SIVA1 (SIVA1, Apoptosis-Inducing Factor)

2013-10-01   Joao Agostinho Machado-Neto , Fabiola Traina 





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).


Atlas Image
Figure 1. Schematic structure of SIVA1 and SIVA2 proteins. The amphipathic helical region (SAH) at the N-terminal region, a death domain homology region (DDHR) in the central section, and a Zinc finger-like (ZF) structure at its C-terminal region are illustrated. The amino acids (aa) positions are indicated.




SIVA1 is found in the nucleus and cytoplasm (Figure 2).
Atlas Image
Figure 2. Intracellular localization of SIVA1 protein in a prostate cancer cell line. Confocal analysis of LNCaP cells displaying SIVA (green), DAPI (blue) and Actin (red) staining; MERGE shows the overlapped images. Scale bar, 10 µm. Note the cytoplasmatic and nuclear localization of SIVA1. Anti-SIVA1 (sc-7436) was from Santa Cruz Biotechnology, (Santa Cruz, CA, USA), Phalloidin (A12379) and DAPI (P-36931) were from Invitrogen (Carlsbad, CA, USA). Personal data.


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).

Atlas Image
Figure 3. SIVA1 signaling pathway. (1) SIVA1 binds to death receptors and modulates the extrinsic apoptosis pathway. (2) SIVA 1 binds to BCL2 proteins family, inhibits the antiapoptotic proteins, BCL2 and BCL-XL, and leads to proapoptotic BAD protein oligomerization, and modulates the intrinsic apoptosis pathway. (3) SIVA1 binds to the XIAP protein and balances the proapoptotic and antiapoptotic signaling through the JNK and NFkB pathway, respectively, and modulates the extrinsic apoptosis pathway. (4) SIVA1 promotes Stathmin 1/CaMKII interaction, Stathmin 1 phosphorylation and inhibition, and modulates microtubule dynamics. (5) The SIVA1 gene is a transcription target of p53, p73 and E2F1. (6) SIVA1 protein acts as an adapter protein between p53 and MDM2, and promotes p53 ubiquitination. (7) SIVA1 acts as an ARF E3 ubiquitin ligase and regulates cell proliferation by the ARF/p53/MDM2 pathway. Abbreviations: P, phosphorylation; Ac, acetylation; Ub, ubiquitination. Figure was produced using Servier Medical Art.


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).
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Table 1. Comparative identity of human SIVA1 with other species. Source: homologene.



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

Implicated in

Entity name
Breast cancer
In breast cancer cells, SIVA1 acts synergistically with cisplatin in inducing apoptosis (Chu et al., 2005). Recently, SIVA1 protein has been reported to be downregulated in primary and metastatic breast cancer tumors and SIVA 1 negatively correlates with Stathmin 1 activity (Li et al., 2011). SIVA1 silencing augments metastasis in a xenograft breast cancer model (Li et al., 2011).
Entity name
Acute lymphoid leukemia
In acute lymphoid leukemia cell lines, SIVA1 overexpression induces apoptosis (Py et al., 2004), while SIVA1 inhibition reduces apoptosis (Resch et al., 2009).
Entity name
Colorectal cancer
In colorectal cancer samples, using a DNA array approach, SIVA1 has been shown to be downregulated when compared to normal tissue (Okuno et al., 2001). In colon cancer cell lines, SIVA1 was found to be a transcriptional target of p53 and E2F1 and to participate in the apoptosis induced by MDM2 inhibition (Ray et al., 2011). In addition, SIVA1 silencing reduces apoptosis in a p53-dependent manner in colon cancer cells treated with cisplatin (Barkinge et al., 2009).
Entity name
In a xenograft osteosarcoma model, SIVA1 silencing increases p53 stability and augments the tumor growth (Du et al., 2009). In osteosarcoma cell lines, SIVA1 silencing increases cell migration and metastasis, while SIVA1 overexpression has an opposite effect (Li et al., 2011).
Entity name
Prostate cancer
In a study focused on the identification of genes modulated in prostate cancer cells under apoptosis, SIVA1 transcripts were found to be upregulated. This finding indicates a possible role of SIVA1 in the apoptotic pathway of prostate cancer cells (Lin and Ying, 1999).


Pubmed IDLast YearTitleAuthors

Other Information

Locus ID:

NCBI: 10572
MIM: 605567
HGNC: 17712
Ensembl: ENSG00000184990


dbSNP: 10572
ClinVar: 10572
TCGA: ENSG00000184990


Gene IDTranscript IDUniprot

Expression (GTEx)



Pubmed IDYearTitleCitations
217683582011Siva1 suppresses epithelial-mesenchymal transition and metastasis of tumor cells by inhibiting stathmin and stabilizing microtubules.39
179650212007The lysophosphatidic acid 2 receptor mediates down-regulation of Siva-1 to promote cell survival.34
150340122004Siva-1 and an alternative splice form lacking the death domain, Siva-2, similarly induce apoptosis in T lymphocytes via a caspase-dependent mitochondrial pathway.29
234629942013Siva1 inhibits p53 function by acting as an ARF E3 ubiquitin ligase.21
147396022004The Siva-1 putative amphipathic helical region (SAH) is sufficient to bind to BCL-XL and sensitize cells to UV radiation induced apoptosis.19
195905122009Suppression of p53 activity by Siva1.18
249587732014SIVA1 directs the E3 ubiquitin ligase RAD18 for PCNA monoubiquitination.16
164911282006Siva-1 negatively regulates NF-kappaB activity: effect on T-cell receptor-mediated activation-induced cell death (AICD).15
173480352007Human papillomavirus-16 E7 interacts with Siva-1 and modulates apoptosis in HaCaT human immortalized keratinocytes.11
258133522015The p53 Target Gene SIVA Enables Non-Small Cell Lung Cancer Development.11


Joao Agostinho Machado-Neto ; Fabiola Traina

SIVA1 (SIVA1, Apoptosis-Inducing Factor)

Atlas Genet Cytogenet Oncol Haematol. 2013-10-01

Online version: