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Atlas of Genetics and Cytogenetics in Oncology and Haematology INIST -CNRS OPEN ACCESS JOURNAL Gene Section Review SIVA1 (SIVA1, Apoptosis-Inducing Factor) João Agostinho Machado-Neto, Fabiola Traina Hematology and Hemotherapy Center-University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciencia e Tecnologia do Sangue, Campinas, Sao Paulo, Brazil (JAMN, FT), Hematology/Oncology Division, Department of Internal Medicine, Medical School of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil (FT) Published in Atlas Database: October 2013 Online updated version : http://AtlasGeneticsOncology.org/Genes/SIVA1ID42301ch14q32.html DOI: 10.4267/2042/53646 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2014 Atlas of Genetics and Cytogenetics in Oncology and Haematology Two alternatively-spliced transcript variants Abstract encoding distinct proteins have been described, Review on SIVA1, with data on DNA/RNA, on the SIVA1 transcript variant 1, which is the protein encoded and where the gene is implicated. predominant transcript variant with a cDNA containing 790 bp (codifying the SIVA1 protein), Identity and the SIVA1 transcript variant 2 lacking the exon 2 with a cDNA containing 595 bp (codifying the Other names: CD27BP, SIVA, Siva-1, Siva-2 SIVA2 protein). HGNC (Hugo): SIVA1 Protein Location: 14q32.33 Description DNA/RNA SIVA1 contains a unique amphipathic helical region (SAH) in the N-terminal region, a death Description domain homology region (DDHR) in the central The entire SIVA1 gene is about 15.3 Kb and part of the protein, and a Zinc finger-like structure contains 4 exons (Start: 105219437 bp and End: at its C-terminal region. The SIVA2 isoform lacks 105234831; Orientation: plus strand). the DDHR domain (Figure 1). 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. Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5) 334 SIVA1 (SIVA1, Apoptosis-Inducing Factor) Machado-Neto JA, Traina F 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. Expression upregulated under stress or following DNA damage (Ray et al., 2011; Fortin et al., 2004). Ubiquitous. Recently, novel partners and functions have been Localisation attributed to SIVA1. SIVA1 binds to and regulates SIVA1 is found in the nucleus and cytoplasm p53 stability by acting as an adapter protein (Figure 2). between p53 and MDM2, and participates in an auto-regulatory feedback loop between p53 and Function SIVA1 (Du et al., 2009; Mei and Wu, 2012). The proapoptotic function of SIVA1 is well SIVA1 associates with ARF, enabling its elucidated and characterized. SIVA1 binds to death ubiquitination and degradation; this mechanisms receptors, including CD27 and TNFRSF18, and also regulates the p53/MDM2 signaling pathway plays a role in the transduction of the proapoptotic (Wang et al., 2013). signal by the extrinsic pathway (Prasad et al., 1997; Finally, SIVA1 is a novel adaptor protein that Spinicelli et al., 2002). SIVA1 interacts with BCL2 promotes Stathmin 1/CaMKII interaction. and BCL-XL, abrogates their antiapoptotic SIVA1 inhibits Stathmin 1 activity through functions and modulates the intrinsic apoptosis Stathmin 1 phosphorylation at serine 16, which pathway (Chu et al., 2004; Chu et al., 2005). In results in reduced cell migration and metastasis by addition, SIVA1 associates with XIAP and stabilizing microtubules of tumor cells (Li et al., regulates the apoptosis mediated by NFkB and JNK 2011). signaling (Resch et al., 2009). The SIVA gene is a The main functions and signaling pathways of transcription target of p53, p73 and E2F1 and is SIVA1 are illustrated in Figure 3. Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5) 335 SIVA1 (SIVA1, Apoptosis-Inducing Factor) Machado-Neto JA, Traina F 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. The binding partners of SIVA1 are: cells expressing the GFP-BCL-XL protein (Xue et CD27: SIVA1 was initially identified by two- al., 2002). Later on, Chu et al. reported that the hybrid (Y2H) screening using CD27 as a bait, and SAH region of SIVA1 was sufficient to specifically its interaction was confirmed by interact with BCL-XL (Chu et al., 2004). immunoprecipitation (IP) of 293 cells co- B-cell CLL/lymphoma 2 (BCL2): The association expressing both proteins (Prasad et al., 1997). In of BCL2 and SIVA1 was verified using GST pull agreement, Yoon et al. found that murine Siva1 and down assays with GST-SIVA in Cos-7 cells Siva2 also bind to CD27 (Yoon et al., 1999). overexpressing full-length BCL2 protein, and this c-abl oncogene 2, non-receptor tyrosine kinase interaction occurred at the SAH region of SIVA1 (ABL2): Y2H screening using ABL2 (previously (Chu et al., 2004). known as ARG) as the bait identified SIVA1 as a CD4: Y2H screen using cytoplasmic domain of binding partner. This protein association was CD4 as the bait identified SIVA1. This protein confirmed by IP of MCF7 cells co-expressing interaction was confirmed by in vitro binding FLAG-ABL2 and GFP-SIVA1 (Cao et al., 2001). assays with GST-SIVA1. The interaction was Tumor necrosis factor receptor superfamily, mapped through GST pull-down assay using GST member 18 (TNFRSF18): TNFRSF18 (previously tagged deletion mutants of SIVA1; the C-terminal known as GITR) presents high homology with region of SIVA1 binds to the cytoplasmic domain CD27. The interaction between TNFRSF18 and of CD4 (Py et al., 2007). SIVA1 was identified using GST pull down and IP Lysophosphatidic acid receptor 2 (LPAR2): Y2H assays (Spinicelli et al., 2002). screening using the C-terminal region of LPAR2 as BCL2-like 1 (BCL-XL): The association of BCL- the bait identified SIVA1. GST pull-down assays XL and SIVA1 was first identified using purified confirmed this protein association and the SIVA1 GST-SIVA and BCL-XL proteins and confirmed by C-terminal region (aa 139-175) is required for this GST pull down assays using GST-SIVA1 in 293 interaction (Lin et al., 2007). Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5) 336 SIVA1 (SIVA1, Apoptosis-Inducing Factor) Machado-Neto JA, Traina F Table 1. Comparative identity of human SIVA1 with other species. Source: homologene. Pyrin (MEFV): Y2H screening using Pyrin as the exogenous or endogenous SIVA1 and Stathmin 1 bait identified SIVA1 binding, and this association proteins (Li et al., 2011). was confirmed by IP. Using deletion mutants of Cyclin-dependent kinase inhibitor 2A Pyrin and of SIVA1 or SIVA2, the C-terminal, rfp (CDKN2A) , also known as ARF: The ARF and and SRPY domain of pyrin were found to interact SIVA interaction was tested by IP assays of H1229 with the N-terminal region of SIVA (Balci- cells containing FLAG-SIVA1 and GFP-ARF, and Peynircioglu et al., 2008). purified recombinant proteins were used for X-linked inhibitor of apoptosis (XIAP): Y2H confirmation. The protein interaction mapping was screening using XIAP as the bait identified SIVA1 performed by GST pull down assays using deletion binding, and this protein association was confirmed mutants of SIVA1 and ARF overexpressed in 293 by IP of 293 cells co-expressing both proteins cells. SIVA1 binds to ARF by its N-terminal region (Resch et al., 2009). and DDHR, while the residue aa 21-64 of ARF is FHL1 four and a half LIM domains 1 (FHL1): required (Wang et al., 2013). Y2H screening using the SLIMMER isoform of Homology FHL1 as the bait identified SIVA; and this protein association was confirmed by IP. Three different SIVA1 shares high homology (around 40%) in its isoforms of FHL1 were used in a Y2H assay for DDHR domain with the FADD and RIP proteins. protein interaction mapping, SIVA1 binds only SIVA1 also shares a high homology with different with the SLIMMER and not with FHL1 and KyoT2 species (Table 1). isoforms (Cottle et al., 2009). p53: The interaction between p53 and SIVA1 was Mutations tested by IP using H1229 cells co-expressing FLAG-p53 and GFP-SIVA1 and confirmed by IP Mutations in the SIVA1 gene are rare, only six using endogenous proteins from A549 cells. GST missense and one nonsense mutations are reported pull-down assays indicate that SIVA1 binds to p53 at COSMIC (Catalogue of somatic mutations in using its N-terminal region and DDHR, while p53 cancer). binds to SIVA1 via its DBD domain (Du et al., 2009). Implicated in Tyrosine kinase 2 (TYK2): Y2H screening using Breast cancer TYK2 as the bait identified SIVA1 binding, and this association was confirmed by IP of 293 cells Note co-expressing FLAG-SIVA1 and full-length TYK2.