Ahmad B, Saleem U, Irshad T, Ahmad B
Chem Biol Drug Des 2013 Sep;82(3):243-51
PMID 23790005
The BIR domain of IAP-like protein 2 is conformationally unstable: implications for caspase inhibition
Shin H, Renatus M, Eckelman BP, Nunes VA, Sampaio CA, Salvesen GS
Biochem J 2005 Jan 1;385(Pt 1):1-10
PMID 15485395
Neem leaf extract induces radiosensitization in human neuroblastoma xenograft through modulation of apoptotic pathway
Veeraraghavan J, Aravindan S, Natarajan M, Awasthi V, Herman TS, Aravindan N
Anticancer Res 2011 Jan;31(1):161-70
PMID 21273594
Inhibitor of apoptosis protein-like protein-2 as a novel serological biomarker for breast cancer
Xiang M, Zhou W, Gao D, Fang X, Liu Q
Int J Mol Sci 2012 Dec 7;13(12):16737-50
PMID 23222679
Inhibitor of apoptosis proteinlike protein2: A novel growth accelerator for breast cancer cells
Zhu L, Zhou W, Zhu X, Xiang S, Wang S, Peng Y, Lu B, Tang P, Chen Q, Wu M, Peng X, Chen Z, Sun Z, Yang K, Xiang M, Yu D
Oncol Rep 2018 Oct;40(4):2047-2055
PMID 30106449


This paper should be referenced as such :
Paola Cristina Branco, Paula Christine Jimenez, João Agostinho Machado-Neto, Letècia Veras Costa-Lotufo
BIRC8 (baculoviral IAP repeat containing 8)
Atlas Genet Cytogenet Oncol Haematol. 2020;24(05):194-196.
Free journal version : [ pdf ]   [ DOI ]

External links


HGNC (Hugo)BIRC8   14878
Entrez_Gene (NCBI)BIRC8    baculoviral IAP repeat containing 8
AliasesILP-2; ILP2; RNF136; hILP2
GeneCards (Weizmann)BIRC8
Ensembl hg19 (Hinxton)ENSG00000163098 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000163098 [Gene_View]  ENSG00000163098 [Sequence]  - [Contig_View]  BIRC8 [Vega]
ICGC DataPortalENSG00000163098
TCGA cBioPortalBIRC8
Genatlas (Paris)BIRC8
SOURCE (Princeton)BIRC8
Genetics Home Reference (NIH)BIRC8
Genomic and cartography
GoldenPath hg38 (UCSC)BIRC8  -  
GoldenPath hg19 (UCSC)BIRC8  -  
GoldenPathBIRC8 - [CytoView hg19]  BIRC8 - [CytoView hg38]
Genome Data Viewer NCBIBIRC8 [Mapview hg19]  
Gene and transcription
Genbank (Entrez)AF420440 BC039318 BC046168 BC056914 BC071665
RefSeq transcript (Entrez)NM_033341
Consensus coding sequences : CCDS (NCBI)BIRC8
Gene ExpressionBIRC8 [ NCBI-GEO ]   BIRC8 [ EBI - ARRAY_EXPRESS ]   BIRC8 [ SEEK ]   BIRC8 [ MEM ]
Gene Expression Viewer (FireBrowse)BIRC8 [ Firebrowse - Broad ]
GenevisibleExpression of BIRC8 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)112401
GTEX Portal (Tissue expression)BIRC8
Human Protein AtlasENSG00000163098-BIRC8 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ96P09   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ96P09  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ96P09
Domaine pattern : Prosite (Expaxy)BIR_REPEAT_1 (PS01282)    BIR_REPEAT_2 (PS50143)    ZF_RING_2 (PS50089)   
Domains : Interpro (EBI)BIR_rpt    XIAP/BIRC8_UBA    Znf_RING    Znf_RING/FYVE/PHD   
Domain families : Pfam (Sanger)BIR (PF00653)   
Domain families : Pfam (NCBI)pfam00653   
Domain families : Smart (EMBL)BIR (SM00238)  RING (SM00184)  
Conserved Domain (NCBI)BIRC8
PDB (RSDB)1XB0    1XB1   
PDB Europe1XB0    1XB1   
PDB (PDBSum)1XB0    1XB1   
PDB (IMB)1XB0    1XB1   
Structural Biology KnowledgeBase1XB0    1XB1   
SCOP (Structural Classification of Proteins)1XB0    1XB1   
CATH (Classification of proteins structures)1XB0    1XB1   
AlphaFold pdb e-kbQ96P09   
Human Protein Atlas [tissue]ENSG00000163098-BIRC8 [tissue]
Protein Interaction databases
IntAct (EBI)Q96P09
Ontologies - Pathways
Ontology : AmiGOnucleus  cytoplasm  spindle microtubule  apoptotic process  protein ubiquitination  positive regulation of protein ubiquitination  cysteine-type endopeptidase inhibitor activity involved in apoptotic process  negative regulation of apoptotic process  negative regulation of cysteine-type endopeptidase activity involved in apoptotic process  metal ion binding  regulation of cell cycle  ubiquitin protein ligase activity  positive regulation of canonical Wnt signaling pathway  
Ontology : EGO-EBInucleus  cytoplasm  spindle microtubule  apoptotic process  protein ubiquitination  positive regulation of protein ubiquitination  cysteine-type endopeptidase inhibitor activity involved in apoptotic process  negative regulation of apoptotic process  negative regulation of cysteine-type endopeptidase activity involved in apoptotic process  metal ion binding  regulation of cell cycle  ubiquitin protein ligase activity  positive regulation of canonical Wnt signaling pathway  
Pathways : KEGGUbiquitin mediated proteolysis    Apoptosis    Toxoplasmosis    Pathways in cancer    Small cell lung cancer   
NDEx NetworkBIRC8
Atlas of Cancer Signalling NetworkBIRC8
Wikipedia pathwaysBIRC8
Orthology - Evolution
GeneTree (enSembl)ENSG00000163098
Phylogenetic Trees/Animal Genes : TreeFamBIRC8
Homologs : HomoloGeneBIRC8
Homology/Alignments : Family Browser (UCSC)BIRC8
Gene fusions - Rearrangements
Fusion : QuiverBIRC8
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerBIRC8 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)BIRC8
Exome Variant ServerBIRC8
GNOMAD BrowserENSG00000163098
Varsome BrowserBIRC8
ACMGBIRC8 variants
Genomic Variants (DGV)BIRC8 [DGVbeta]
DECIPHERBIRC8 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisBIRC8 
ICGC Data PortalBIRC8 
TCGA Data PortalBIRC8 
Broad Tumor PortalBIRC8
OASIS PortalBIRC8 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICBIRC8  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DBIRC8
Mutations and Diseases : HGMDBIRC8
LOVD (Leiden Open Variation Database)[gene] [transcripts] [variants]
DgiDB (Drug Gene Interaction Database)BIRC8
DoCM (Curated mutations)BIRC8
CIViC (Clinical Interpretations of Variants in Cancer)BIRC8
NCG (London)BIRC8
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Genetic Testing Registry BIRC8
NextProtQ96P09 [Medical]
Target ValidationBIRC8
Huge Navigator BIRC8 [HugePedia]
Clinical trials, drugs, therapy
Protein Interactions : CTDBIRC8
Pharm GKB GenePA25365
Clinical trialBIRC8
DataMed IndexBIRC8
PubMed19 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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