The entire SIVA1 gene is about 15.3 Kb and contains 4 exons (Start: 105219437 bp and End: 105234831; Orientation: plus strand). Two alternatively-spliced transcript variants encoding distinct proteins have been described, SIVA1 transcript variant 1, which is the predominant transcript variant with a cDNA containing 790 bp (codifying the SIVA1 protein), and the SIVA1 transcript variant 2 lacking the exon 2 with a cDNA containing 595 bp (codifying the SIVA2 protein).

Ubiquitous.

SIVA1 is found in the nucleus and cytoplasm (Figure 2).

The proapoptotic function of SIVA1 is well elucidated and characterized. SIVA1 binds to death receptors, including CD27 and TNFRSF18, and plays a role in the transduction of the proapoptotic signal by the extrinsic pathway (Prasad et al., 1997; Spinicelli et al., 2002). SIVA1 interacts with BCL2 and BCL-XL, abrogates their antiapoptotic functions and modulates the intrinsic apoptosis pathway (Chu et al., 2004; Chu et al., 2005). In addition, SIVA1 associates with XIAP and regulates the apoptosis mediated by NFkB and JNK signaling (Resch et al., 2009). The SIVA gene is a transcription target of p53, p73 and E2F1 and is upregulated under stress or following DNA damage (Ray et al., 2011; Fortin et al., 2004).
Recently, novel partners and functions have been attributed to SIVA1. SIVA1 binds to and regulates p53 stability by acting as an adapter protein between p53 and MDM2, and participates in an auto-regulatory feedback loop between p53 and SIVA1 (Du et al., 2009; Mei and Wu, 2012). SIVA1 associates with ARF, enabling its ubiquitination and degradation; this mechanisms also regulates the p53/MDM2 signaling pathway (Wang et al., 2013).
Finally, SIVA1 is a novel adaptor protein that promotes Stathmin 1/CaMKII interaction. SIVA1 inhibits Stathmin 1 activity through Stathmin 1 phosphorylation at serine 16, which results in reduced cell migration and metastasis by stabilizing microtubules of tumor cells (Li et al., 2011). The main functions and signaling pathways of SIVA1 are illustrated in Figure 3.

The binding partners of SIVA1 are:
CD27: SIVA1 was initially identified by two-hybrid (Y2H) screening using CD27 as a bait, and its interaction was confirmed by immunoprecipitation (IP) of 293 cells co-expressing both proteins (Prasad et al., 1997). In agreement, Yoon et al. found that murine Siva1 and Siva2 also bind to CD27 (Yoon et al., 1999).
c-abl oncogene 2, non-receptor tyrosine kinase (ABL2): Y2H screening using ABL2 (previously known as ARG) as the bait identified SIVA1 as a binding partner. This protein association was confirmed by IP of MCF7 cells co-expressing FLAG-ABL2 and GFP-SIVA1 (Cao et al., 2001).
Tumor necrosis factor receptor superfamily, member 18 (TNFRSF18): TNFRSF18 (previously known as GITR) presents high homology with CD27. The interaction between TNFRSF18 and SIVA1 was identified using GST pull down and IP assays (Spinicelli et al., 2002).
BCL2-like 1 (BCL-XL): The association of BCL-XL and SIVA1 was first identified using purified GST-SIVA and BCL-XL proteins and confirmed by GST pull down assays using GST-SIVA1 in 293 cells expressing the GFP-BCL-XL protein (Xue et al., 2002). Later on, Chu et al. reported that the SAH region of SIVA1 was sufficient to specifically interact with BCL-XL (Chu et al., 2004).
B-cell CLL/lymphoma 2 (BCL2): The association of BCL2 and SIVA1 was verified using GST pull down assays with GST-SIVA in Cos-7 cells overexpressing full-length BCL2 protein, and this interaction occurred at the SAH region of SIVA1 (Chu et al., 2004).
CD4: Y2H screen using cytoplasmic domain of CD4 as the bait identified SIVA1. This protein interaction was confirmed by in vitro binding assays with GST-SIVA1. The interaction was mapped through GST pull-down assay using GST tagged deletion mutants of SIVA1; the C-terminal region of SIVA1 binds to the cytoplasmic domain of CD4 (Py et al., 2007).
Lysophosphatidic acid receptor 2 (LPAR2): Y2H screening using the C-terminal region of LPAR2 as the bait identified SIVA1. GST pull-down assays confirmed this protein association and the SIVA1 C-terminal region (aa 139-175) is required for this interaction (Lin et al., 2007).
Pyrin (MEFV): Y2H screening using Pyrin as the bait identified SIVA1 binding, and this association was confirmed by IP. Using deletion mutants of Pyrin and of SIVA1 or SIVA2, the C-terminal, rfp and SRPY domain of pyrin were found to interact with the N-terminal region of SIVA (Balci-Peynircioglu et al., 2008).
X-linked inhibitor of apoptosis (XIAP): Y2H screening using XIAP as the bait identified SIVA1 binding, and this protein association was confirmed by IP of 293 cells co-expressing both proteins (Resch et al., 2009).
FHL1 four and a half LIM domains 1 (FHL1): Y2H screening using the SLIMMER isoform of FHL1 as the bait identified SIVA; and this protein association was confirmed by IP. Three different isoforms of FHL1 were used in a Y2H assay for protein interaction mapping, SIVA1 binds only with the SLIMMER and not with FHL1 and KyoT2 isoforms (Cottle et al., 2009).
p53: The interaction between p53 and SIVA1 was tested by IP using H1229 cells co-expressing FLAG-p53 and GFP-SIVA1 and confirmed by IP using endogenous proteins from A549 cells. GST pull-down assays indicate that SIVA1 binds to p53 using its N-terminal region and DDHR, while p53 binds to SIVA1 via its DBD domain (Du et al., 2009).
Tyrosine kinase 2 (TYK2): Y2H screening using TYK2 as the bait identified SIVA1 binding, and this association was confirmed by IP of 293 cells co-expressing FLAG-SIVA1 and full-length TYK2. The SIVA1 N-terminal region binds to TYK2, as demonstrated by IP of 293T cells overexpressing GFP tagged deletion mutants of SIVA1 and FLAG-TYK2 (Shimoda et al., 2010).
Stathmin 1: Y2H screening using SIVA1 as bait identified Stathmin 1, and this association was confirmed by IP of U2OS cells co-expressing exogenous or endogenous SIVA1 and Stathmin 1 proteins (Li et al., 2011).
Cyclin-dependent kinase inhibitor 2A (CDKN2A), also known as ARF: The ARF and SIVA interaction was tested by IP assays of H1229 cells containing FLAG-SIVA1 and GFP-ARF, and purified recombinant proteins were used for confirmation. The protein interaction mapping was performed by GST pull down assays using deletion mutants of SIVA1 and ARF overexpressed in 293 cells. SIVA1 binds to ARF by its N-terminal region and DDHR, while the residue aa 21-64 of ARF is required (Wang et al., 2013).

SIVA1 shares high homology (around 40%) in its DDHR domain with the FADD and RIP proteins. SIVA1 also shares a high homology with different species (Table 1).

Mutations in the SIVA1 gene are rare, only six missense and one nonsense mutations are reported at COSMIC (Catalogue of somatic mutations in cancer).