BIRC8 (baculoviral IAP repeat containing 8)

2019-07-01 Paola Cristina Branco , Paula Christine Jimenez , Joao Agostinho Machado-Neto , Let´cia Veras Costa-Lotufo Affiliation

Identity

HGNC

BIRC8

LOCATION

19q13.42

LOCUSID

112401

ALIAS

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,ILP-2,BIRC8

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.

DNA/RNA

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 (http://www.ensembl.org/): one processed transcript (1826 bases) and one transcribed processed pseudogene (1468), however, neither generated protein.

Proteins

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 (http://www.ncbi.nlm.nih.gov/homologene).

Description

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).

Mutations

Somatic

Among the 148 mutations reported in COSMIC (Catalogue of Somatic Mutations in Cancer; http://cancer.sanger.ac.uk/cancergenome/projects/cosmic) for BIRC8, 77.03% are missense substitutions, 17.57% synonymous substitutions, and 8.11% nonsense substitutions. Similar findings are reported in cBioPortal (http://www.cbioportal.org): 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 name

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 cells migratory capacity (Zhu et al., 2018).

Entity name

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 name

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 name

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 name

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 name

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).

Bibliography

Pubmed ID	Last Year	Title	Authors
16038738	2005	Bone 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
25800559	2015	Fumonisin B₁ inhibits apoptosis in HepG2 cells by inducing Birc-8/ILP-2.	Chuturgoon AA et al
24266799	2014	Differential expression of BIRC family genes in chronic myeloid leukaemia--BIRC3 and BIRC8 as potential new candidates to identify disease progression.	Glodkowska-Mrowka E et al
11597143	2001	Genomic organization of the X-linked inhibitor of apoptosis and identification of a novel testis-specific transcript.	Lagacé M et al
27028992	2016	The putative tumor activator ARHGEF3 promotes nasopharyngeal carcinoma cell pathogenesis by inhibiting cellular apoptosis.	Liu TH et al
11390657	2001	Molecular cloning of ILP-2, a novel member of the inhibitor of apoptosis protein family.	Richter BW et al
23790005	2013	Inhibitors of apoptotic proteins: new targets for anticancer therapy.	Saleem M et al
15485395	2005	The BIR domain of IAP-like protein 2 is conformationally unstable: implications for caspase inhibition.	Shin H et al
21273594	2011	Neem leaf extract induces radiosensitization in human neuroblastoma xenograft through modulation of apoptotic pathway.	Veeraraghavan J et al
23222679	2012	Inhibitor of apoptosis protein-like protein-2 as a novel serological biomarker for breast cancer.	Xiang M et al
30106449	2018	Inhibitor of apoptosis protein‑like protein‑2: A novel growth accelerator for breast cancer cells.	Zhu L et al

Other Information

Locus ID:

NCBI: 112401
HGNC: 14878
Ensembl: ENSG00000163098

Variants:

dbSNP: 112401
ClinVar: 112401
TCGA: ENSG00000163098
COSMIC: BIRC8

RNA/Proteins

Expression (GTEx)

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Ubiquitin mediated proteolysis	KEGG	ko04120
Small cell lung cancer	KEGG	ko05222
Ubiquitin mediated proteolysis	KEGG	hsa04120
Pathways in cancer	KEGG	hsa05200
Small cell lung cancer	KEGG	hsa05222
Toxoplasmosis	KEGG	ko05145
Toxoplasmosis	KEGG	hsa05145
Apoptosis - multiple species	KEGG	ko04215
Apoptosis - multiple species	KEGG	hsa04215

References

Pubmed ID	Year	Title	Citations
15485395	2005	The BIR domain of IAP-like protein 2 is conformationally unstable: implications for caspase inhibition.	13
20800603	2010	Investigation of genetic susceptibility factors for human longevity - a targeted nonsynonymous SNP study.	12
23222679	2012	Inhibitor of apoptosis protein-like protein-2 as a novel serological biomarker for breast cancer.	7
24266799	2014	Differential expression of BIRC family genes in chronic myeloid leukaemia--BIRC3 and BIRC8 as potential new candidates to identify disease progression.	5
25800559	2015	Fumonisin B₁ inhibits apoptosis in HepG2 cells by inducing Birc-8/ILP-2.	4
12372615	2002	Induction of human inhibitor of apoptosis protein-2 by shear stress in endothelial cells.	3
30106449	2018	Inhibitor of apoptosis protein‑like protein‑2: A novel growth accelerator for breast cancer cells.	0

Citation

Paola Cristina Branco ; Paula Christine Jimenez ; Joao Agostinho Machado-Neto ; Let´cia Veras Costa-Lotufo

BIRC8 (baculoviral IAP repeat containing 8)

Atlas Genet Cytogenet Oncol Haematol. 2019-07-01

Online version: http://atlasgeneticsoncology.org/gene/43169/birc8