{"gene":"BIRC5","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":1999,"finding":"Two novel splice variants of survivin were identified: survivin-deltaEx3 (lacking exon 3) and survivin-2B (retaining part of intron 2 as a cryptic exon). Both cause structural changes in the BIR domain. In transfection experiments, survivin-deltaEx3 retained antiapoptotic properties while survivin-2B showed markedly reduced antiapoptotic potential.","method":"Northern blot, RT-PCR, transfection assays in renal cell carcinoma cell lines","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional transfection assays with two isoforms, single lab, two orthogonal methods (molecular cloning + functional assay)","pmids":["10626797"],"is_preprint":false},{"year":2000,"finding":"Survivin interacts with cyclin-dependent kinase 4 (CDK4), and overexpression of survivin releases p21(WAF1/Cip1) from CDK4, thereby promoting cell cycle progression (decrease in G0/G1, increase in S phase) in hepatocellular carcinoma cells.","method":"Co-immunoprecipitation, cell cycle analysis after survivin transfection, immunofluorescence","journal":"Hepatology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP showing CDK4 interaction combined with functional cell cycle readout, single lab","pmids":["10796883"],"is_preprint":false},{"year":2003,"finding":"Hsp90 associates with survivin via an interaction involving the ATPase domain of Hsp90 and the survivin BIR domain. Disruption of this complex (by global Hsp90 inhibition or antibody-mediated targeting) causes proteasomal degradation of survivin, mitochondrial-dependent apoptosis, and mitotic defects.","method":"Co-immunoprecipitation, antibody-mediated complex disruption, proteasome inhibitor rescue, cell death and mitosis assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP mapping interaction domains, multiple orthogonal functional assays (proteasomal degradation, apoptosis, mitotic defects), single lab but multiple methods","pmids":["14614132"],"is_preprint":false},{"year":2005,"finding":"Survivin is ubiquitinated in mitosis through both Lys48 and Lys63 ubiquitin linkages. The deubiquitinating enzyme hFAM mediates Lys63 deubiquitination required for dissociation of survivin from centromeres, while Lys63 ubiquitination mediated by Ufd1 is required for association of survivin with centromeres. This ubiquitination cycle regulates chromosome alignment and segregation independently of protein degradation.","method":"Biochemical ubiquitination assays, siRNA knockdown of hFAM and Ufd1, live-cell imaging, chromosome segregation assays","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (biochemical ubiquitination, genetic knockdown, functional chromosome segregation readout), rigorous mechanistic dissection in a high-impact journal","pmids":["16322459"],"is_preprint":false},{"year":2006,"finding":"Depletion of survivin by siRNA increased centrosomal microtubule nucleation and increased microtubule catastrophe frequency, whereas survivin overexpression reduced centrosomal microtubule nucleation and suppressed microtubule dynamics in mitotic spindles and midbodies. This effect was specific to survivin and not recapitulated by Aurora B depletion, indicating survivin directly modulates microtubule dynamics.","method":"siRNA depletion, time-lapse imaging of GFP-alpha-tubulin and GFP-EB1, pharmacologic Aurora B inhibition","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — live imaging with multiple reporters plus pharmacologic controls, loss-of-function and gain-of-function experiments, orthogonal validation","pmids":["16407408"],"is_preprint":false},{"year":2006,"finding":"Survivin acts as a subunit of the chromosomal passenger complex (CPC), together with Aurora B kinase, Borealin, and INCENP. Within this complex, survivin dictates CPC localization to centromeres and is essential for proper chromosome segregation and cytokinesis. This mitotic regulatory function is conserved throughout evolution.","method":"Review/synthesis citing multiple experimental studies (Co-IP, localization, genetic knockdown)","journal":"Current opinion in cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — CPC membership established by multiple independent labs using Co-IP, localization, and functional epistasis across species","pmids":["16962308"],"is_preprint":false},{"year":2007,"finding":"The nuclear export receptor CRM1 interacts with a leucine-rich nuclear export signal (NES) conserved in all mammalian survivin proteins, tethering the CPC to the centromere. Export-deficient survivin fails to protect tumor cells against apoptosis, indicating the CRM1/survivin interaction is required for both centromere localization and cytoprotective activity.","method":"Identification of NES by sequence analysis, CRM1 interaction assays, export-deficient mutant analysis, cell viability assays","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — NES mutagenesis and functional rescue experiments, single lab, limited methodological detail in abstract","pmids":["17361097"],"is_preprint":false},{"year":2007,"finding":"Sp1 and Sp3 transcription factors regulate basal survivin promoter activity. Two Sp1-binding sites within the proximal 269 bp GC-rich, TATA-less promoter (at positions -148 to -153 and -127 to -140) are essential. Both Sp1 and Sp3 activate the survivin promoter, as shown by EMSA, RNAi knockdown of Sp1/Sp3, mithramycin treatment, and overexpression.","method":"Promoter cloning, EMSA, RNAi knockdown, mithramycin treatment, Sp1/Sp3 overexpression, luciferase reporter assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA plus functional reporter assays plus RNAi knockdown, single lab, multiple orthogonal methods","pmids":["17350596"],"is_preprint":false},{"year":2009,"finding":"DNA methylation of the survivin CpG island inhibits p53 binding to the survivin promoter, thereby preventing p53-mediated repression of survivin. Demethylation by decitabine restores p53-dependent survivin repression. This represents a mechanism of survivin de-repression via promoter methylation blocking a transcriptional repressor.","method":"Methylation-specific PCR, pyrosequencing, decitabine treatment, p53 binding assays, microarray analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple complementary methods (MSP, pyrosequencing, pharmacologic demethylation with functional readout), single lab","pmids":["19363521"],"is_preprint":false},{"year":2010,"finding":"PLK1 (polo-like kinase 1) phosphorylates survivin at Ser20, a priming phosphorylation required for Aurora B kinase activation within the CPC. Inhibition of PLK1 or expression of non-phosphorylatable survivin (S20A mutant) prevents Aurora B activation and correct spindle microtubule attachment, leading to chromosome segregation errors.","method":"PLK1 kinase assays, survivin S20A phospho-dead mutant expression, FRET-based Aurora B activity reporter, quantitative phosphorylation assays, live-cell mitosis imaging","journal":"Journal of molecular cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay identifying writer (PLK1), mutagenesis of phospho-site, FRET reporter for functional validation, multiple orthogonal approaches","pmids":["21148584"],"is_preprint":false},{"year":2010,"finding":"The PI3K/Akt/p70S6K1 signaling pathway regulates survivin mRNA expression. Overexpression of activated PI3K or Akt induces survivin mRNA, while PTEN overexpression decreases it. p70S6K1 alone is sufficient to induce survivin expression, and rapamycin treatment decreases survivin mRNA, placing p70S6K1 as a key downstream effector.","method":"Overexpression of active PI3K (v-P3k), wild-type and mutant PTEN, p70S6K1; rapamycin treatment; survivin siRNA; mRNA quantification","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic overexpression and pharmacologic inhibition with mRNA readout, pathway placement by epistasis, single lab","pmids":["20361940"],"is_preprint":false},{"year":2012,"finding":"Survivin induces mitochondrial fragmentation by recruiting the fission regulator DRP1/DNM1L to mitochondria, inhibits mitochondrial respiratory complex I (preventing ROS accumulation and FOXO3-induced apoptosis), represses BCL2L11/Bim expression, and shifts cells from oxidative phosphorylation to aerobic glycolysis. Glycolysis inhibitors neutralize the antiapoptotic effect of survivin.","method":"Survivin overexpression/knockdown in neuroblastoma cells, mitochondrial imaging, mitochondrial respiration assays, ROS measurement, glycolysis inhibitor treatment, DRP1 localization by fractionation/imaging","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal functional assays (mitochondrial morphology, respiration, ROS, metabolic shift), gain- and loss-of-function, mechanistic pathway placement, single lab","pmids":["23146905"],"is_preprint":false},{"year":2013,"finding":"OCT4 upregulates BIRC5 expression indirectly by increasing BIRC5 promoter activity (no direct OCT4 binding site in BIRC5 promoter), while directly binding an octamer motif in the CCND1 promoter to upregulate cyclin D1. Co-suppression of OCT4 and BIRC5 induces apoptosis and cell cycle arrest in HCC cells and suppresses xenograft growth.","method":"OCT4 overexpression/knockdown, BIRC5 promoter luciferase reporter assays, ChIP for CCND1 promoter, apoptosis assays, xenograft mouse model","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter reporter assays with gain/loss-of-function, ChIP for direct binding, functional in vivo validation, single lab","pmids":["23433354"],"is_preprint":false},{"year":2013,"finding":"HER2 stabilizes survivin protein by activating the HER2/Akt/CDK1-cyclin B1 pathway, which phosphorylates survivin at Thr34, the most important residue for survivin stability. Simultaneously, HER2/ERK signaling downregulates γ-secretase activity, reducing Notch cleavage and Notch-dependent survivin transcription. ERK also decreases XAF1, reducing the XIAP-XAF1 E3 ligase complex that ubiquitinates survivin.","method":"HER2 overexpression, Thr34 mutagenesis, pathway inhibitor treatments, XAF1 knockdown, ubiquitination assays","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis of key phosphorylation site, multiple pathway inhibitors, ubiquitination assays, single lab","pmids":["23323858"],"is_preprint":false},{"year":2014,"finding":"Survivin knockdown causes polyploidization, merotelic kinetochore-spindle assemblies, γH2AX foci, and DNA damage response (DDR) with transient p53-mediated G1 arrest in p53 wild-type cells. Chromosomal aberrations indicative of NHEJ-based DSB repair occur only in survivin-depleted cells. These effects are independent of p53 status, establishing survivin as essential for amphitelic kinetochore-spindle assembly.","method":"Stable RNAi knockdown in isogenic p53 WT and p53-null cell lines, spectral karyotyping, confocal microscopy, western blot, proliferation assays, ATM/DNA-PK inhibition","journal":"Molecular cancer","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple isogenic cell lines with p53 status controlled, spectral karyotyping, multiple orthogonal readouts, mechanistic dissection of DDR pathway","pmids":["24886358"],"is_preprint":false},{"year":2015,"finding":"Glycolysis inhibitor 2-deoxy-D-glucose (2DG) selectively acts on survivin-overexpressing neuroblastoma cells by inducing autophagic degradation of survivin via activation of the E3-ubiquitin ligase Parkin (a downstream target of PINK1). Survivin degradation releases bound Beclin-1, enhancing autophagy and cell death. Parkin knockdown reduces sensitivity of survivin-expressing cells to glycolysis inhibition.","method":"2DG treatment, Parkin knockdown, Beclin-1 co-immunoprecipitation, xenograft mouse model, mitochondrial network imaging","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway (PINK1-Parkin-survivin-Beclin1) with Co-IP, genetic knockdown of Parkin, in vivo validation, single lab","pmids":["26148234"],"is_preprint":false},{"year":2013,"finding":"BIRC5 is a direct transcriptional target of activating E2F transcription factors in neuroblastoma, primarily when p21Cip1 and p27Kip1 are suppressed. MYCN indirectly induces BIRC5 by suppressing CDKN1A/p21Cip1 and inducing Skp2 (which promotes p27Kip1 degradation). CDC2 phosphorylates BIRC5 to increase its protein stability; selective CDC2 knockdown inhibits BIRC5 abundance and antiapoptotic activity.","method":"E2F overexpression/reporter assays, CDC2 siRNA knockdown, ChIP, protein stability assays, neuroblastoma tumor samples","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for E2F binding, siRNA knockdown with functional readout, protein stability assays, single lab","pmids":["19497660"],"is_preprint":false},{"year":2018,"finding":"Survivin is present on the outer cell membrane of a wide variety of cancer cell types (murine and human glioma, melanoma). Anti-survivin monoclonal antibodies generated against a survivin immunogen display antitumor activity in vivo against murine GL261 gliomas (flank and intracranial) and B16 melanoma, beyond CD8-mediated lysis.","method":"Flow cytometry and immunofluorescence for cell-surface survivin, in vivo tumor models with antibody treatment, immune serum analysis","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct surface localization by flow cytometry and immunofluorescence, in vivo functional validation, single lab","pmids":["29540489"],"is_preprint":false},{"year":2018,"finding":"Exosomal survivin facilitates exosome internalization by recipient cancer cells. Blocking exosomal survivin reduces exosome uptake. Membrane receptors transferrin receptor, endothelin B receptor, insulin receptor alpha, and membrane glucocorticoid receptor all facilitate exosomal internalization.","method":"Exosome isolation, PKH67 lipophilic staining, immunofluorescence, flow cytometry, receptor blocking experiments","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct tracking of exosome uptake with survivin blocking, receptor identification by pharmacologic inhibition, single lab","pmids":["30405884"],"is_preprint":false},{"year":2021,"finding":"BIRC5 downregulation (by siRNA) induces autophagy-dependent ROS production that causes DNA damage/strand breaks, and concurrently downregulates RAD54L, RAD51, and MRE11 (homologous recombination factors). Autophagic vesicles form proximal to the nucleus and trigger DNA leakage, revealing survivin as an autophagy negative-modulator that protects genome stability.","method":"BIRC5 siRNA in MCF7, MDA-MB-231, SK-BR-3, and MEF cells; RAD54L/RAD51 siRNA; ROS measurement; DNA damage assays (γH2AX); autophagic vesicle imaging","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple cell lines, genetic knockdown of pathway components, multiple orthogonal readouts (ROS, DNA damage, autophagy), single lab","pmids":["33549731"],"is_preprint":false},{"year":2021,"finding":"Mutant p53 (Trp53R172H) binds YAP in esophageal squamous cell carcinoma cells, and this complex induces Survivin (BIRC5) expression. Depletion of Survivin specifically decreases mutant p53-driven lung metastasis in a tail-vein injection model. Wild-type p53 does not bind YAP, establishing a gain-of-function mutant p53–YAP–BIRC5 axis in metastasis.","method":"shRNA depletion of Trp53R172H, Co-IP for mutant p53–YAP interaction, bulk RNA-seq, tail-vein lung metastasis mouse model, survivin depletion rescue experiment","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP identifying complex, RNA-seq pathway identification, in vivo metastasis model with genetic rescue, multiple orthogonal methods in single rigorous study","pmids":["33737385"],"is_preprint":false},{"year":2013,"finding":"Survivin downregulation reduces metalloproteinases, β-catenin, and vimentin, limiting synovial invasive capacity in experimental arthritis. The inhibition leads to p53-independent reduction of T cell proliferation and favors Blimp-1 transcription and activity, limiting IL-2 production and facilitating regulatory Foxp3+CD4+ and effector CD8+ T cells.","method":"Lentivirus shRNA knockdown of survivin in mouse arthritis models (mBSA-induced and collagen type II-induced), metalloproteinase assays, β-catenin/vimentin western blot, T cell proliferation and differentiation assays","journal":"Journal of leukocyte biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic knockdown with multiple downstream mechanistic readouts, two arthritis models, single lab","pmids":["25381389"],"is_preprint":false},{"year":2017,"finding":"Survivin overexpression in mature adipocytes downregulates Adrb3 (reducing cAMP production), upregulates Fsp27 protein (via reduced degradation), and inhibits isoproterenol-stimulated lipolysis. Survivin expression in adipocytes is induced by insulin through the PI3K/mTOR pathway and is suppressed by starvation.","method":"Ectopic survivin overexpression in 3T3-L1 and C3H10T1/2 cells, cAMP measurement, Fsp27 protein stability assays, lipolysis assays, PI3K/mTOR inhibitor treatment","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function with multiple downstream readouts (cAMP, Fsp27 stability, lipolysis), pathway inhibitors, single lab","pmids":["28055005"],"is_preprint":false},{"year":2003,"finding":"HIV-1 Vpr protein upregulates survivin expression via survivin promoter transactivation, dependent on Vpr-induced G2/M cell cycle arrest. Blocking Vpr-induced G2/M arrest eliminates survivin promoter transactivation, linking cell cycle position to survivin transcriptional regulation.","method":"Survivin promoter reporter assays, Vpr expression, G2/M arrest inhibition experiments","journal":"Apoptosis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter reporter assays with pharmacologic rescue experiment establishing causality, single lab","pmids":["12510154"],"is_preprint":false}],"current_model":"BIRC5/Survivin is a multifunctional IAP family protein that operates as an essential subunit of the chromosomal passenger complex (with Aurora B, INCENP, and Borealin), where it directs CPC centromere localization via a CRM1-interacting nuclear export signal and enables amphitelic kinetochore-spindle assembly, proper chromosome segregation, and cytokinesis; its mitotic activity is primed by PLK1 phosphorylation at Ser20, which activates Aurora B, while dynamic association with centromeres is regulated by Lys63-linked ubiquitination/deubiquitination; survivin also modulates microtubule dynamics, suppresses apoptosis by protecting against mitochondrial pathway activation (partly through Hsp90 chaperoning and interaction with CDK4/p21), shifts metabolism toward aerobic glycolysis via DRP1-dependent mitochondrial fragmentation and complex I inhibition, negatively regulates autophagy to protect genomic stability, and is transcriptionally controlled by Sp1/Sp3, E2F factors, the PI3K/Akt/p70S6K1 axis, and can be de-repressed by promoter methylation blocking p53 binding, while mutant p53 can actively induce it through a YAP co-complex to promote metastasis."},"narrative":{"mechanistic_narrative":"BIRC5 (survivin) is a dual-function mitotic regulator and apoptosis suppressor that operates principally as an essential subunit of the chromosomal passenger complex (CPC) alongside Aurora B, Borealin, and INCENP, where it dictates CPC localization to centromeres and is required for proper chromosome segregation and cytokinesis [PMID:16962308]. Centromere targeting is achieved through a leucine-rich CRM1-binding nuclear export signal that tethers the CPC and is concurrently required for survivin's cytoprotective activity [PMID:17361097], while dynamic centromere association is controlled by a degradation-independent Lys63 ubiquitination/deubiquitination cycle in which Ufd1-mediated Lys63 ubiquitination promotes association and hFAM-mediated deubiquitination drives dissociation [PMID:16322459]. Within the CPC, PLK1 phosphorylates survivin at Ser20 as a priming event required for Aurora B activation and correct spindle-microtubule attachment [PMID:21148584], and survivin additionally modulates microtubule dynamics directly, independently of Aurora B, by suppressing centrosomal microtubule nucleation and catastrophe [PMID:16407408]. Loss of survivin produces merotelic kinetochore attachments, polyploidy, and a DNA damage response, establishing it as essential for amphitelic kinetochore-spindle assembly and genomic stability [PMID:24886358]. Beyond mitosis, survivin suppresses apoptosis: its stability and antiapoptotic function depend on an Hsp90 ATPase-domain/survivin BIR-domain interaction whose disruption triggers proteasomal degradation and mitochondrial apoptosis [PMID:14614132], and it reprograms metabolism by recruiting DRP1 to drive mitochondrial fragmentation, inhibiting respiratory complex I, repressing Bim, and shifting cells toward aerobic glycolysis [PMID:23146905]. Survivin also negatively regulates autophagy to protect genome integrity, with its knockdown inducing autophagy-dependent ROS, DNA damage, and downregulation of homologous-recombination factors [PMID:33549731]. Its expression is governed by Sp1/Sp3 at a GC-rich TATA-less promoter [PMID:17350596], by E2F factors [PMID:19497660], and by the PI3K/Akt/p70S6K1 axis [PMID:20361940], and a gain-of-function mutant p53–YAP complex induces BIRC5 to promote metastasis [PMID:33737385].","teleology":[{"year":1999,"claim":"Established that survivin exists as functionally distinct splice isoforms, showing that structural changes in the BIR domain alter antiapoptotic capacity.","evidence":"Northern blot, RT-PCR and transfection assays in renal cell carcinoma lines identifying survivin-deltaEx3 and survivin-2B","pmids":["10626797"],"confidence":"Medium","gaps":["Does not define the molecular mechanism by which BIR-domain alterations change antiapoptotic activity","Physiological abundance and roles of the isoforms unresolved"]},{"year":2000,"claim":"Linked survivin to cell cycle progression by showing it engages CDK4 and liberates p21 to promote S-phase entry, framing survivin as more than a passive apoptosis inhibitor.","evidence":"Co-immunoprecipitation and cell cycle analysis after survivin transfection in hepatocellular carcinoma cells","pmids":["10796883"],"confidence":"Medium","gaps":["Single-lab Co-IP without reciprocal mapping","Direct vs indirect nature of the CDK4 interaction not resolved"]},{"year":2003,"claim":"Defined a chaperone dependency for survivin stability, showing the Hsp90 ATPase domain binds the survivin BIR domain to prevent proteasomal degradation and apoptosis.","evidence":"Reciprocal Co-IP with domain mapping, antibody-mediated disruption, proteasome rescue, apoptosis and mitosis assays","pmids":["14614132"],"confidence":"High","gaps":["Does not identify the E3 ligase acting on uncomplexed survivin","Structural basis of the BIR–ATPase interaction not solved"]},{"year":2003,"claim":"Connected viral cell-cycle manipulation to survivin transcription, showing HIV-1 Vpr transactivates the survivin promoter contingent on G2/M arrest.","evidence":"Survivin promoter reporter assays with Vpr expression and G2/M arrest blockade","pmids":["12510154"],"confidence":"Medium","gaps":["Promoter element mediating cell-cycle-dependent activation not mapped","Reporter-based, not endogenous locus"]},{"year":2005,"claim":"Revealed a non-proteolytic ubiquitin code controlling survivin's centromere residency, distinguishing Lys63 ubiquitination/deubiquitination from degradative Lys48 signaling.","evidence":"Biochemical ubiquitination assays, siRNA of hFAM and Ufd1, live imaging and chromosome segregation readouts","pmids":["16322459"],"confidence":"High","gaps":["How the ubiquitin cycle is spatially timed at centromeres unresolved","Other deubiquitinases/ligases not excluded"]},{"year":2006,"claim":"Separated a CPC-independent activity of survivin, demonstrating it directly modulates microtubule nucleation and catastrophe rather than acting solely through Aurora B.","evidence":"siRNA depletion and overexpression with time-lapse imaging of GFP-tubulin/EB1 and pharmacologic Aurora B inhibition","pmids":["16407408"],"confidence":"High","gaps":["Molecular basis of direct microtubule modulation not defined","Whether monomeric or complexed survivin mediates this is unclear"]},{"year":2006,"claim":"Consolidated survivin's identity as an evolutionarily conserved CPC subunit that dictates centromere localization and is essential for segregation and cytokinesis.","evidence":"Synthesis of Co-IP, localization and genetic knockdown studies across species","pmids":["16962308"],"confidence":"High","gaps":["Review-level synthesis rather than a single primary dataset","Stoichiometry and assembly order within the CPC not detailed here"]},{"year":2007,"claim":"Identified the CRM1-binding nuclear export signal as the determinant linking centromere targeting to cytoprotection, unifying mitotic and antiapoptotic functions.","evidence":"NES identification, CRM1 interaction and export-deficient mutant analysis with viability assays","pmids":["17361097"],"confidence":"Medium","gaps":["Limited methodological detail; single lab","How export status mechanistically alters apoptosis protection not dissected"]},{"year":2007,"claim":"Mapped the basal transcriptional control of BIRC5 to Sp1/Sp3 acting through defined GC-box elements in a TATA-less promoter.","evidence":"Promoter cloning, EMSA, RNAi of Sp1/Sp3, mithramycin treatment and luciferase reporters","pmids":["17350596"],"confidence":"Medium","gaps":["Does not address inducible/context-specific regulation","Combinatorial control with other factors not tested"]},{"year":2009,"claim":"Explained survivin de-repression in cancer epigenetically, showing CpG-island methylation blocks p53 binding and thus relieves p53-mediated repression.","evidence":"Methylation-specific PCR, pyrosequencing, decitabine demethylation and p53 binding assays","pmids":["19363521"],"confidence":"Medium","gaps":["Direct p53 occupancy change at the locus inferred pharmacologically","Cell-context dependence of p53 repression not surveyed"]},{"year":2010,"claim":"Placed survivin downstream of growth-factor signaling by establishing the PI3K/Akt/p70S6K1 axis as a controller of its mRNA, with p70S6K1 sufficient for induction.","evidence":"Overexpression of active PI3K/Akt/PTEN/p70S6K1, rapamycin treatment and mRNA quantification","pmids":["20361940"],"confidence":"Medium","gaps":["Transcriptional vs stability contribution to mRNA change not separated","Direct effector at the promoter not identified"]},{"year":2010,"claim":"Defined the kinase trigger of survivin's mitotic function, showing PLK1 phosphorylation at Ser20 primes Aurora B activation and correct kinetochore attachment.","evidence":"In vitro PLK1 kinase assay, S20A phospho-dead mutant, FRET Aurora B activity reporter and live mitosis imaging","pmids":["21148584"],"confidence":"High","gaps":["How Ser20 phosphorylation structurally activates Aurora B unresolved","Phosphatase reversing Ser20 not identified"]},{"year":2012,"claim":"Uncovered a metabolic arm of survivin's antiapoptotic role, showing it recruits DRP1 to fragment mitochondria, inhibits complex I, and drives aerobic glycolysis.","evidence":"Gain/loss of function in neuroblastoma with mitochondrial imaging, respiration, ROS and glycolysis-inhibitor assays","pmids":["23146905"],"confidence":"High","gaps":["Direct vs indirect DRP1 recruitment mechanism not resolved","Whether this occurs in non-cancer cells unaddressed"]},{"year":2013,"claim":"Extended transcriptional control of BIRC5 to E2F/MYCN networks and added CDC2 phosphorylation as a post-translational stability mechanism in neuroblastoma.","evidence":"E2F reporter/ChIP, CDC2 siRNA, protein stability assays and tumor sample analysis","pmids":["19497660"],"confidence":"Medium","gaps":["CDC2 phospho-site on survivin not mapped here","Relative weight of E2F vs MYCN inputs unresolved"]},{"year":2013,"claim":"Showed that oncogenic HER2 stabilizes survivin protein via Akt/CDK1-cyclin B1 phosphorylation at Thr34 while limiting its ubiquitination, integrating receptor signaling with survivin abundance.","evidence":"HER2 overexpression, Thr34 mutagenesis, pathway inhibitors, XAF1 knockdown and ubiquitination assays","pmids":["23323858"],"confidence":"Medium","gaps":["Multiple parallel mechanisms not quantitatively ranked","Direct kinase–substrate contacts not validated in vitro"]},{"year":2013,"claim":"Connected stemness factor OCT4 to BIRC5 induction, demonstrating an indirect promoter-activating route and therapeutic synergy of co-suppression.","evidence":"OCT4 gain/loss, BIRC5 promoter reporters, CCND1 ChIP, apoptosis assays and xenografts","pmids":["23433354"],"confidence":"Medium","gaps":["Mediator bridging OCT4 to the BIRC5 promoter not identified","Direct vs indirect remains formally open"]},{"year":2013,"claim":"Demonstrated a survivin role in inflammatory/immune contexts, linking its downregulation to reduced invasiveness and altered T-cell differentiation via Blimp-1.","evidence":"Lentiviral shRNA in two mouse arthritis models with metalloproteinase, β-catenin/vimentin and T-cell assays","pmids":["25381389"],"confidence":"Medium","gaps":["Direct molecular targets of survivin in T cells not defined","Cell-intrinsic vs extrinsic effects not separated"]},{"year":2014,"claim":"Established survivin as essential for amphitelic kinetochore-spindle assembly and genome stability, with depletion causing merotely, polyploidy and DDR independent of p53 status.","evidence":"Stable RNAi in isogenic p53 WT/null lines, spectral karyotyping, microscopy and ATM/DNA-PK inhibition","pmids":["24886358"],"confidence":"High","gaps":["Mechanistic step at which merotely arises not pinpointed","Contribution of CPC vs direct microtubule roles not separated"]},{"year":2015,"claim":"Identified a therapeutically exploitable degradation route, showing glycolysis inhibition triggers PINK1/Parkin-mediated autophagic degradation of survivin, releasing Beclin-1 to enhance death.","evidence":"2DG treatment, Parkin knockdown, Beclin-1 Co-IP, xenografts and mitochondrial imaging","pmids":["26148234"],"confidence":"Medium","gaps":["Direct Parkin-survivin ubiquitination not demonstrated","Generality beyond survivin-overexpressing neuroblastoma unknown"]},{"year":2017,"claim":"Revealed a metabolic-hormonal function in adipocytes, where survivin suppresses lipolysis via Adrb3/cAMP downregulation and Fsp27 stabilization, downstream of insulin/PI3K/mTOR.","evidence":"Ectopic overexpression in adipocyte lines with cAMP, Fsp27 stability, lipolysis assays and pathway inhibitors","pmids":["28055005"],"confidence":"Medium","gaps":["In vivo adipose relevance not established","Mechanism of Adrb3 downregulation unresolved"]},{"year":2018,"claim":"Localized survivin to the cancer cell surface and validated it as an extracellular antibody target with in vivo antitumor efficacy.","evidence":"Flow cytometry/immunofluorescence for surface survivin and antibody treatment in glioma and melanoma models","pmids":["29540489"],"confidence":"Medium","gaps":["Mechanism of survivin externalization/membrane association unknown","Surface partner anchoring it not identified"]},{"year":2018,"claim":"Assigned a function to extracellular survivin, showing exosomal survivin promotes recipient-cell exosome internalization.","evidence":"Exosome uptake tracking with survivin blocking and receptor inhibition","pmids":["30405884"],"confidence":"Medium","gaps":["Direct interaction of exosomal survivin with named receptors not shown","Single-lab pharmacologic evidence"]},{"year":2021,"claim":"Defined survivin as a negative regulator of autophagy protecting genome integrity, with its loss inducing autophagy-dependent ROS, DNA damage and HR-factor downregulation.","evidence":"BIRC5 and RAD54L/RAD51 siRNA across multiple cell lines with ROS, γH2AX and autophagic vesicle imaging","pmids":["33549731"],"confidence":"Medium","gaps":["Direct molecular link from survivin to autophagy machinery not mapped","Causal ordering of ROS vs DNA damage not fully resolved"]},{"year":2021,"claim":"Established a gain-of-function oncogenic axis, showing mutant p53 binds YAP to induce BIRC5 and drive metastasis, distinct from wild-type p53 behavior.","evidence":"Co-IP of mutant p53–YAP, RNA-seq, tail-vein lung metastasis model with survivin depletion rescue","pmids":["33737385"],"confidence":"High","gaps":["Direct mutant p53–YAP occupancy at the BIRC5 promoter not shown","Downstream survivin effectors driving metastasis not defined"]},{"year":null,"claim":"How survivin's distinct molecular pools — CPC-bound mitotic, mitochondrial/metabolic, autophagy-regulating, and surface/exosomal — are partitioned and coordinated within a single cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying structural model links the BIR domain, NES, and post-translational marks to functional pool selection","Mechanism of survivin externalization to the cell surface and exosomes is unknown","Direct effectors of the metabolic and autophagy functions not fully identified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[9,5,6]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[4]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[5,6]}],"localization":[{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[3,5]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[4]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[11]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[17]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[3,5,9,14]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[2,11]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[15,19]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[11]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[7,10,16,20]}],"complexes":["chromosomal passenger complex (CPC)"],"partners":["AURKB","INCENP","CDK4","HSP90","CRM1","DNM1L","TP53","YAP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O15392","full_name":"Baculoviral IAP repeat-containing protein 5","aliases":["Apoptosis inhibitor 4","Apoptosis inhibitor survivin"],"length_aa":142,"mass_kda":16.4,"function":"Multitasking protein that has dual roles in promoting cell proliferation and preventing apoptosis (PubMed:20627126, PubMed:21364656, PubMed:25778398, PubMed:28218735, PubMed:9859993). Component of a chromosome passage protein complex (CPC) which is essential for chromosome alignment and segregation during mitosis and cytokinesis (PubMed:16322459). Acts as an important regulator of the localization of this complex; directs CPC movement to different locations from the inner centromere during prometaphase to midbody during cytokinesis and participates in the organization of the center spindle by associating with polymerized microtubules (PubMed:20826784). Involved in the recruitment of CPC to centromeres during early mitosis via association with histone H3 phosphorylated at 'Thr-3' (H3pT3) during mitosis (PubMed:20929775). The complex with RAN plays a role in mitotic spindle formation by serving as a physical scaffold to help deliver the RAN effector molecule TPX2 to microtubules (PubMed:18591255). May counteract a default induction of apoptosis in G2/M phase (PubMed:9859993). The acetylated form represses STAT3 transactivation of target gene promoters (PubMed:20826784). May play a role in neoplasia (PubMed:10626797). Inhibitor of CASP3 and CASP7 (PubMed:21536684). Essential for the maintenance of mitochondrial integrity and function (PubMed:25778398). Isoform 2 and isoform 3 do not appear to play vital roles in mitosis (PubMed:12773388, PubMed:16291752). Isoform 3 shows a marked reduction in its anti-apoptotic effects when compared with the displayed wild-type isoform (PubMed:10626797)","subcellular_location":"Cytoplasm; Nucleus; Chromosome; Chromosome, centromere; Cytoplasm, cytoskeleton, spindle; Chromosome, centromere, kinetochore; Midbody","url":"https://www.uniprot.org/uniprotkb/O15392/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/BIRC5","classification":"Common Essential","n_dependent_lines":1204,"n_total_lines":1208,"dependency_fraction":0.9966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ATL3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/BIRC5","total_profiled":1310},"omim":[{"mim_id":"620959","title":"UBIQUITIN-SPECIFIC PEPTIDASE 35; USP35","url":"https://www.omim.org/entry/620959"},{"mim_id":"617224","title":"GROWTH ARREST-SPECIFIC 2-LIKE 3; GAS2L3","url":"https://www.omim.org/entry/617224"},{"mim_id":"616147","title":"CYCLIN-DEPENDENT KINASE 15; CDK15","url":"https://www.omim.org/entry/616147"},{"mim_id":"611712","title":"HOMEODOMAIN-INTERACTING PROTEIN KINASE 4; HIPK4","url":"https://www.omim.org/entry/611712"},{"mim_id":"609977","title":"CELL DIVISION CYCLE-ASSOCIATED PROTEIN 8; CDCA8","url":"https://www.omim.org/entry/609977"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytokinetic bridge","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":35.8},{"tissue":"lymphoid tissue","ntpm":38.1},{"tissue":"testis","ntpm":18.8}],"url":"https://www.proteinatlas.org/search/BIRC5"},"hgnc":{"alias_symbol":["EPR-1","survivin"],"prev_symbol":["API4"]},"alphafold":{"accession":"O15392","domains":[{"cath_id":"1.10.1170.10","chopping":"10-141","consensus_level":"high","plddt":96.3606,"start":10,"end":141}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O15392","model_url":"https://alphafold.ebi.ac.uk/files/AF-O15392-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O15392-F1-predicted_aligned_error_v6.png","plddt_mean":94.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=BIRC5","jax_strain_url":"https://www.jax.org/strain/search?query=BIRC5"},"sequence":{"accession":"O15392","fasta_url":"https://rest.uniprot.org/uniprotkb/O15392.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O15392/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O15392"}},"corpus_meta":[{"pmid":"27340370","id":"PMC_27340370","title":"Survivin: 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from p53.","date":"2014","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/24886358","citation_count":29,"is_preprint":false},{"pmid":"25020159","id":"PMC_25020159","title":"The emerging role of exosomes in survivin secretion.","date":"2014","source":"Histology and histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/25020159","citation_count":29,"is_preprint":false},{"pmid":"15540897","id":"PMC_15540897","title":"Survivin and leukemia.","date":"2004","source":"International journal of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/15540897","citation_count":28,"is_preprint":false},{"pmid":"36166738","id":"PMC_36166738","title":"Survivin in Breast Cancer: A Review.","date":"2022","source":"Genetic testing and molecular biomarkers","url":"https://pubmed.ncbi.nlm.nih.gov/36166738","citation_count":27,"is_preprint":false},{"pmid":"21611091","id":"PMC_21611091","title":"Survivin and pancreatic cancer.","date":"2011","source":"World journal of clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/21611091","citation_count":26,"is_preprint":false},{"pmid":"25381389","id":"PMC_25381389","title":"Down-regulation of survivin alleviates experimental arthritis.","date":"2014","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/25381389","citation_count":26,"is_preprint":false},{"pmid":"32751449","id":"PMC_32751449","title":"BIRC5/Survivin Expression as a Non-Invasive Biomarker of Endometriosis.","date":"2020","source":"Diagnostics (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/32751449","citation_count":25,"is_preprint":false},{"pmid":"26159786","id":"PMC_26159786","title":"An Old Flame Never Dies: Survivin in Cancer and Cellular Senescence.","date":"2015","source":"Gerontology","url":"https://pubmed.ncbi.nlm.nih.gov/26159786","citation_count":25,"is_preprint":false},{"pmid":"16534789","id":"PMC_16534789","title":"Survivin: an inhibitor of apoptosis in pediatric cancer.","date":"2006","source":"Pediatric blood & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/16534789","citation_count":25,"is_preprint":false},{"pmid":"33441606","id":"PMC_33441606","title":"Survivin and caspases serum protein levels and survivin variants mRNA expression in sepsis.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/33441606","citation_count":24,"is_preprint":false},{"pmid":"16644787","id":"PMC_16644787","title":"Transcriptional expression of survivin and its splice variants in endometriosis.","date":"2006","source":"Molecular human reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/16644787","citation_count":24,"is_preprint":false},{"pmid":"23323858","id":"PMC_23323858","title":"HER2 stabilizes survivin while concomitantly down-regulating survivin gene transcription by suppressing Notch cleavage.","date":"2013","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/23323858","citation_count":24,"is_preprint":false},{"pmid":"19186007","id":"PMC_19186007","title":"Differential expression of survivin and its splice variants, survivin-DeltaEx3 and survivin-2B, in bladder cancer.","date":"2009","source":"Cancer detection and prevention","url":"https://pubmed.ncbi.nlm.nih.gov/19186007","citation_count":24,"is_preprint":false},{"pmid":"33549731","id":"PMC_33549731","title":"YM155 and BIRC5 downregulation induce genomic instability via autophagy-mediated ROS production and inhibition in DNA repair.","date":"2021","source":"Pharmacological research","url":"https://pubmed.ncbi.nlm.nih.gov/33549731","citation_count":24,"is_preprint":false},{"pmid":"19497660","id":"PMC_19497660","title":"Regulation of BIRC5 and its isoform BIRC5-2B in neuroblastoma.","date":"2009","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/19497660","citation_count":22,"is_preprint":false},{"pmid":"33737385","id":"PMC_33737385","title":"Mutant p53 regulates Survivin to foster lung metastasis.","date":"2021","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/33737385","citation_count":22,"is_preprint":false},{"pmid":"15512811","id":"PMC_15512811","title":"Survivin expression in acute leukemias and myelodysplastic syndromes.","date":"2004","source":"Leukemia & lymphoma","url":"https://pubmed.ncbi.nlm.nih.gov/15512811","citation_count":22,"is_preprint":false},{"pmid":"31020660","id":"PMC_31020660","title":"Survivin modulatory role in autoimmune and autoinflammatory diseases.","date":"2019","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/31020660","citation_count":21,"is_preprint":false},{"pmid":"27539959","id":"PMC_27539959","title":"Reciprocal regulation of BMF and BIRC5 (Survivin) linked to Eomes overexpression in colorectal cancer.","date":"2016","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/27539959","citation_count":21,"is_preprint":false},{"pmid":"21585553","id":"PMC_21585553","title":"Survivin in skin pathologies.","date":"2011","source":"Experimental dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/21585553","citation_count":20,"is_preprint":false},{"pmid":"27644605","id":"PMC_27644605","title":"Survivin, a Promising Gene for Targeted Cancer Treatment.","date":"2016","source":"Asian Pacific journal of cancer prevention : APJCP","url":"https://pubmed.ncbi.nlm.nih.gov/27644605","citation_count":20,"is_preprint":false},{"pmid":"32814079","id":"PMC_32814079","title":"Survivin modulation in the antimelanoma activity of prodiginines.","date":"2020","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/32814079","citation_count":20,"is_preprint":false},{"pmid":"33845641","id":"PMC_33845641","title":"CircANKRD52 Promotes the Tumorigenesis of Hepatocellular Carcinoma by Sponging miR-497-5p and Upregulating BIRC5 Expression.","date":"2021","source":"Cell transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/33845641","citation_count":20,"is_preprint":false},{"pmid":"30405884","id":"PMC_30405884","title":"Exosomal survivin facilitates vesicle internalization.","date":"2018","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/30405884","citation_count":19,"is_preprint":false},{"pmid":"31959045","id":"PMC_31959045","title":"Targeting survivin sensitizes cervical cancer cells to radiation treatment.","date":"2020","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/31959045","citation_count":19,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":40673,"output_tokens":6391,"usd":0.108942,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15290,"output_tokens":6860,"usd":0.123975,"stage2_stop_reason":"end_turn"},"total_usd":0.232917,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"Two novel splice variants of survivin were identified: survivin-deltaEx3 (lacking exon 3) and survivin-2B (retaining part of intron 2 as a cryptic exon). Both cause structural changes in the BIR domain. In transfection experiments, survivin-deltaEx3 retained antiapoptotic properties while survivin-2B showed markedly reduced antiapoptotic potential.\",\n      \"method\": \"Northern blot, RT-PCR, transfection assays in renal cell carcinoma cell lines\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional transfection assays with two isoforms, single lab, two orthogonal methods (molecular cloning + functional assay)\",\n      \"pmids\": [\"10626797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Survivin interacts with cyclin-dependent kinase 4 (CDK4), and overexpression of survivin releases p21(WAF1/Cip1) from CDK4, thereby promoting cell cycle progression (decrease in G0/G1, increase in S phase) in hepatocellular carcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation, cell cycle analysis after survivin transfection, immunofluorescence\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP showing CDK4 interaction combined with functional cell cycle readout, single lab\",\n      \"pmids\": [\"10796883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Hsp90 associates with survivin via an interaction involving the ATPase domain of Hsp90 and the survivin BIR domain. Disruption of this complex (by global Hsp90 inhibition or antibody-mediated targeting) causes proteasomal degradation of survivin, mitochondrial-dependent apoptosis, and mitotic defects.\",\n      \"method\": \"Co-immunoprecipitation, antibody-mediated complex disruption, proteasome inhibitor rescue, cell death and mitosis assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP mapping interaction domains, multiple orthogonal functional assays (proteasomal degradation, apoptosis, mitotic defects), single lab but multiple methods\",\n      \"pmids\": [\"14614132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Survivin is ubiquitinated in mitosis through both Lys48 and Lys63 ubiquitin linkages. The deubiquitinating enzyme hFAM mediates Lys63 deubiquitination required for dissociation of survivin from centromeres, while Lys63 ubiquitination mediated by Ufd1 is required for association of survivin with centromeres. This ubiquitination cycle regulates chromosome alignment and segregation independently of protein degradation.\",\n      \"method\": \"Biochemical ubiquitination assays, siRNA knockdown of hFAM and Ufd1, live-cell imaging, chromosome segregation assays\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (biochemical ubiquitination, genetic knockdown, functional chromosome segregation readout), rigorous mechanistic dissection in a high-impact journal\",\n      \"pmids\": [\"16322459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Depletion of survivin by siRNA increased centrosomal microtubule nucleation and increased microtubule catastrophe frequency, whereas survivin overexpression reduced centrosomal microtubule nucleation and suppressed microtubule dynamics in mitotic spindles and midbodies. This effect was specific to survivin and not recapitulated by Aurora B depletion, indicating survivin directly modulates microtubule dynamics.\",\n      \"method\": \"siRNA depletion, time-lapse imaging of GFP-alpha-tubulin and GFP-EB1, pharmacologic Aurora B inhibition\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — live imaging with multiple reporters plus pharmacologic controls, loss-of-function and gain-of-function experiments, orthogonal validation\",\n      \"pmids\": [\"16407408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Survivin acts as a subunit of the chromosomal passenger complex (CPC), together with Aurora B kinase, Borealin, and INCENP. Within this complex, survivin dictates CPC localization to centromeres and is essential for proper chromosome segregation and cytokinesis. This mitotic regulatory function is conserved throughout evolution.\",\n      \"method\": \"Review/synthesis citing multiple experimental studies (Co-IP, localization, genetic knockdown)\",\n      \"journal\": \"Current opinion in cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CPC membership established by multiple independent labs using Co-IP, localization, and functional epistasis across species\",\n      \"pmids\": [\"16962308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The nuclear export receptor CRM1 interacts with a leucine-rich nuclear export signal (NES) conserved in all mammalian survivin proteins, tethering the CPC to the centromere. Export-deficient survivin fails to protect tumor cells against apoptosis, indicating the CRM1/survivin interaction is required for both centromere localization and cytoprotective activity.\",\n      \"method\": \"Identification of NES by sequence analysis, CRM1 interaction assays, export-deficient mutant analysis, cell viability assays\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — NES mutagenesis and functional rescue experiments, single lab, limited methodological detail in abstract\",\n      \"pmids\": [\"17361097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Sp1 and Sp3 transcription factors regulate basal survivin promoter activity. Two Sp1-binding sites within the proximal 269 bp GC-rich, TATA-less promoter (at positions -148 to -153 and -127 to -140) are essential. Both Sp1 and Sp3 activate the survivin promoter, as shown by EMSA, RNAi knockdown of Sp1/Sp3, mithramycin treatment, and overexpression.\",\n      \"method\": \"Promoter cloning, EMSA, RNAi knockdown, mithramycin treatment, Sp1/Sp3 overexpression, luciferase reporter assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA plus functional reporter assays plus RNAi knockdown, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"17350596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"DNA methylation of the survivin CpG island inhibits p53 binding to the survivin promoter, thereby preventing p53-mediated repression of survivin. Demethylation by decitabine restores p53-dependent survivin repression. This represents a mechanism of survivin de-repression via promoter methylation blocking a transcriptional repressor.\",\n      \"method\": \"Methylation-specific PCR, pyrosequencing, decitabine treatment, p53 binding assays, microarray analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple complementary methods (MSP, pyrosequencing, pharmacologic demethylation with functional readout), single lab\",\n      \"pmids\": [\"19363521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PLK1 (polo-like kinase 1) phosphorylates survivin at Ser20, a priming phosphorylation required for Aurora B kinase activation within the CPC. Inhibition of PLK1 or expression of non-phosphorylatable survivin (S20A mutant) prevents Aurora B activation and correct spindle microtubule attachment, leading to chromosome segregation errors.\",\n      \"method\": \"PLK1 kinase assays, survivin S20A phospho-dead mutant expression, FRET-based Aurora B activity reporter, quantitative phosphorylation assays, live-cell mitosis imaging\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay identifying writer (PLK1), mutagenesis of phospho-site, FRET reporter for functional validation, multiple orthogonal approaches\",\n      \"pmids\": [\"21148584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The PI3K/Akt/p70S6K1 signaling pathway regulates survivin mRNA expression. Overexpression of activated PI3K or Akt induces survivin mRNA, while PTEN overexpression decreases it. p70S6K1 alone is sufficient to induce survivin expression, and rapamycin treatment decreases survivin mRNA, placing p70S6K1 as a key downstream effector.\",\n      \"method\": \"Overexpression of active PI3K (v-P3k), wild-type and mutant PTEN, p70S6K1; rapamycin treatment; survivin siRNA; mRNA quantification\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic overexpression and pharmacologic inhibition with mRNA readout, pathway placement by epistasis, single lab\",\n      \"pmids\": [\"20361940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Survivin induces mitochondrial fragmentation by recruiting the fission regulator DRP1/DNM1L to mitochondria, inhibits mitochondrial respiratory complex I (preventing ROS accumulation and FOXO3-induced apoptosis), represses BCL2L11/Bim expression, and shifts cells from oxidative phosphorylation to aerobic glycolysis. Glycolysis inhibitors neutralize the antiapoptotic effect of survivin.\",\n      \"method\": \"Survivin overexpression/knockdown in neuroblastoma cells, mitochondrial imaging, mitochondrial respiration assays, ROS measurement, glycolysis inhibitor treatment, DRP1 localization by fractionation/imaging\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal functional assays (mitochondrial morphology, respiration, ROS, metabolic shift), gain- and loss-of-function, mechanistic pathway placement, single lab\",\n      \"pmids\": [\"23146905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"OCT4 upregulates BIRC5 expression indirectly by increasing BIRC5 promoter activity (no direct OCT4 binding site in BIRC5 promoter), while directly binding an octamer motif in the CCND1 promoter to upregulate cyclin D1. Co-suppression of OCT4 and BIRC5 induces apoptosis and cell cycle arrest in HCC cells and suppresses xenograft growth.\",\n      \"method\": \"OCT4 overexpression/knockdown, BIRC5 promoter luciferase reporter assays, ChIP for CCND1 promoter, apoptosis assays, xenograft mouse model\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter reporter assays with gain/loss-of-function, ChIP for direct binding, functional in vivo validation, single lab\",\n      \"pmids\": [\"23433354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"HER2 stabilizes survivin protein by activating the HER2/Akt/CDK1-cyclin B1 pathway, which phosphorylates survivin at Thr34, the most important residue for survivin stability. Simultaneously, HER2/ERK signaling downregulates γ-secretase activity, reducing Notch cleavage and Notch-dependent survivin transcription. ERK also decreases XAF1, reducing the XIAP-XAF1 E3 ligase complex that ubiquitinates survivin.\",\n      \"method\": \"HER2 overexpression, Thr34 mutagenesis, pathway inhibitor treatments, XAF1 knockdown, ubiquitination assays\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis of key phosphorylation site, multiple pathway inhibitors, ubiquitination assays, single lab\",\n      \"pmids\": [\"23323858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Survivin knockdown causes polyploidization, merotelic kinetochore-spindle assemblies, γH2AX foci, and DNA damage response (DDR) with transient p53-mediated G1 arrest in p53 wild-type cells. Chromosomal aberrations indicative of NHEJ-based DSB repair occur only in survivin-depleted cells. These effects are independent of p53 status, establishing survivin as essential for amphitelic kinetochore-spindle assembly.\",\n      \"method\": \"Stable RNAi knockdown in isogenic p53 WT and p53-null cell lines, spectral karyotyping, confocal microscopy, western blot, proliferation assays, ATM/DNA-PK inhibition\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple isogenic cell lines with p53 status controlled, spectral karyotyping, multiple orthogonal readouts, mechanistic dissection of DDR pathway\",\n      \"pmids\": [\"24886358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Glycolysis inhibitor 2-deoxy-D-glucose (2DG) selectively acts on survivin-overexpressing neuroblastoma cells by inducing autophagic degradation of survivin via activation of the E3-ubiquitin ligase Parkin (a downstream target of PINK1). Survivin degradation releases bound Beclin-1, enhancing autophagy and cell death. Parkin knockdown reduces sensitivity of survivin-expressing cells to glycolysis inhibition.\",\n      \"method\": \"2DG treatment, Parkin knockdown, Beclin-1 co-immunoprecipitation, xenograft mouse model, mitochondrial network imaging\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway (PINK1-Parkin-survivin-Beclin1) with Co-IP, genetic knockdown of Parkin, in vivo validation, single lab\",\n      \"pmids\": [\"26148234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"BIRC5 is a direct transcriptional target of activating E2F transcription factors in neuroblastoma, primarily when p21Cip1 and p27Kip1 are suppressed. MYCN indirectly induces BIRC5 by suppressing CDKN1A/p21Cip1 and inducing Skp2 (which promotes p27Kip1 degradation). CDC2 phosphorylates BIRC5 to increase its protein stability; selective CDC2 knockdown inhibits BIRC5 abundance and antiapoptotic activity.\",\n      \"method\": \"E2F overexpression/reporter assays, CDC2 siRNA knockdown, ChIP, protein stability assays, neuroblastoma tumor samples\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for E2F binding, siRNA knockdown with functional readout, protein stability assays, single lab\",\n      \"pmids\": [\"19497660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Survivin is present on the outer cell membrane of a wide variety of cancer cell types (murine and human glioma, melanoma). Anti-survivin monoclonal antibodies generated against a survivin immunogen display antitumor activity in vivo against murine GL261 gliomas (flank and intracranial) and B16 melanoma, beyond CD8-mediated lysis.\",\n      \"method\": \"Flow cytometry and immunofluorescence for cell-surface survivin, in vivo tumor models with antibody treatment, immune serum analysis\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct surface localization by flow cytometry and immunofluorescence, in vivo functional validation, single lab\",\n      \"pmids\": [\"29540489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Exosomal survivin facilitates exosome internalization by recipient cancer cells. Blocking exosomal survivin reduces exosome uptake. Membrane receptors transferrin receptor, endothelin B receptor, insulin receptor alpha, and membrane glucocorticoid receptor all facilitate exosomal internalization.\",\n      \"method\": \"Exosome isolation, PKH67 lipophilic staining, immunofluorescence, flow cytometry, receptor blocking experiments\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct tracking of exosome uptake with survivin blocking, receptor identification by pharmacologic inhibition, single lab\",\n      \"pmids\": [\"30405884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"BIRC5 downregulation (by siRNA) induces autophagy-dependent ROS production that causes DNA damage/strand breaks, and concurrently downregulates RAD54L, RAD51, and MRE11 (homologous recombination factors). Autophagic vesicles form proximal to the nucleus and trigger DNA leakage, revealing survivin as an autophagy negative-modulator that protects genome stability.\",\n      \"method\": \"BIRC5 siRNA in MCF7, MDA-MB-231, SK-BR-3, and MEF cells; RAD54L/RAD51 siRNA; ROS measurement; DNA damage assays (γH2AX); autophagic vesicle imaging\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple cell lines, genetic knockdown of pathway components, multiple orthogonal readouts (ROS, DNA damage, autophagy), single lab\",\n      \"pmids\": [\"33549731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Mutant p53 (Trp53R172H) binds YAP in esophageal squamous cell carcinoma cells, and this complex induces Survivin (BIRC5) expression. Depletion of Survivin specifically decreases mutant p53-driven lung metastasis in a tail-vein injection model. Wild-type p53 does not bind YAP, establishing a gain-of-function mutant p53–YAP–BIRC5 axis in metastasis.\",\n      \"method\": \"shRNA depletion of Trp53R172H, Co-IP for mutant p53–YAP interaction, bulk RNA-seq, tail-vein lung metastasis mouse model, survivin depletion rescue experiment\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP identifying complex, RNA-seq pathway identification, in vivo metastasis model with genetic rescue, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"33737385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Survivin downregulation reduces metalloproteinases, β-catenin, and vimentin, limiting synovial invasive capacity in experimental arthritis. The inhibition leads to p53-independent reduction of T cell proliferation and favors Blimp-1 transcription and activity, limiting IL-2 production and facilitating regulatory Foxp3+CD4+ and effector CD8+ T cells.\",\n      \"method\": \"Lentivirus shRNA knockdown of survivin in mouse arthritis models (mBSA-induced and collagen type II-induced), metalloproteinase assays, β-catenin/vimentin western blot, T cell proliferation and differentiation assays\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic knockdown with multiple downstream mechanistic readouts, two arthritis models, single lab\",\n      \"pmids\": [\"25381389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Survivin overexpression in mature adipocytes downregulates Adrb3 (reducing cAMP production), upregulates Fsp27 protein (via reduced degradation), and inhibits isoproterenol-stimulated lipolysis. Survivin expression in adipocytes is induced by insulin through the PI3K/mTOR pathway and is suppressed by starvation.\",\n      \"method\": \"Ectopic survivin overexpression in 3T3-L1 and C3H10T1/2 cells, cAMP measurement, Fsp27 protein stability assays, lipolysis assays, PI3K/mTOR inhibitor treatment\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function with multiple downstream readouts (cAMP, Fsp27 stability, lipolysis), pathway inhibitors, single lab\",\n      \"pmids\": [\"28055005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"HIV-1 Vpr protein upregulates survivin expression via survivin promoter transactivation, dependent on Vpr-induced G2/M cell cycle arrest. Blocking Vpr-induced G2/M arrest eliminates survivin promoter transactivation, linking cell cycle position to survivin transcriptional regulation.\",\n      \"method\": \"Survivin promoter reporter assays, Vpr expression, G2/M arrest inhibition experiments\",\n      \"journal\": \"Apoptosis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter reporter assays with pharmacologic rescue experiment establishing causality, single lab\",\n      \"pmids\": [\"12510154\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"BIRC5/Survivin is a multifunctional IAP family protein that operates as an essential subunit of the chromosomal passenger complex (with Aurora B, INCENP, and Borealin), where it directs CPC centromere localization via a CRM1-interacting nuclear export signal and enables amphitelic kinetochore-spindle assembly, proper chromosome segregation, and cytokinesis; its mitotic activity is primed by PLK1 phosphorylation at Ser20, which activates Aurora B, while dynamic association with centromeres is regulated by Lys63-linked ubiquitination/deubiquitination; survivin also modulates microtubule dynamics, suppresses apoptosis by protecting against mitochondrial pathway activation (partly through Hsp90 chaperoning and interaction with CDK4/p21), shifts metabolism toward aerobic glycolysis via DRP1-dependent mitochondrial fragmentation and complex I inhibition, negatively regulates autophagy to protect genomic stability, and is transcriptionally controlled by Sp1/Sp3, E2F factors, the PI3K/Akt/p70S6K1 axis, and can be de-repressed by promoter methylation blocking p53 binding, while mutant p53 can actively induce it through a YAP co-complex to promote metastasis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"BIRC5 (survivin) is a dual-function mitotic regulator and apoptosis suppressor that operates principally as an essential subunit of the chromosomal passenger complex (CPC) alongside Aurora B, Borealin, and INCENP, where it dictates CPC localization to centromeres and is required for proper chromosome segregation and cytokinesis [#5]. Centromere targeting is achieved through a leucine-rich CRM1-binding nuclear export signal that tethers the CPC and is concurrently required for survivin's cytoprotective activity [#6], while dynamic centromere association is controlled by a degradation-independent Lys63 ubiquitination/deubiquitination cycle in which Ufd1-mediated Lys63 ubiquitination promotes association and hFAM-mediated deubiquitination drives dissociation [#3]. Within the CPC, PLK1 phosphorylates survivin at Ser20 as a priming event required for Aurora B activation and correct spindle-microtubule attachment [#9], and survivin additionally modulates microtubule dynamics directly, independently of Aurora B, by suppressing centrosomal microtubule nucleation and catastrophe [#4]. Loss of survivin produces merotelic kinetochore attachments, polyploidy, and a DNA damage response, establishing it as essential for amphitelic kinetochore-spindle assembly and genomic stability [#14]. Beyond mitosis, survivin suppresses apoptosis: its stability and antiapoptotic function depend on an Hsp90 ATPase-domain/survivin BIR-domain interaction whose disruption triggers proteasomal degradation and mitochondrial apoptosis [#2], and it reprograms metabolism by recruiting DRP1 to drive mitochondrial fragmentation, inhibiting respiratory complex I, repressing Bim, and shifting cells toward aerobic glycolysis [#11]. Survivin also negatively regulates autophagy to protect genome integrity, with its knockdown inducing autophagy-dependent ROS, DNA damage, and downregulation of homologous-recombination factors [#19]. Its expression is governed by Sp1/Sp3 at a GC-rich TATA-less promoter [#7], by E2F factors [#16], and by the PI3K/Akt/p70S6K1 axis [#10], and a gain-of-function mutant p53\\u2013YAP complex induces BIRC5 to promote metastasis [#20].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established that survivin exists as functionally distinct splice isoforms, showing that structural changes in the BIR domain alter antiapoptotic capacity.\",\n      \"evidence\": \"Northern blot, RT-PCR and transfection assays in renal cell carcinoma lines identifying survivin-deltaEx3 and survivin-2B\",\n      \"pmids\": [\"10626797\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not define the molecular mechanism by which BIR-domain alterations change antiapoptotic activity\", \"Physiological abundance and roles of the isoforms unresolved\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Linked survivin to cell cycle progression by showing it engages CDK4 and liberates p21 to promote S-phase entry, framing survivin as more than a passive apoptosis inhibitor.\",\n      \"evidence\": \"Co-immunoprecipitation and cell cycle analysis after survivin transfection in hepatocellular carcinoma cells\",\n      \"pmids\": [\"10796883\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab Co-IP without reciprocal mapping\", \"Direct vs indirect nature of the CDK4 interaction not resolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defined a chaperone dependency for survivin stability, showing the Hsp90 ATPase domain binds the survivin BIR domain to prevent proteasomal degradation and apoptosis.\",\n      \"evidence\": \"Reciprocal Co-IP with domain mapping, antibody-mediated disruption, proteasome rescue, apoptosis and mitosis assays\",\n      \"pmids\": [\"14614132\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not identify the E3 ligase acting on uncomplexed survivin\", \"Structural basis of the BIR\\u2013ATPase interaction not solved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Connected viral cell-cycle manipulation to survivin transcription, showing HIV-1 Vpr transactivates the survivin promoter contingent on G2/M arrest.\",\n      \"evidence\": \"Survivin promoter reporter assays with Vpr expression and G2/M arrest blockade\",\n      \"pmids\": [\"12510154\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Promoter element mediating cell-cycle-dependent activation not mapped\", \"Reporter-based, not endogenous locus\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Revealed a non-proteolytic ubiquitin code controlling survivin's centromere residency, distinguishing Lys63 ubiquitination/deubiquitination from degradative Lys48 signaling.\",\n      \"evidence\": \"Biochemical ubiquitination assays, siRNA of hFAM and Ufd1, live imaging and chromosome segregation readouts\",\n      \"pmids\": [\"16322459\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the ubiquitin cycle is spatially timed at centromeres unresolved\", \"Other deubiquitinases/ligases not excluded\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Separated a CPC-independent activity of survivin, demonstrating it directly modulates microtubule nucleation and catastrophe rather than acting solely through Aurora B.\",\n      \"evidence\": \"siRNA depletion and overexpression with time-lapse imaging of GFP-tubulin/EB1 and pharmacologic Aurora B inhibition\",\n      \"pmids\": [\"16407408\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of direct microtubule modulation not defined\", \"Whether monomeric or complexed survivin mediates this is unclear\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Consolidated survivin's identity as an evolutionarily conserved CPC subunit that dictates centromere localization and is essential for segregation and cytokinesis.\",\n      \"evidence\": \"Synthesis of Co-IP, localization and genetic knockdown studies across species\",\n      \"pmids\": [\"16962308\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Review-level synthesis rather than a single primary dataset\", \"Stoichiometry and assembly order within the CPC not detailed here\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified the CRM1-binding nuclear export signal as the determinant linking centromere targeting to cytoprotection, unifying mitotic and antiapoptotic functions.\",\n      \"evidence\": \"NES identification, CRM1 interaction and export-deficient mutant analysis with viability assays\",\n      \"pmids\": [\"17361097\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Limited methodological detail; single lab\", \"How export status mechanistically alters apoptosis protection not dissected\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Mapped the basal transcriptional control of BIRC5 to Sp1/Sp3 acting through defined GC-box elements in a TATA-less promoter.\",\n      \"evidence\": \"Promoter cloning, EMSA, RNAi of Sp1/Sp3, mithramycin treatment and luciferase reporters\",\n      \"pmids\": [\"17350596\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not address inducible/context-specific regulation\", \"Combinatorial control with other factors not tested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Explained survivin de-repression in cancer epigenetically, showing CpG-island methylation blocks p53 binding and thus relieves p53-mediated repression.\",\n      \"evidence\": \"Methylation-specific PCR, pyrosequencing, decitabine demethylation and p53 binding assays\",\n      \"pmids\": [\"19363521\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct p53 occupancy change at the locus inferred pharmacologically\", \"Cell-context dependence of p53 repression not surveyed\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Placed survivin downstream of growth-factor signaling by establishing the PI3K/Akt/p70S6K1 axis as a controller of its mRNA, with p70S6K1 sufficient for induction.\",\n      \"evidence\": \"Overexpression of active PI3K/Akt/PTEN/p70S6K1, rapamycin treatment and mRNA quantification\",\n      \"pmids\": [\"20361940\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcriptional vs stability contribution to mRNA change not separated\", \"Direct effector at the promoter not identified\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined the kinase trigger of survivin's mitotic function, showing PLK1 phosphorylation at Ser20 primes Aurora B activation and correct kinetochore attachment.\",\n      \"evidence\": \"In vitro PLK1 kinase assay, S20A phospho-dead mutant, FRET Aurora B activity reporter and live mitosis imaging\",\n      \"pmids\": [\"21148584\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Ser20 phosphorylation structurally activates Aurora B unresolved\", \"Phosphatase reversing Ser20 not identified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Uncovered a metabolic arm of survivin's antiapoptotic role, showing it recruits DRP1 to fragment mitochondria, inhibits complex I, and drives aerobic glycolysis.\",\n      \"evidence\": \"Gain/loss of function in neuroblastoma with mitochondrial imaging, respiration, ROS and glycolysis-inhibitor assays\",\n      \"pmids\": [\"23146905\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect DRP1 recruitment mechanism not resolved\", \"Whether this occurs in non-cancer cells unaddressed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended transcriptional control of BIRC5 to E2F/MYCN networks and added CDC2 phosphorylation as a post-translational stability mechanism in neuroblastoma.\",\n      \"evidence\": \"E2F reporter/ChIP, CDC2 siRNA, protein stability assays and tumor sample analysis\",\n      \"pmids\": [\"19497660\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CDC2 phospho-site on survivin not mapped here\", \"Relative weight of E2F vs MYCN inputs unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed that oncogenic HER2 stabilizes survivin protein via Akt/CDK1-cyclin B1 phosphorylation at Thr34 while limiting its ubiquitination, integrating receptor signaling with survivin abundance.\",\n      \"evidence\": \"HER2 overexpression, Thr34 mutagenesis, pathway inhibitors, XAF1 knockdown and ubiquitination assays\",\n      \"pmids\": [\"23323858\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Multiple parallel mechanisms not quantitatively ranked\", \"Direct kinase\\u2013substrate contacts not validated in vitro\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected stemness factor OCT4 to BIRC5 induction, demonstrating an indirect promoter-activating route and therapeutic synergy of co-suppression.\",\n      \"evidence\": \"OCT4 gain/loss, BIRC5 promoter reporters, CCND1 ChIP, apoptosis assays and xenografts\",\n      \"pmids\": [\"23433354\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mediator bridging OCT4 to the BIRC5 promoter not identified\", \"Direct vs indirect remains formally open\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated a survivin role in inflammatory/immune contexts, linking its downregulation to reduced invasiveness and altered T-cell differentiation via Blimp-1.\",\n      \"evidence\": \"Lentiviral shRNA in two mouse arthritis models with metalloproteinase, \\u03b2-catenin/vimentin and T-cell assays\",\n      \"pmids\": [\"25381389\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular targets of survivin in T cells not defined\", \"Cell-intrinsic vs extrinsic effects not separated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established survivin as essential for amphitelic kinetochore-spindle assembly and genome stability, with depletion causing merotely, polyploidy and DDR independent of p53 status.\",\n      \"evidence\": \"Stable RNAi in isogenic p53 WT/null lines, spectral karyotyping, microscopy and ATM/DNA-PK inhibition\",\n      \"pmids\": [\"24886358\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic step at which merotely arises not pinpointed\", \"Contribution of CPC vs direct microtubule roles not separated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified a therapeutically exploitable degradation route, showing glycolysis inhibition triggers PINK1/Parkin-mediated autophagic degradation of survivin, releasing Beclin-1 to enhance death.\",\n      \"evidence\": \"2DG treatment, Parkin knockdown, Beclin-1 Co-IP, xenografts and mitochondrial imaging\",\n      \"pmids\": [\"26148234\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct Parkin-survivin ubiquitination not demonstrated\", \"Generality beyond survivin-overexpressing neuroblastoma unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed a metabolic-hormonal function in adipocytes, where survivin suppresses lipolysis via Adrb3/cAMP downregulation and Fsp27 stabilization, downstream of insulin/PI3K/mTOR.\",\n      \"evidence\": \"Ectopic overexpression in adipocyte lines with cAMP, Fsp27 stability, lipolysis assays and pathway inhibitors\",\n      \"pmids\": [\"28055005\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo adipose relevance not established\", \"Mechanism of Adrb3 downregulation unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Localized survivin to the cancer cell surface and validated it as an extracellular antibody target with in vivo antitumor efficacy.\",\n      \"evidence\": \"Flow cytometry/immunofluorescence for surface survivin and antibody treatment in glioma and melanoma models\",\n      \"pmids\": [\"29540489\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of survivin externalization/membrane association unknown\", \"Surface partner anchoring it not identified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Assigned a function to extracellular survivin, showing exosomal survivin promotes recipient-cell exosome internalization.\",\n      \"evidence\": \"Exosome uptake tracking with survivin blocking and receptor inhibition\",\n      \"pmids\": [\"30405884\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct interaction of exosomal survivin with named receptors not shown\", \"Single-lab pharmacologic evidence\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined survivin as a negative regulator of autophagy protecting genome integrity, with its loss inducing autophagy-dependent ROS, DNA damage and HR-factor downregulation.\",\n      \"evidence\": \"BIRC5 and RAD54L/RAD51 siRNA across multiple cell lines with ROS, \\u03b3H2AX and autophagic vesicle imaging\",\n      \"pmids\": [\"33549731\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link from survivin to autophagy machinery not mapped\", \"Causal ordering of ROS vs DNA damage not fully resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established a gain-of-function oncogenic axis, showing mutant p53 binds YAP to induce BIRC5 and drive metastasis, distinct from wild-type p53 behavior.\",\n      \"evidence\": \"Co-IP of mutant p53\\u2013YAP, RNA-seq, tail-vein lung metastasis model with survivin depletion rescue\",\n      \"pmids\": [\"33737385\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct mutant p53\\u2013YAP occupancy at the BIRC5 promoter not shown\", \"Downstream survivin effectors driving metastasis not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How survivin's distinct molecular pools \\u2014 CPC-bound mitotic, mitochondrial/metabolic, autophagy-regulating, and surface/exosomal \\u2014 are partitioned and coordinated within a single cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying structural model links the BIR domain, NES, and post-translational marks to functional pool selection\", \"Mechanism of survivin externalization to the cell surface and exosomes is unknown\", \"Direct effectors of the metabolic and autophagy functions not fully identified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [9, 5, 6]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [3, 5]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [17]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3, 5, 9, 14]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [2, 11]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [15, 19]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [7, 10, 16, 20]}\n    ],\n    \"complexes\": [\"chromosomal passenger complex (CPC)\"],\n    \"partners\": [\"AURKB\", \"INCENP\", \"CDK4\", \"HSP90\", \"CRM1\", \"DNM1L\", \"TP53\", \"YAP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}