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