BIRC5 (baculoviral IAP repeat containing 5)

	Figure 1. BIRC5 structure and its splices variants. BIRC5 (also kwon as survivin) presents at least five variants with biological relevance for cancer. A. The protein structure of the most common variant observed presents 142 aa and is composed of a BIR domain that is responsible for its anti-apoptotic activity and a coiled coil. B. The BIRC5 pre mRNA of the most common expressed variant is composed of 3 exons that codifies the BIR domain and the exon 4 that codifies the coiled coil. This variant present anti-apoptotic activity. Survivin Ex3 has its exon 3 deleted and an insertion of a 3'UTR, this isoform codes a protein of 143 aa and also exerts anti-apoptotic functions. Survivin-2B presents an insertion of an exon 2b located between exon 2 and exon 3, generates a protein of 165 aa with pro-apoptotic characteristics. Survivin-2α is characterized by the presence of exon 1 and 2 and the insertion of a 3'UTR, this isoform codifies a protein of 74 aa with pro-apoptotic functions. Survivin-3B presents the insertion of exon 3 b between exon 3 and exon 4, which generates a protein of 165 aa with anti-apoptotic properties. Survivin-3α presents a deletion of exon 3 and generates a protein of 78 aa whose function remain controversial. Arrows indicate the stop codon. UTR- untranslated region. Red line indicates the BIR structure.
Description	The entire BIRC5 gene is approximately 11.4 Kb (start: 78214186 and end: 78225636 bp; orientation: Plus strand).
Transcription	There are three transcript variants deposited in the NCBI database (https://www.ncbi.nlm.nih.gov/gene). In general, they present three exons (exon 1, 2 and 3) that are responsible for encoding the BIR domain, which is conserved in all BIRC family members, and the exon 4 that is related to the coiled-coil (CC) domain. Variant 1 is the predominant transcript (cDNA: 2574 bp), and encodes isoform 1 (142 amino acids [aa]). Variant 2 lacks an exon in the 3' coding region, which results in a frameshift (cDNA: 2537 bp) and, thus, in a changed protein (143 aa) with a different C-terminus from that of isoform 1 (isoform 2, also known survivin-ΔEx3). Variant 3 exhibits an alternate in-frame segment (cDNA: 2724 bp) and generates a longer (165 aa) and distinct protein (isoform 3, also known survivin-2B), compared to isoform 1. Moreover, three additional transcript variants are reported in Ensembl (http://www.ensembl.org/): a transcript variant containing 568 bp, which generates a protein of 74 aa (also known as Survivin-2α); a transcript variant with 492 bp (cDNA) that produces a protein of 121 aa (also known as Survivin-3B); and a transcript variant comprised of 386 bp (cDNA) that gives a protein of 78 aa (also known as Survivin-3α) (Figure 1).

Description	The IAPs (Inhibitors of Apoptosis Proteins) are a family of proteins primarily known for inhibiting caspase activity, either directly or indirectly, thus preventing apoptotic cell death (Gyrd-Hansen and Meier, 2010). Still, the IAPs are further implicated in key roles in other processes, such as cell cycle, cell migration, inflammation and, even, in the innate immune response (de Almagro and Vucic, 2012). Structurally, members of the IAPs are characterized by the presence of at least one BIR (Baculovirus IAP repeat) domain, which contains nearly 80 amino acid residues and carries Zn2+ in the center. Such domain is a highly conserved sequence that mediates protein-protein interactions, an essential feature for their anti-apoptotic function. Within the eight human IAPs recognized ( NAIP [BIRC1], BIRC2 [cIAP1], BIRC3 [cIAP2], XIAP [BIRC4], survivin [BIRC5], BIRC6 [bruce], BIRC7 [livin] and BIRC8 [ILP-2]) there may be between one and three BIR domains, typically arranged in their N-terminal portion (Budhidarmo and Day, 2015; Lopez and Meier, 2010). BIRC5 (survivin), the smallest among the IAPs (16.5 kDa), was discovered in 1997 (Ambrosini et al., 1997), is 142 amino acids (aa) long and has a single BIR domain (Peery et al., 2017). This protein is presented as a stable loop-shaped homodimer, formed by interactions of the N-terminal region through a predominantly hydrophobic interface (Chantalat et al., 2000; Verdecia et al., 2000). Furthermore, on the C-terminal portion, survivin carries an alpha-helix CC (coiled coil) domain, its unique structure (Chantalat et al., 2000; Coumar et al., 2013) which convenes the ability to associate to microtubules and a range of other proteins involved, mainly, in the process of mitosis, and further allowing for translocation among the different cellular compartments, such as mitochondria, cytoplasm and nucleus (Rodel et al., 2012) (Figure 1). Since BIRC5 is connected to a diverse network of biochemical processes and therefore has remarkable multifunctionality, its modulation in cancer therapy continues to be extensively explored. Several survivin inhibitors have been identified by in vitro and in silico methods, such as antisense oligonucleotides, siRNA, dominant-negative mutants, peptidomimetic molecules and other small inhibitory molecules, and even as anticancer vaccine (Fenstermaker et al., 2016; Sarvagalla et al., 2016).
Expression	BIRC5 is normally expressed in embryonic tissues and during fetal development, as well as in fast dividing normal cells (like bone marrow stem cells, basal epithelial cells and thymocytes, even if at lower concentrations), but is virtually undetectable in fully differentiated and healthy adult tissues (Adida et al., 1998; Sah et al., 2006; Stauber et al., 2007). Throughout the cell cycle, BIRC5 is expressed only during mitosis, in a highly regulated manner comprising the chromosomal passenger complex (CPC), as it interacts with tubulin and kinetochores during metaphase, then participates in central spindle organization and cytokinesis, throughout anaphase (Szafer-Glusman et al., 2011). However, BIRC5 is expressed in cells that undergo malignant transformation, being overexpressed in numerous tumors (Altieri, 2001; LaCasse et al., 2008). Recent studies evidenced that transcriptional activation is not the only cause for BIRC5 overexpression, but also post-transcriptional regulation, specially coordinated by many alternative polyadenylation (APA) sites. For instance, in ovarian cancer, aberrant APA leads to shortening of the 3'-UTR region, enabling escape from negative regulation of miRNAs and causing up-regulation of BIRC5 (He et al., 2016). Clinically, overexpression of BIRC5 has been correlated with a poor prognosis of cancer, resistance to apoptosis induced by chemotherapy, decreased survival of patients and greater chances of relapse (Islam et al., 2000; Rodel et al., 2012).
Localisation	BIRC5 is located both in the cytoplasm and in the nucleus. Nuclear expression has been associated with a poor prognosis and chemoresistance (Du et al., 2015), which may differ among the different types of cancers (Shintani et al., 2013). BIRC5 splice variants were also related to subcellular localization. This has been shown in samples from acute myeloid leukemia patients, where wild-type survivin and the 2B splice variant were expressed in the nucleus, cytoplasm or both, whereas the ΔEx3 isoform was only expressed in the nucleus (Serrano-Lopez et al., 2013). However, considering pro-survival factors, localization is not the only relevant feature: it has been recently demonstrated that BIRC5 can be packaged into extracellular vesicles (endosomes) and its delivery may be guided by antiapoptosis stimuli from cancer cells and tumor microenvironment, inducing pro-survival competences in fibroblasts after treatment with paclitaxel. Conversely, knockdown of BIRC5 in those vesicles promoted increased cell sensitivity to chemotherapeutic agents (Kreger et al., 2016).
	Figure 2. BIRC5: a multitask protein. BIRC5 (survivin) acts on cytoplasm and nucleus and is involved different cellular functions: cell survival, cell cycle progression, mitotic spindle formation and transcription activation. In cytoplasm, BIRC5 modulates apoptosis pathway by binding to and blocking initiator caspase 9 and effectors caspases 3 and 7, demonstrating to be involved in extrinsic and intrinsic apoptosis and contributing to cell survival. BIRC5 may be blocked by SMAC/DIABLO, a factor released by mitochondria. Also BIRC5 potentiates apoptosis inhibition through stabilization of BIRC4 (also kwon as XIAP). TGF-β signaling negatively regulates BIRC 5 by phosphorylating SMAD protein. p53-mediated signaling also downregulates BIRC5 functions. CDC phosphorylates BIRC5 and promotes its binding to CDK4 that may be translocated to nucleus, and thus promotes cell cycle progression. In nucleus, BIRC5 is involved in the mitotic spindle formation modulated by Wnt pathway through the phosphorylation inhibiton and nuclear translocation of β-catenin activating BIRC5 and associated to other proteins (not shown) form the Chromosomal Passenger Complex (CPC). The transcription activation of BIRC5 mRNA is mainly promoted by β-catenin, STAT3 (signal transducer and activator of transcription-3) and HIF 1 α (hypoxia-inducible factor-1α).
Function	Studies have shown that overexpression of BIRC5 inhibits both the intrinsic and extrinsic pathways of apoptosis and the depletion of survivin in human cell culture impairs apoptosis and triggers cell division defects (Li et al., 1998; Roy et al., 2015). The antiapoptotic mechanism of BIRC5 still needs to be better clarified, however, both the direct or indirect binding of BIRC5 to caspases are proposed (Figure 2) (Altieri, 2013; Garg et al., 2016; Li et al., 1998). Evidences also indicate that BIRC5 binds to XIAP, one of the best studied IAPs, forming a complex that protects XIAP against ubiquitination and proteosomal degradation. This complex then activates multiple signaling pathways, including NF-κB, inhibits caspases CASP3, CASP7 and CASP9, suppresses apoptosis and accelerates tumor progression. Other cytoprotective mechanisms have been proposed for BIRC5, including the ability of mitochondrial BIRC5 to sequester the pro-apoptotic DIABLO (Smac) protein from its binding to BIRC4 (also known as XIAP), or even preventing its release from mitochondria (Altieri, 2013; Coumar et al., 2013; Song et al., 2003). Interaction of BIRC5 with CDK4 has been associated with progression of the cell cycle. In mitosis, BIRC5 plays a key role in integrating the transient chromosome complex (CPC), along with INCENP, CDCA8 (borealin) and AURKB, which controls the formation and stabilization of the mitotic spindle (Altieri, 2013; Coumar et al., 2013). Activation of Wnt signaling induces β-catenin ( CTNNB1) and BIRC5 nuclear translocation, which contributes in mitotic spindle formation, further regulating CPC, β-catenin, STAT3 and HIF1A (Figure 2). BIRC5 also appears to be involved in the cellular response to stress through the interaction with various chaperones, such as AIP, HSPD1 (HSP60) and HSP90AA1 (HSP90) (Altieri, 2013; Fortugno et al., 2003). Moreover, BIRC5 also partakes in the process of autophagy (Wang et al., 2011) and in DNA repair among several tumor cell lines (Jiang et al., 2009). BIRC5 has also been shown to induce cell motility, metastasis and increased colonization capacity by AKT-mediated upregulation of the α5 integrin pathway in a melanoma model (McKenzie et al., 2013). Additionally, BIRC5 plays an important role in angiogenesis, contributing to endothelial cell proliferation and migration, which was then linked to increased β-catenin protein levels that consequently promotes an elevated expression of BIRC5 and VEGF (Fernandez et al., 2014). BIRC5 is also directly involved in enhancing anoikis resistance through miR-141/KLF12/Sp1/survivin axis. It is a consensus that anoikis resistance is crucial for establishing a metastatic niche and consequently promoting cancer progression and dissemination (Mak et al., 2017). Dissimilar functions have been attributed to the different isoforms of BIRC5. Survivin-2α and survivin-2B portray a proapoptotic activity profile, whereas Survivin-ΔEx3 and Survivin-3B show prominent antiapoptotic activity, with similar activities to those of survivin itself. These distinct variants can predict aggressiveness of cancer phenotype, thus contributing to prognosis (Caldas et al., 2005). BIRC5 can be released from tumor cells in exosomes (Khan et al., 2011). This information provided new insights into biomarkers for determination of early diagnosis and also to predict prognosis. In this context, the splice variant survivin-2B, in breast cancer, was shown to be expressed mostly in primary tumors and exclusively in early stage disease. Conversely, Survivin-ΔEx3 variant was most commonly expressed in late stages of breast cancer (Khan et al., 2014). Survivin-2B has been further reported to promote cell death in some cancer cells by promoting autophagy followed by cell death induced by accumulation and stabilization of IKBKB (IKKB) in the nucleus (Shi et al., 2014).
Homology	The BIRC5 gene is highly homologous among different species, as shown in Table 1, which demonstrates the comparison of variant 1 among different species. Table 1. Comparative identity of human BIRC5 with other species % Identity for: Homo sapiens BIRC5 Symbol Protein DNA vs. P. troglodytes BIRC5 98.3 98.8 vs. M. mulatta BIRC5 97.9 97.9 vs. C. lupus BIRC5 90.8 90.1 vs. B. taurus BIRC5 90.1 90.1 vs. M. musculus Birc5 83.6 82.6 vs. R. norvegicus Birc5 83.0 81.3 vs. G. gallus BIRC5 60.6 65.7 vs. X. tropicalis birc5.2 57.8 64.2 vs. D. rerio Birc5a 54.3 58.0 (Source: http://www.ncbi.nlm.nih.gov/homologene)

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