Affinage

SIVA1

Apoptosis regulatory protein Siva · UniProt O15304

Length
175 aa
Mass
18.7 kDa
Annotated
2026-06-10
63 papers in source corpus 31 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SIVA1 is a stress-responsive proapoptotic adaptor and E3 ubiquitin ligase that couples death-receptor and transcription-factor signals to the mitochondrial apoptotic pathway, while exerting separable roles in DNA damage tolerance, cytoskeletal regulation, and development (PMID:9177220, PMID:15105421, PMID:21768358). It was discovered as a CD27-binding protein whose overexpression induces apoptosis, and it engages additional surface receptors including CD4 and the LPA2 receptor through its C-terminal cysteine-rich region (PMID:9177220, PMID:17653867, PMID:17965021). SIVA1 is a direct transcriptional target of both p53 and E2F1, linking its induction to genotoxic and proliferative stress (PMID:15105421). Its proapoptotic output is executed by a unique amphipathic helical (SAH) region (residues 36-55) that binds and antagonizes the anti-apoptotic proteins BCL-XL and BCL-2 — but not BAX — thereby driving loss of mitochondrial integrity, cytochrome c release, and activation of caspase-9 and caspase-3 (PMID:14739602, PMID:15034012). Beyond apoptosis, SIVA1 acts as an E3 ubiquitin ligase for ARF, destabilizing ARF to reduce p53 stability and modulate cell-cycle progression, and serves as an adaptor that bridges RAD18 to PCNA to direct PCNA monoubiquitination for translesion synthesis (PMID:23462994, PMID:24958773). SIVA1 restrains NF-κB signaling downstream of TCR engagement by promoting K48-linked polyubiquitination and degradation of TRAF2, and it is required for activation-induced cell death in T cells (PMID:19392652, PMID:16491128). Through binding and inhibiting the microtubule destabilizer stathmin in a CaMKII-dependent manner, SIVA1 suppresses cell migration, EMT, and metastasis (PMID:21768358). SIVA1 function is gated by its activating tyrosine phosphorylation (by ARG on Tyr48), its oligomerization state, and its regulated nuclear-versus-cytosolic distribution (PMID:11278261, PMID:19590512, PMID:22343716). Genetic studies establish a p53-independent role: SIVA loss inhibits NSCLC development via mTOR signaling, and Siva-null mice are embryonic lethal with neural tube and placental defects not rescued by p53 or Ripk3 deficiency (PMID:25813352, PMID:31164717).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1997 High

    Established SIVA1 as a CD27-coupled proapoptotic effector, defining its founding role downstream of a TNFR-family receptor.

    Evidence Yeast two-hybrid screen against the CD27 cytoplasmic tail plus overexpression-induced apoptosis in cell lines

    PMID:9177220

    Open questions at the time
    • Endogenous requirement not yet tested
    • Mechanism linking CD27 binding to death machinery undefined
  2. 1999 Medium

    Resolved that splice isoform identity controls activity, showing Siva-1 but not Siva-2 is proapoptotic despite both binding CD27.

    Evidence Cotransfection/Co-IP in 293T cells and apoptosis assays comparing the two splice forms

    PMID:10597319

    Open questions at the time
    • Did not identify the domain responsible for the activity difference
    • Whether Siva-2 actively antagonizes Siva-1 untested
  3. 2001 High

    Identified an activating post-translational switch by showing ARG kinase phosphorylates Siva-1 on Tyr48, required for its oxidative-stress proapoptotic activity.

    Evidence In vitro kinase assay, Tyr48 mutagenesis, and ARG knockout/reconstitution apoptosis assays

    PMID:11278261

    Open questions at the time
    • How Tyr48 phosphorylation alters Siva-1 conformation or partner binding unknown
    • Whether other stresses converge on this site untested
  4. 2002 High

    Defined the molecular basis of mitochondrial apoptosis induction by mapping a unique SAH region that binds BCL-XL and localizes Siva-1 to mitochondria.

    Evidence Reciprocal Co-IP in HUT78 cells and thymocytes, deletion mutagenesis, and subcellular fractionation

    PMID:12011449

    Open questions at the time
    • Structural basis of SAH-BCL-XL contact not resolved
    • Stoichiometry of inhibition unknown
  5. 2004 High

    Established SAH sufficiency and placed Siva-1 firmly in the intrinsic apoptotic cascade, and demonstrated transcriptional control by p53 and E2F1.

    Evidence SAH peptide microinjection with cytochrome c and caspase-9/-3 readouts; EMSA and luciferase reporter assays for p53/E2F1 promoter binding

    PMID:14739602 PMID:15034012 PMID:15105421

    Open questions at the time
    • Relative in vivo contribution of p53 versus E2F1 induction unresolved
    • Whether SAH targets only BCL-XL/BCL-2 or broader anti-apoptotic set
  6. 2006 High

    Demonstrated an endogenous requirement for Siva-1 in TCR-driven activation-induced cell death and revealed it negatively regulates NF-κB.

    Evidence siRNA/shRNA knockdown and Jurkat Siva-1 knockout with apoptosis and p65/RelB NF-κB readouts

    PMID:16491128

    Open questions at the time
    • Molecular link between Siva-1 and NF-κB suppression not yet defined
    • Selectivity for CD3 over Fas signaling unexplained at this stage
  7. 2009 High

    Identified the ubiquitin-based mechanisms by which Siva-1 both restrains NF-κB (TRAF2/XIAP K48-ubiquitination) and destabilizes p53 (Hdm2 adaptor function), and is itself ubiquitinated by XIAP.

    Evidence Co-IP, domain mapping, K48/K63-specific ubiquitination assays, NF-κB/AP-1 reporters, and xenograft models

    PMID:19392652 PMID:19584092 PMID:19590512

    Open questions at the time
    • Whether Siva-1 carries intrinsic ligase activity or recruits other ligases in these contexts not fully separated
    • Cellular conditions favoring p53 destabilization versus apoptosis promotion undefined
  8. 2011 High

    Extended Siva-1 beyond apoptosis to cytoskeletal control, showing it inhibits stathmin to stabilize microtubules and suppress migration, EMT, and metastasis.

    Evidence Co-IP, in vitro microtubule polymerization, CaMKII kinase assay, focal adhesion/migration assays, and mouse metastasis models

    PMID:21768358

    Open questions at the time
    • How this cytoplasmic role is coordinated with nuclear/apoptotic functions unknown
    • Whether stathmin inhibition is constitutive or stimulus-gated
  9. 2013 High

    Established SIVA1 as a bona fide E3 ubiquitin ligase for ARF, mechanistically connecting it to the ARF-Mdm2-p53 axis and cell-cycle control.

    Evidence In vitro and in vivo ubiquitination assays, proteasome inhibitor experiments, and cell-cycle/proliferation assays

    PMID:23462994

    Open questions at the time
    • Catalytic residues mediating ligase activity not mapped
    • How ligase activity is regulated by upstream signals unknown
  10. 2014 High

    Defined a DNA damage tolerance function by showing SIVA1 bridges RAD18 to PCNA via a PIP motif to enable PCNA monoubiquitination and translesion synthesis.

    Evidence Affinity purification, PIP-motif mutagenesis, PCNA monoubiquitination assay, Polη focus formation, and UV sensitivity/mutation assays

    PMID:24958773

    Open questions at the time
    • How this nuclear adaptor role is balanced against its proapoptotic role unclear
    • Regulation of SIVA1-PCNA binding by damage signaling not defined
  11. 2015 High

    Revealed a p53-independent oncogenic function, with SIVA loss suppressing NSCLC through reduced mTOR signaling and metabolism.

    Evidence Conditional knockout mice, NSCLC cell line knockdown, and mTOR pathway/metabolic assays

    PMID:25813352

    Open questions at the time
    • Molecular link between SIVA and mTOR activation undefined
    • Reconciliation with the proapoptotic/tumor-suppressive functions unresolved
  12. 2019 High

    Demonstrated an essential developmental role independent of apoptosis and necroptosis, since Siva-null embryonic lethality is not rescued by p53 or Ripk3 loss.

    Evidence Siva knockout mice with p53-null and Ripk3-null genetic rescue experiments and embryo histology

    PMID:31164717

    Open questions at the time
    • Molecular pathway underlying developmental requirement unknown
    • Tissue-specific contributions to neural tube and placental defects not dissected
  13. 2024 Medium

    Continued mapping of SIVA1's interaction network and regulation, including m6A/FTO-controlled mRNA stability, neuronal FAIM-L/XIAP regulation, and BCL2 coupling.

    Evidence MeRIP/YTHDF2 epistasis, Co-IP, AMPAR internalization, and drug rescue assays across colorectal, neuronal, and gastric cancer systems

    PMID:32015347 PMID:36307991 PMID:41998706

    Open questions at the time
    • Several interactions (SSBP3, BCL2) rest on single-lab Co-IP without reciprocal validation
    • Physiological significance of m6A regulation outside chemoresistance untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SIVA1's distinct activities — SAH-mediated apoptosis, ARF/p53/TRAF2 ligase functions, RAD18-PCNA bridging, stathmin inhibition, and the p53-independent developmental/mTOR roles — are coordinated within a cell by localization, oligomerization, and phosphorylation remains unresolved.
  • No structural model integrating SAH, ring-finger, zinc-finger, and PIP elements
  • Switch determining proapoptotic versus survival/developmental output not defined
  • Whether intrinsic E3 ligase activity underlies all ubiquitination roles untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 3 GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 2 GO:0016874 ligase activity 1
Localization
GO:0005634 nucleus 2 GO:0005739 mitochondrion 1 GO:0005829 cytosol 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-168256 Immune System 2 R-HSA-392499 Metabolism of proteins 2 R-HSA-73894 DNA Repair 1
Partners
BCL-XLBCL2MDM2PCNARAD18STMN1TRAF2XIAP
Complex memberships
XIAP-Siva1-TAK1 ternary complex

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 SIVA1 (Siva) was identified as a novel protein that binds to the cytoplasmic tail of CD27 (a TNFR family member) via yeast two-hybrid screening. Siva contains a death domain homology region, a box-B-like ring finger, and a zinc finger-like domain. Overexpression of Siva in cell lines induces apoptosis, placing it downstream of CD27 in a proapoptotic signaling pathway. Yeast two-hybrid screening, overexpression in cell lines Proceedings of the National Academy of Sciences of the United States of America High 9177220
2002 Siva-1, but not the splice variant Siva-2, binds to BCL-XL and inhibits BCL-XL-mediated protection against UV radiation-induced apoptosis. Natural Siva-1/BCL-XL complexes were detected in HUT78 cells and murine thymocytes. The unique 20-aa amphipathic helical region (SAH, residues 36-55) present in Siva-1 but absent in Siva-2 is required for BCL-XL binding and for sensitizing cells to UV radiation. Siva-1 is partly localized to mitochondria. Co-immunoprecipitation, deletion mutagenesis, cell viability assays, subcellular fractionation Proceedings of the National Academy of Sciences of the United States of America High 12011449
2004 The SAH region of Siva-1 (residues 36-55) is sufficient (not just necessary) to specifically bind anti-apoptotic BCL-XL and BCL-2 but not pro-apoptotic BAX, and is sufficient to inhibit BCL-XL-mediated cell survival and enhance UV radiation-induced apoptosis via loss of mitochondrial integrity, cytochrome c release, and activation of caspase-9 and caspase-3. Deletion mutagenesis, transient transfection, microinjection of synthetic SAH peptides, caspase activity assays, cytochrome c release assay Apoptosis : an international journal on programmed cell death High 14739602
2004 Siva-1 and Siva-2 both mediate apoptosis in T lymphocytes via a caspase-dependent mitochondrial pathway involving Bid activation and cytochrome c release. The apoptotic determinants reside in the N-terminal and C-terminal regions shared by both isoforms, not in the death domain unique to Siva-1. The N-terminal region also mediates nuclear translocation of Siva proteins. Overexpression in T lymphocytes, caspase activation assays, cytochrome c release, ultrastructural analysis, domain deletion studies Journal of immunology (Baltimore, Md. : 1950) High 15034012
2004 SIVA is a direct transcriptional target of both p53 and E2F1. p53 recognition sequences are located in intron 1 and E2F consensus sites in the SIVA promoter. Both transcription factors bind their respective sites (shown by EMSA) and activate SIVA promoter-driven transcription (shown by luciferase reporter assays). SIVA upregulation is sufficient to initiate the apoptotic cascade in neurons. DNA microarray, EMSA, luciferase reporter assays, promoter analysis, gene delivery The Journal of biological chemistry High 15105421
2001 ARG (Abl-related gene) tyrosine kinase associates with Siva-1 and phosphorylates it on Tyr48. ARG is activated by oxidative stress, and this ARG-Siva-1 interaction is required for full proapoptotic activity of Siva-1; mutation of Tyr48 abrogates Siva-1-induced apoptosis. ARG-deficient cells show attenuated apoptotic response to oxidative stress, rescued by ARG reconstitution. Co-immunoprecipitation, in vitro phosphorylation assay, site-directed mutagenesis, ARG knockout/reconstitution, apoptosis assays The Journal of biological chemistry High 11278261
2007 LPA2 receptor (but not LPA1 or LPA3) specifically associates with the C-terminal cysteine-rich domain of Siva-1. Prolonged LPA stimulation promotes co-association of Siva-1 with LPA2 receptor and targets both for ubiquitination and proteasomal degradation. This attenuates adriamycin-induced Siva-1 stabilization and Siva-1-dependent apoptosis. Co-immunoprecipitation, domain mapping, ubiquitination assay, siRNA knockdown, apoptosis/caspase-3 assays The Journal of biological chemistry High 17965021
2009 Siva1 binds to both p53 and Hdm2 through distinct regions, and acts as an adaptor that promotes Hdm2-mediated ubiquitination and degradation of p53. Siva1 thereby inhibits p53-mediated gene expression and apoptosis. On DNA damage, the interactions of Siva1 with both p53 and Hdm2 are diminished. The oligomerization-competent Siva1 (but not the splice variant Siva2 which lacks oligomerization) is required for p53 destabilization. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, overexpression, xenograft mouse models Cell death and differentiation High 19590512
2009 Siva1 interacts with XIAP via the RING domain of XIAP and the N-terminal SAH-containing and DHR-containing domains of Siva1. XIAP, Siva1, and TAK1 form a ternary complex in Jurkat T cells. Siva1 inhibits XIAP/TAK1-TAB1-mediated NF-κB activation while enhancing XIAP- and TNFα-mediated AP-1/JNK activity, shifting the balance toward apoptosis. XIAP ubiquitinates Siva1 via K48-linked polyubiquitination. Co-immunoprecipitation, reporter gene assays (NF-κB, AP-1), JNK activation assays, caspase-3 assay, ubiquitination assay Journal of cell science High 19584092
2009 Siva-1 interacts with the RING finger domain of TRAF2 and promotes K48-linked polyubiquitination of TRAF2, leading to its degradation and inhibition of NF-κB (and AP-1) activation downstream of TCR signaling. In Siva-1 knockdown Jurkat cells, TRAF2 shows lower K48- but elevated K63-ubiquitination, resulting in sustained NF-κB activation. Co-immunoprecipitation, ubiquitination assay (K48/K63-specific), NF-κB reporter assay, siRNA knockdown Journal of environmental pathology, toxicology and oncology Medium 19392652
2006 Endogenous Siva-1 is required for TCR-mediated activation-induced cell death (AICD) in T cells. Knockdown of Siva-1 renders T cells resistant to anti-CD3- but not Fas-induced apoptosis. In Siva-1 knockout Jurkat cells, TCR-mediated activation of both canonical (p65) and non-canonical (RelB) NF-κB pathways is significantly enhanced, accompanied by elevated expression of anti-apoptotic NF-κB target genes (Bcl-xL, c-FLIP). siRNA/shRNA knockdown, Jurkat Siva-1 knockout cells, apoptosis assays, NF-κB pathway analysis (nuclear p65, RelB), immunoblotting Oncogene High 16491128
2011 Siva1 interacts with stathmin (a microtubule destabilizer) and inhibits stathmin's microtubule-destabilizing activity both directly and indirectly through CaMKII-mediated phosphorylation of stathmin at Ser16. Via stathmin inhibition, Siva1 enhances microtubule formation and impedes focal adhesion assembly, cell migration, and epithelial-mesenchymal transition (EMT). Knockdown of Siva1 promotes cancer dissemination in mouse models; overexpression inhibits it. Co-immunoprecipitation, in vitro microtubule polymerization assay, CaMKII kinase assay, focal adhesion assays, migration assays, mouse metastasis models, shRNA knockdown Proceedings of the National Academy of Sciences of the United States of America High 21768358
2013 Siva1 functions as a specific E3 ubiquitin ligase for ARF (p14ARF/p19ARF). Siva1 physically interacts with ARF both in vitro and in vivo, promotes ARF ubiquitination and proteasomal degradation, which in turn reduces p53 stability. Siva1 regulates cell cycle progression and cell proliferation in an ARF/p53-dependent manner. Co-immunoprecipitation, in vitro ubiquitination assay, in vivo ubiquitination, proteasome inhibitor experiments, cell cycle analysis, proliferation assays Nature communications High 23462994
2014 SIVA1 constitutively interacts with PCNA via a conserved PCNA-interacting peptide (PIP) motif, and also interacts with RAD18. SIVA1 serves as a molecular bridge between RAD18 (E3 ubiquitin ligase) and PCNA, targeting RAD18 to monoubiquitinate PCNA. Knockdown of SIVA1 compromises RAD18-dependent PCNA monoubiquitination, Polη focus formation, and leads to elevated UV sensitivity and mutation frequency. Affinity purification, Co-immunoprecipitation, PIP motif mutagenesis, PCNA monoubiquitination assay, siRNA knockdown, UV sensitivity assays, Polη focus formation The Journal of cell biology High 24958773
1999 Mouse Siva gene encodes two splice forms: Siva-1 (full-length) and Siva-2 (lacking exon 2). Both bind to mouse CD27 in cotransfection/co-immunoprecipitation experiments in 293T cells. However, only Siva-1 triggers apoptosis in transient transfection experiments; Siva-2 has much less proapoptotic activity, suggesting Siva-2 may regulate Siva-1 function. Yeast two-hybrid, cotransfection/co-immunoprecipitation in 293T cells, apoptosis assays Oncogene Medium 10597319
2007 Siva-1 associates with the cytoplasmic domain of CD4, mediated by the cysteine-rich region in the C-terminal part of Siva-1. Expression of Siva-1 increases susceptibility of T cells to CD4-mediated apoptosis triggered by HIV-1 envelope via a caspase-dependent mitochondrial pathway, independent of p56Lck kinase activity. Co-immunoprecipitation, truncation mutant analysis, apoptosis assays, caspase activation assays, primary CD4+ T cell experiments Apoptosis : an international journal on programmed cell death Medium 17653867
2007 Siva is a p53 apoptosis-selective target gene expressed at the plasma membrane in cerebellar granule neurons. Endogenous Siva is required for p53-dependent apoptosis in cerebellar granule neurons, and Caspase-8 and Bid are important downstream mediators in this neuronal apoptotic pathway. Microarray analysis, shRNA knockdown, subcellular fractionation/localization, apoptosis assays, caspase-8/Bid activation assays Cell death and differentiation Medium 17464332
2008 Pyrin (MEFV gene product) interacts with Siva via the C-terminal B30.2/rfp/SRPY domain of pyrin and exon 1 of Siva. Siva and pyrin are co-expressed in human neutrophils, monocytes, and synovial cells. Pyrin recruits Siva to ASC specks and modulates the apoptotic response to oxidative stress mediated by Siva. Yeast two-hybrid, co-immunoprecipitation, protein-protein interaction assay, ASC speck recruitment assay, apoptosis assay Journal of cellular physiology Medium 18330885
2009 SLIMMER (FHL1B/KyoT3) specifically interacts with Siva-1 (identified by yeast two-hybrid, direct binding studies, and GST pulldown from skeletal muscle lysates). SLIMMER and Siva-1 co-localize in the nucleus of C2C12 myoblasts and redistribute to cytoplasm upon differentiation. SLIMMER delays Siva-1-dependent apoptosis in C2C12 myoblasts. Yeast two-hybrid, GST pulldown from muscle lysates, co-localization imaging, apoptosis assays The Journal of biological chemistry Medium 19643733
2010 Tyrosine kinase 2 (Tyk2) interacts with Siva-1 via Siva-1's N-terminal region and phosphorylates Siva-1 at Tyr53 and Tyr162. Expression of Tyk2 augments Siva-1-induced apoptosis in Ba/F3 pro-B cells; this augmentation requires the physical Tyk2-Siva-1 association but is independent of Siva-1 phosphorylation status. Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis, apoptosis assays in Ba/F3 cells Biochemical and biophysical research communications Medium 20727854
2012 Upon stimulation of the thromboxane A2 receptor (TP), Siva1 degradation is impeded and Siva1 accumulates and translocates from the nucleus to the cytosol. Cytosolic Siva1 shows reduced interaction with Mdm2 and increased interaction with TRAF2 and XIAP, promoting apoptosis. Siva1 expression is required for TP-stimulated enhancement of cisplatin-induced apoptosis (shown by siRNA knockdown). Yeast two-hybrid, co-immunoprecipitation, siRNA knockdown, subcellular fractionation, apoptosis assays Cell death and differentiation Medium 22343716
2014 Electrical stimulation (ES) upregulates SIVA1, which promotes phospho-p53-SIVA1 interaction. SIVA1 facilitates HDM2-mediated regulation of p53. In the absence of SIVA1, HDM2 alone cannot downregulate nuclear-accumulated phospho-p53, leading to decreased proliferation. ES-inducible SIVA1 modulates p53 activities in proliferating keratinocytes. Co-immunoprecipitation (phospho-p53-SIVA1), siRNA knockdown, flow cytometry (cell cycle/sub-G1), human skin explant model, wound healing model The Journal of investigative dermatology Medium 25431847
2015 SIVA loss in conditional knockout mice inhibits non-small cell lung cancer (NSCLC) development in a p53-independent manner. SIVA stimulates mTOR signaling and metabolism in NSCLC cells; SIVA knockdown in NSCLC cell lines decreases proliferation and transformation. Conditional knockout mice, NSCLC cell line knockdown, mTOR pathway analysis, metabolic assays, colony formation assays Cancer discovery High 25813352
2019 Siva knockout mice display early embryonic lethality with developmental delay, abnormal neural tube closure, and defective placenta and yolk sac formation. These embryonic phenotypes are not rescued by p53 deficiency or by loss of Ripk3 (necroptosis), indicating Siva plays a p53-independent, non-apoptotic/non-necroptotic role in development. Siva knockout mouse generation, genetic rescue experiments (p53 null, Ripk3 null double knockouts), embryo morphology/histology Cell death and differentiation High 31164717
2020 SIVA-1 regulates FAIM-L function by disrupting the FAIM-L-XIAP interaction, promoting XIAP ubiquitination, caspase-3 activation, and neuronal death. SIVA-1 is upregulated upon chemical LTD induction and modulates AMPA receptor internalization via non-apoptotic caspase activation, placing SIVA-1 as a regulator of synaptic plasticity. Yeast two-hybrid screening, co-immunoprecipitation, ubiquitination assay, caspase-3 activation assay, AMPAR internalization assay, chemical LTD induction Cell death & disease Medium 32015347
2022 FTO-mediated m6A demethylation of SIVA1 mRNA at its CDS region induces SIVA1 mRNA degradation via a YTHDF2-dependent mechanism. Inhibition of FTO increases SIVA1 levels; depletion of FTO decreases 5-FU resistance in CRC cells via the FTO-SIVA1 axis. m6A RNA immunoprecipitation (MeRIP), YTHDF2 knockdown, FTO knockdown/overexpression, mRNA stability assays, functional apoptosis/growth assays Molecular therapy : the journal of the American Society of Gene Therapy Medium 36307991
2013 The N-terminal 33 amino acid residues of Siva-1 are sufficient for its nuclear localization; fusion of these 33 residues to GFP directs nuclear import. Mutation of residues 1-18 affects nuclear compartmentalization but is insufficient on its own for nuclear localization. GFP fusion constructs, site-directed mutagenesis of individual residues, fluorescence microscopy Brazilian journal of medical and biological research Medium 24345910
2018 SIVA1 interacts with SSBP3 (single-stranded DNA-binding protein 3) and enhances SSBP3 ubiquitination, regulating SSBP3 protein abundance via the proteasomal degradation pathway. This identifies SIVA1 as a ubiquitin ligase regulating the stability of LIM-HD complex components. Co-immunoprecipitation, GST pulldown, ubiquitination assay Molekuliarnaia biologiia Low 30363057
2006 Siva binds zinc ions (three per molecule) as demonstrated by expression in E. coli, suggesting a complex three-dimensional structure. The N-terminal part of Siva was determined to be the binding region for CD27 by directed two-hybrid assays. Siva also interacts with peroxisomal membrane protein PMP22, identified by screening a human heart cDNA library. Yeast two-hybrid, E. coli expression with zinc-binding analysis, GST pulldown/directed two-hybrid Molecular and cellular biochemistry Low 16683188
2008 Siva specifically interacts with the heart and skeletal muscle protein telethonin (identified by screening a human heart cDNA library). Siva and telethonin co-localize in cardiomyocytes during CVB3 infection. cDNA library screening (yeast two-hybrid), co-localization in cardiomyocytes Cardiovascular research Low 18849585
2024 BCL2 and SIVA1 directly interact, as confirmed by co-immunoprecipitation in gastric cancer cells. Dihydroergotamine suppresses both BCL2 and SIVA1 levels and promotes apoptosis; BCL2 overexpression partially restores SIVA1 protein levels during drug treatment, whereas SIVA1 overexpression does not restore BCL2, supporting BCL2-linked coupling within this axis. Co-immunoprecipitation, single-cell RNA-seq/spatial transcriptomics (for expression context), in vitro drug treatment with rescue experiments Biology direct Low 41998706

Source papers

Stage 0 corpus · 63 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 CD27, a member of the tumor necrosis factor receptor family, induces apoptosis and binds to Siva, a proapoptotic protein. Proceedings of the National Academy of Sciences of the United States of America 250 9177220
2000 Apoptosis in coxsackievirus B3-caused diseases: interaction between the capsid protein VP2 and the proapoptotic protein siva. Journal of virology 113 10756043
2011 Siva1 suppresses epithelial-mesenchymal transition and metastasis of tumor cells by inhibiting stathmin and stabilizing microtubules. Proceedings of the National Academy of Sciences of the United States of America 88 21768358
2011 Mdm2 inhibition induces apoptosis in p53 deficient human colon cancer cells by activating p73- and E2F1-mediated expression of PUMA and Siva-1. Apoptosis : an international journal on programmed cell death 74 20812030
2004 The proapoptotic gene SIVA is a direct transcriptional target for the tumor suppressors p53 and E2F1. The Journal of biological chemistry 72 15105421
2022 N6-methyladenosine demethylase FTO enhances chemo-resistance in colorectal cancer through SIVA1-mediated apoptosis. Molecular therapy : the journal of the American Society of Gene Therapy 71 36307991
2002 Siva-1 binds to and inhibits BCL-X(L)-mediated protection against UV radiation-induced apoptosis. Proceedings of the National Academy of Sciences of the United States of America 69 12011449
2004 Siva-1 and an alternative splice form lacking the death domain, Siva-2, similarly induce apoptosis in T lymphocytes via a caspase-dependent mitochondrial pathway. Journal of immunology (Baltimore, Md. : 1950) 68 15034012
2001 The ARG tyrosine kinase interacts with Siva-1 in the apoptotic response to oxidative stress. The Journal of biological chemistry 55 11278261
2007 The lysophosphatidic acid 2 receptor mediates down-regulation of Siva-1 to promote cell survival. The Journal of biological chemistry 54 17965021
2001 The apoptotic capability of coxsackievirus B3 is influenced by the efficient interaction between the capsid protein VP2 and the proapoptotic host protein Siva. Virology 49 11601913
2013 Siva1 inhibits p53 function by acting as an ARF E3 ubiquitin ligase. Nature communications 47 23462994
2014 Electrical stimulation enhances epidermal proliferation in human cutaneous wounds by modulating p53-SIVA1 interaction. The Journal of investigative dermatology 45 25431847
1999 Murine Siva-1 and Siva-2, alternate splice forms of the mouse Siva gene, both bind to CD27 but differentially transduce apoptosis. Oncogene 45 10597319
2004 The Siva-1 putative amphipathic helical region (SAH) is sufficient to bind to BCL-XL and sensitize cells to UV radiation induced apoptosis. Apoptosis : an international journal on programmed cell death 43 14739602
2014 SIVA1 directs the E3 ubiquitin ligase RAD18 for PCNA monoubiquitination. The Journal of cell biology 37 24958773
2009 Suppression of p53 activity by Siva1. Cell death and differentiation 36 19590512
2007 Siva is an apoptosis-selective p53 target gene important for neuronal cell death. Cell death and differentiation 36 17464332
2006 Siva-1 negatively regulates NF-kappaB activity: effect on T-cell receptor-mediated activation-induced cell death (AICD). Oncogene 33 16491128
2009 Siva1 is a XIAP-interacting protein that balances NFkappaB and JNK signalling to promote apoptosis. Journal of cell science 31 19584092
2005 Expression of Siva-1 protein or its putative amphipathic helical region enhances cisplatin-induced apoptosis in breast cancer cells: effect of elevated levels of BCL-2. Cancer research 31 15958577
1998 Expression of CD27 and ischemia/reperfusion-induced expression of its ligand Siva in rat kidneys. Kidney international 30 9853261
2011 p53 target Siva regulates apoptosis in ischemic kidneys. American journal of physiology. Renal physiology 28 21307125
2007 Human papillomavirus-16 E7 interacts with Siva-1 and modulates apoptosis in HaCaT human immortalized keratinocytes. Journal of cellular physiology 28 17348035
2015 The p53 Target Gene SIVA Enables Non-Small Cell Lung Cancer Development. Cancer discovery 26 25813352
2019 Plumbagin inhibits proliferation and induces apoptosis of hepatocellular carcinoma by downregulating the expression of SIVA. Drug design, development and therapy 24 31118568
2008 Pyrin, product of the MEFV locus, interacts with the proapoptotic protein, Siva. Journal of cellular physiology 23 18330885
2014 Egr-1 upregulates Siva-1 expression and induces cardiac fibroblast apoptosis. International journal of molecular sciences 19 24451137
2020 PM2.5 exposure induces alveolar epithelial cell apoptosis and causes emphysema through p53/Siva-1. European review for medical and pharmacological sciences 18 32329870
2009 Siva-1 promotes K-48 polyubiquitination of TRAF2 and inhibits TCR-mediated activation of NF-kappaB. Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer 17 19392652
2009 SLIMMER (FHL1B/KyoT3) interacts with the proapoptotic protein Siva-1 (CD27BP) and delays skeletal myoblast apoptosis. The Journal of biological chemistry 17 19643733
2020 Siva‑1 regulates multidrug resistance of gastric cancer by targeting MDR1 and MRP1 via the NF‑κB pathway. Molecular medicine reports 16 32626967
2012 Thromboxane A2 modulates cisplatin-induced apoptosis through a Siva1-dependent mechanism. Cell death and differentiation 16 22343716
2012 Multifaceted functions of Siva-1: more than an Indian God of Destruction. Protein & cell 16 22426980
2017 Siva 1 inhibits proliferation, migration and invasion by phosphorylating Stathmin in ovarian cancer cells. Oncology letters 15 28789373
2009 The p53-induced Siva-1 plays a significant role in cisplatin-mediated apoptosis. Journal of carcinogenesis 15 19240372
2007 The Siva protein is a novel intracellular ligand of the CD4 receptor that promotes HIV-1 envelope-induced apoptosis in T-lymphoid cells. Apoptosis : an international journal on programmed cell death 15 17653867
2020 SIVA-1 regulates apoptosis and synaptic function by modulating XIAP interaction with the death receptor antagonist FAIM-L. Cell death & disease 14 32015347
2023 Inhibition of apoptosis-regulatory protein Siva-1 reverses multidrug resistance in gastric cancer by targeting PCBP1. Oncology research 10 37303491
2010 Tyrosine kinase 2 interacts with the proapoptotic protein Siva-1 and augments its apoptotic functions. Biochemical and biophysical research communications 10 20727854
2010 Requirement for Siva-1 for replication of influenza A virus through apoptosis induction. The Journal of general virology 10 21048035
2018 Siva-1 emerges as a tissue-specific oncogene beyond its classic role of a proapoptotic gene. OncoTargets and therapy 9 30319276
2008 Proapoptotic protein Siva binds to the muscle protein telethonin in cardiomyocytes during coxsackieviral infection. Cardiovascular research 9 18849585
2006 The zinc containing pro-apoptotic protein siva interacts with the peroxisomal membrane protein pmp22. Molecular and cellular biochemistry 8 16683188
2020 Lentivirus-Mediated Overexpression of SIVA-1 Reverses Cisplatin Resistance in Gastric Cancer in vitro. Cell biochemistry and biophysics 6 32648086
2019 Siva plays a critical role in mouse embryonic development. Cell death and differentiation 5 31164717
2010 The role of the pro-apoptotic protein Siva in the pathogenesis of Familial Mediterranean fever: A structural and functional analysis. Biochemical and biophysical research communications 5 20934406
2016 Overexpression and Characterization of The C-Terminal Domain of Human Siva1, A Proapoptotic Factor and Cytoskeleton Binding Protein. Protein and peptide letters 4 26497317
2015 Two Faces of SIVA. Cancer discovery 4 26037915
2024 SIVA-1 enhances acquired chemotherapeutic drug resistance of gastric cancer in vivo by regulating the ARF/MDM2/p53 pathway. Heliyon 3 38312638
2024 SIVA-1 interaction with PCBP1 serves as a predictive biomarker for cisplatin sensitivity in gastric cancer and its inhibitory effect on tumor growth in vivo. Journal of Cancer 3 38947376
2015 Anticancer activity of recombinant Siva1 protein in human nasopharyngeal carcinoma cell line CNE-2. Cancer biomarkers : section A of Disease markers 3 26406409
2013 The N-terminal 33 amino acid domain of Siva-1 is sufficient for nuclear localization. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas 3 24345910
2024 Mutation of SIVA, a candidate metastasis gene identified from clonally related bilateral breast cancers, promotes breast cancer cell spread in vitro and in vivo. PloS one 2 38722955
2022 FAIM-L - SIVA-1: Two Modulators of XIAP in Non-Apoptotic Caspase Function. Frontiers in cell and developmental biology 2 35083225
2021 Molecular characterization, expression, and apoptosis regulation of siva1 in protogynous hermaphrodite fish ricefield eel (Monopterus albus). Fish physiology and biochemistry 2 34414556
2018 [SIVA1 Regulates the Stability of Single-Stranded DNA-Binding Protein 3 Isoforms]. Molekuliarnaia biologiia 2 30363057
2014 Commentary on "A systematic review of stereotactic radiotherapy ablation for primary renal cell carcinoma." Siva S, Pham D, Gill S, Corcoran NM, Foroudi F. Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, Victoria, Australia.: BJU Int 2012;110(11 Pt B):E737-43. doi: 10.1111/j.1464-410X.2012.11550.x. [Epub 2012 Oct 29]. Urologic oncology 2 24679465
2025 Exploring the dual role of SIVA1 in cancer biology. Gene 1 40024298
2025 Retraction notice to "SIVA-1 enhances acquired chemotherapeutic drug resistance of gastric cancer in vivo by regulating the ARF/MDM2/p53 pathway" [Heliyon 10 (2024) e24394]. Heliyon 1 41497854
2020 Helicobacter pylori: preying on SIVA for survival in the stomach. The Journal of clinical investigation 1 32250343
2026 Silencing of SIVA‑1 promotes cisplatin resistance in gastric cancer via the Bcl‑2/BAX‑mediated mitochondria‑dependent apoptosis pathway. Oncology reports 0 41823560
2026 Gene-guided repurposing identifies dihydroergotamine as a candidate inhibitor of the BCL2-SIVA1 axis in advanced gastric cancer in vitro. Biology direct 0 41998706

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