{"gene":"CSE1L","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":1993,"finding":"Yeast CSE1 (ortholog of human CSE1L) is an essential gene required for accurate mitotic chromosome segregation; cse1 mutants accumulate large-budded cells with aberrant binucleate morphologies and show predominantly nondisjunction events, placing Cse1 in the chromosome segregation pathway.","method":"Conditional yeast mutant screen, complementation cloning, gene disruption","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — genetic complementation, loss-of-function mutant with defined mitotic phenotype, replicated across multiple alleles in a dedicated study","pmids":["8336709"],"is_preprint":false},{"year":1995,"finding":"Human CSE1L (CAS) is the functional homologue of yeast CSE1 (59% overall protein homology, similar length); antisense reduction of CAS protein confers resistance to Pseudomonas exotoxin, diphtheria toxin, and TNF-mediated apoptosis, establishing CAS as a factor in selected apoptotic pathways.","method":"Expression/selection cloning, antisense cDNA, cDNA sequence analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — antisense knockdown with defined apoptosis phenotype, single lab but multiple toxin paradigms tested","pmids":["7479798"],"is_preprint":false},{"year":1996,"finding":"CAS reduction by antisense cDNA confers resistance to TNF-alpha, TNF-beta, Pseudomonas exotoxin, and diphtheria toxin-induced apoptosis but not to staurosporine, cycloheximide, or etoposide, indicating pathway-selective involvement of CAS in apoptosis.","method":"Antisense cDNA expression, cell viability and apoptosis assays","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined phenotypic selectivity, single lab, multiple apoptotic stimuli tested","pmids":["8639641"],"is_preprint":false},{"year":1996,"finding":"CAS protein localizes to microtubules and the mitotic spindle in proliferating cells; it shows microtubule-like distribution in interphase and labels the mitotic spindle, but is removed by mild detergent treatment and disperses in taxol/vincristine-treated cells, indicating it is associated with but not an integral part of microtubules.","method":"Immunofluorescence microscopy, cytoskeleton preparations, drug treatment","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by antibody staining with functional perturbation experiments, single lab","pmids":["8610099"],"is_preprint":false},{"year":1997,"finding":"Antisense-mediated reduction of CAS protein in HeLa cells perturbs G2-to-G1 cell cycle progression and causes G2/M arrest, with elevated cyclin B levels, consistent with a role in mitosis and cyclin B degradation analogous to yeast Cse1.","method":"Antisense CAS cDNA expression, flow cytometry, cyclin B western blot","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cell-cycle phenotype, single lab, two orthogonal readouts (FACS and cyclin B)","pmids":["9235994"],"is_preprint":false},{"year":2001,"finding":"Homozygous knockout of Cse1l in mice causes embryonic lethality by E5.5, demonstrating that CSE1L is essential for early embryonic development and cannot be compensated by other genes in vivo.","method":"Gene targeting in embryonic stem cells, mouse knockout, embryo analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — null knockout with clear lethal phenotype, statistical analysis, in vivo model","pmids":["11564884"],"is_preprint":false},{"year":2005,"finding":"Crystal structure of cargo-free yeast Cse1 at 3.1 Å reveals a closed ring conformation formed by N- and C-terminal HEAT-repeat arches; comparison with cargo-bound Cse1 shows a major conformational change at HEAT repeat 8 upon cargo binding, where the insertion connects RanGTP and importin-α contact sites. In the closed state, RanGTP binding sites are occluded and importin-α sites are distorted. Mutations destabilizing the N-to-C interaction uncouple importin-α and Ran binding.","method":"X-ray crystallography (3.1 Å), structure comparison, site-directed mutagenesis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with mutagenesis validation in a single rigorous study","pmids":["15866177"],"is_preprint":false},{"year":2007,"finding":"hCAS/CSE1L associates with a subset of p53 target promoters (including PIG3) in a p53-autonomous manner; its downregulation decreases transcription from those promoters and reduces apoptosis, and its silencing leads to increased methylation of histone H3 lysine 27 at the PIG3 gene, establishing a chromatin regulatory role.","method":"ChIP, siRNA knockdown, transcription assays, histone methylation analysis","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal ChIP and functional transcription assays, histone modification readout, published in Cell with multiple orthogonal methods","pmids":["17719542"],"is_preprint":false},{"year":2007,"finding":"PPM1H (protein phosphatase 1H/PP2C family) physically associates with CSE1L as identified by co-immunoprecipitation/mass spectrometry; PPM1H dephosphorylates CSE1L in vitro and in cells (shown by altered SDS-PAGE mobility), identifying PPM1H as a phosphatase (eraser) for CSE1L phosphorylation.","method":"Co-immunoprecipitation/mass spectrometry, in vitro phosphatase assay, SDS-PAGE mobility shift","journal":"Cancer biology & therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP/MS plus in vitro dephosphorylation assay, single lab","pmids":["18059182"],"is_preprint":false},{"year":2008,"finding":"CAS/CSE1L associates with alpha-tubulin and beta-tubulin, enhances tubulin heterodimer association, and its overexpression reduces paclitaxel-induced G2/M arrest and microtubule aster formation while enhancing apoptosis from other chemotherapeutic agents; knockdown produces opposite effects.","method":"Co-immunoprecipitation, flow cytometry, immunofluorescence, overexpression/knockdown","journal":"BMB reports","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP demonstrating tubulin interaction plus functional cell-cycle readouts, single lab","pmids":["18377724"],"is_preprint":false},{"year":2008,"finding":"CAS/CSE1L overexpression enhances MMP-2 secretion and cancer cell invasion while failing to increase proliferation; CAS localizes to cytoplasmic vesicles and vesicle membranes (immunogold EM); CAS reduction inhibits B16-F10 melanoma metastasis in vivo by 56%.","method":"Overexpression/knockdown, Matrigel invasion assay, immunofluorescence, immunogold electron microscopy, animal metastasis model","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (EM localization, invasion assay, in vivo), single lab","pmids":["18597698"],"is_preprint":false},{"year":2009,"finding":"CAS/CSE1L co-localizes with MMP-2 in vesicles at the cell membrane exterior; its C-terminal domain associates with MMP-2-containing vesicles; CAS is secreted and detected in conditioned medium and patient sera, establishing CAS as a secretory protein associated with vesicular MMP-2 trafficking.","method":"Co-localization (immunofluorescence), vesicle fractionation, immunoblotting of conditioned medium and sera","journal":"Cancer epidemiology, biomarkers & prevention","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-localization and biochemical fractionation, single lab, replicated in patient samples","pmids":["19383891"],"is_preprint":false},{"year":2009,"finding":"CAS/CSE1L overexpression induces polarization of HT-29 colorectal cells, increases translocation of CAS-stained vesicles to the cell membrane/protrusions, and enhances secretion of CEA and cathepsin D, demonstrating a role in directed epithelial secretion.","method":"CAS overexpression, immunofluorescence, ELISA for secreted proteins","journal":"Molecular and cellular biochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single overexpression approach with secretion readout","pmids":["19224336"],"is_preprint":false},{"year":2010,"finding":"Loss-of-function mutation in zebrafish cse1l causes dramatic fluid accumulation in the gut due to uncontrolled CFTR channel activation; analyses in zebrafish larvae and mammalian cells confirmed that Cse1l is a negative regulator of CFTR-dependent fluid secretion.","method":"Forward genetic screen (zebrafish), mutant characterization, fluid secretion assays in zebrafish and mammalian cells","journal":"Current biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — forward genetic identification, vertebrate model, functional validation in two species with mechanistic readout","pmids":["20933420"],"is_preprint":false},{"year":2010,"finding":"CSE1L associates with E-cadherin in GST pull-down and co-immunoprecipitation experiments; both proteins co-distribute basolaterally in polarized colorectal gland epithelium, linking CSE1L to E-cadherin-mediated epithelial polarity.","method":"GST pull-down, co-immunoprecipitation, immunohistochemistry","journal":"Journal of molecular histology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pull-down/Co-IP without mutagenesis or in vitro reconstitution","pmids":["20734115"],"is_preprint":false},{"year":2012,"finding":"v-H-Ras expression triggers ERK-dependent phosphorylation of CSE1L and induces microvesicle biogenesis; CSE1L overexpression triggers microvesicle generation; CSE1L knockdown reduces Ras-induced microvesicle biogenesis, MMP-2/MMP-9 secretion, and B16F10 melanoma metastasis, identifying CSE1L as a Ras/ERK-regulated microvesicle membrane protein.","method":"Ras overexpression, ERK inhibition, CSE1L knockdown/overexpression, vesicle fractionation, MMP secretion assay, animal metastasis model","journal":"Molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis (Ras→ERK→CSE1L) with multiple functional readouts, single lab","pmids":["22952058"],"is_preprint":false},{"year":2012,"finding":"In ovarian cancer cells, nuclear localization of CSE1L depends on constitutively active AKT; AKT inactivation translocates CSE1L to the cytoplasm, and expression of constitutively active AKT forces cytoplasmic CSE1L into the nucleus. Nuclear CSE1L transcriptionally suppresses the proapoptotic RASSF1C gene, mediating ovarian cancer cell survival.","method":"AKT inhibition/activation, immunofluorescence, RNA interference, apoptosis assays, gene expression analysis","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis (AKT→CSE1L nuclear localization→RASSF1C suppression), multiple methods, single lab","pmids":["22389439"],"is_preprint":false},{"year":2013,"finding":"AKT-driven nuclear localization of CSE1L in ovarian cancer cells is associated with nuclear accumulation of phosphorylated RanBP3 (also AKT-dependent); nuclear CSE1L is required for expression of invasion/metastasis-promoting genes and for cell motility and invasiveness.","method":"AKT inhibition, immunofluorescence, expression profiling after CSE1L silencing, invasion/motility assays","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic epistasis with RanBP3, expression profiling, functional assays, single lab","pmids":["23948303"],"is_preprint":false},{"year":2015,"finding":"hCAS/CSE1L associates with RAD51 in human cells; under normal conditions, hCAS/CSE1L negatively regulates nuclear RAD51 levels and represses DNA damage-induced RAD51 focus formation and homologous recombination (HR) activity, thereby controlling chromosome stability.","method":"Co-immunoprecipitation, siRNA knockdown, RAD51 focus formation assay, HR reporter assay, chromosomal stability assay","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional HR assays, single lab, multiple readouts","pmids":["26123175"],"is_preprint":false},{"year":2015,"finding":"CSE1L regulates Ras-induced ERK1/2 phosphorylation and links cAMP/PKA and Ras/ERK pathways; IBMX (cAMP/PKA activator) induces CSE1L phosphorylation and augments Ras-induced ERK1/2 phosphorylation; CSE1L knockdown inhibits Ras-induced ERK1/2, phospho-CREB, MITF, and tyrosinase expression in melanoma cells.","method":"CSE1L shRNA knockdown, pharmacological pathway activation, immunoblotting","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis between cAMP/PKA and Ras/ERK through CSE1L, multiple downstream readouts, single lab","pmids":["26331446"],"is_preprint":false},{"year":2018,"finding":"CSE1L depletion causes genome-wide derepression of methylated genes without altering DNA methylation; the silencing defect overlaps with that caused by HDAC inhibitors. CSE1L depletion mislocalizes HDAC1, HDAC2, HDAC8, and NOVA1 to the cytosol, demonstrating that CSE1L's nuclear import function for specific cargo proteins is required to maintain epigenetic gene silencing.","method":"Genome-wide siRNA screen, reporter gene assay, DNA methylation analysis, subcellular fractionation, western blot for nuclear/cytoplasmic HDAC distribution","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide siRNA screen plus mechanistic follow-up with multiple orthogonal methods (fractionation, DNA methylation, HDAC localization) in a single rigorous study","pmids":["29636421"],"is_preprint":false},{"year":2019,"finding":"CSE1L silencing in gastric cancer cells decreases MITF expression and consequently reduces GPNMB expression, thereby regulating PI3K/Akt/mTOR and MEK/ERK signaling; GPNMB overexpression rescues the anti-tumor effects of CSE1L inhibition, establishing a CSE1L→MITF→GPNMB→PI3K-Akt/MEK-ERK axis.","method":"shRNA knockdown, overexpression rescue, immunoblotting, proliferation/invasion/apoptosis assays","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis confirmed by rescue experiment, multiple pathway readouts, single lab","pmids":["31347172"],"is_preprint":false},{"year":2020,"finding":"In yeast, Cse1 and Nup2 function in concert with RanGTP to mediate cNLS-cargo release in the nucleus; reversing the charge of key residues in importin-α (Arg44) or Cse1 (Asp220) abolishes complex formation both in vitro and in vivo; Nup2 N-terminal basic residues are required for importin-α interaction and Nup2 function, establishing a mechanistic model of cooperative importin-α recycling.","method":"Structure-guided mutagenesis, in vitro binding assay, in vivo yeast functional assay, complex formation analysis","journal":"Traffic","confidence":"High","confidence_rationale":"Tier 1 / Strong — structure-guided mutagenesis validated in vitro and in vivo with multiple residues and complexes","pmids":["32734712"],"is_preprint":false},{"year":2021,"finding":"CSE1L promotes nuclear accumulation of the transcriptional coactivator TAZ (WWTR1) by facilitating importin-α5-dependent nuclear import; in vitro Co-IP shows a compound (TI-4) strengthens CSE1L–importin-α5 interaction and blocks importin-α5 binding to TAZ. CSE1L silencing delays TAZ nuclear import, and TAZ silencing attenuates CSE1L-promoted colony formation, motility, and invasiveness.","method":"Affinity bead pull-down, in vitro co-immunoprecipitation, overexpression/silencing, subcellular fractionation, invasion/motility assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro Co-IP plus functional rescue/epistasis experiments, single lab, multiple orthogonal methods","pmids":["34022224"],"is_preprint":false},{"year":2021,"finding":"CSE1L interacts with RELA (p65) by co-immunoprecipitation/mass spectrometry and affects its nuclear localization; CSE1L promotes NSCLC cell proliferation and inhibits apoptosis through activation of the NF-κB/MAPK signaling pathway.","method":"Immunoprecipitation/mass spectrometry, gain- and loss-of-function experiments, in vitro and in vivo tumor models, pathway analysis","journal":"Molecular therapy oncolytics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP/MS for interaction, epistasis with NF-κB pathway, single lab","pmids":["33869740"],"is_preprint":false},{"year":2022,"finding":"PHY34 treatment identifies CAS/CSE1L (via chemoproteomics pulldown) as a target in the nucleocytoplasmic transport pathway; CAS overexpression reduces PHY34-induced apoptosis; PHY34 also inhibits ATP6V0A2 (V-ATPase subunit) to block late-stage autophagy, while simultaneously altering CSE1L-dependent nuclear cargo localization.","method":"Mass spectrometry-based chemoproteomics pulldown, CAS overexpression, Annexin V/PARP cleavage apoptosis assays, ATP6V0A2 mutant cell lines","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — unbiased chemoproteomics identification with functional validation by overexpression and mutant resistance, single lab","pmids":["35013112"],"is_preprint":false},{"year":2023,"finding":"CSE1L is a negative regulator of the RB-DREAM pathway; CSE1L knockdown in p53 wild-type NSCLC cells increases p21, activates RB1 and RBL2, and represses DREAM target genes, inducing toxicity in a p53-dependent manner; this effect can be phenocopied by the HDAC1/2 inhibitor mocetinostat.","method":"siRNA knockdown, immunoblotting for DREAM pathway components, cell viability assays, pharmacological HDAC inhibition","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with multiple pathway readouts and pharmacological validation, single lab","pmids":["37759078"],"is_preprint":false},{"year":2021,"finding":"In zebrafish/yeast, Cse1 (yeast ortholog) participates in TLC1 telomerase RNA import into the nucleus and Sm-ring stabilization on TLC1; Cse1 mutation leads to Y' element amplification and elongated telomere ends, identifying Cse1 as a quality control factor in telomerase maturation.","method":"Yeast genetics, RNAi, telomere southern blot, RNA import assay","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — yeast model, novel non-canonical function, single lab, limited mechanistic follow-up","pmids":["34773052"],"is_preprint":false},{"year":2024,"finding":"CSE1L physically interacts with DDX27 (Co-IP confirmed) in oral cancer cells and acts as a downstream effector; CSE1L silencing impairs cell growth promoted by DDX27 overexpression, establishing CSE1L as a downstream target in the DDX27 oncogenic axis.","method":"Co-immunoprecipitation, shRNA knockdown, cell rescue experiments","journal":"Life sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP and rescue experiment, single lab","pmids":["38301874"],"is_preprint":false},{"year":2024,"finding":"CSE1L upregulates the focal adhesion pathway and p-FAK (Y397) in gastric cancer cells; CSE1L knockout reduces p-FAK(Y397) levels and enhances sensitivity to the FAK inhibitor defactinib, identifying CSE1L as a regulator of FAK phosphorylation.","method":"CSE1L knockout and overexpression, RNA-seq pathway analysis, western blot, immunofluorescence, drug sensitivity assay","journal":"Translational cancer research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, RNA-seq and western blot without direct binding evidence between CSE1L and FAK","pmids":["39816536"],"is_preprint":false},{"year":2025,"finding":"CSE1L interacts with TRIP13 (co-immunoprecipitation); CSE1L represses TRIP13 ubiquitination-dependent degradation, stabilizing TRIP13 expression, while TRIP13 reciprocally regulates CSE1L protein stability, forming a bidirectional regulatory loop that promotes gastric cancer progression.","method":"Co-immunoprecipitation, ubiquitination assay, knockdown/overexpression, in vitro and in vivo tumor models","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay demonstrating bidirectional regulation, single lab","pmids":["41260444"],"is_preprint":false},{"year":2025,"finding":"Conditional neural crest-specific ablation of Cse1l (Wnt1-Cre2; Cse1l) causes severe forebrain/midbrain/hindbrain malformations, craniofacial hypoplasia, embryonic lethality by E11.5 from ventricular myocardium defects, and dramatically increased apoptosis with elevated p53 expression at E9.5, establishing a cell-autonomous requirement for CSE1L in neural crest cell survival.","method":"Conditional Cre/lox knockout, CRISPR-Cas9 null allele generation, histology, immunofluorescence for apoptosis and p53","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout with tissue-specific driver, complementation with CRISPR null, multiple phenotypic readouts including mechanistic p53 elevation","pmids":["41380931"],"is_preprint":false}],"current_model":"CSE1L/CAS functions primarily as a nuclear export receptor that recycles importin-α from the nucleus to the cytoplasm (forming a ternary complex with RanGTP and importin-α that undergoes a major conformational change); this transport function is required for nuclear import of specific repressive cargo (e.g., HDAC1/2/8) that maintains epigenetic gene silencing, for nuclear accumulation of pro-oncogenic factors such as TAZ, and for DNA repair factor (RAD51) distribution. Beyond transport, CSE1L associates with microtubules and the mitotic spindle and is essential for mitosis and early embryonic development; it is phosphorylated by ERK downstream of Ras signaling and, when phosphorylated, localizes to cytoplasmic vesicles where it promotes MMP-containing microvesicle biogenesis and cancer cell invasion/metastasis; its nuclear localization—driven by AKT-mediated RanBP3 phosphorylation—additionally controls transcription of pro- and anti-apoptotic genes including suppression of RASSF1C and selective co-activation of p53 target promoters, while its cytoplasmic form negatively regulates CFTR-dependent fluid secretion."},"narrative":{"mechanistic_narrative":"CSE1L/CAS is an essential nuclear transport receptor that recycles importin-α from the nucleus to the cytoplasm, a function conserved from the essential yeast CSE1 gene to the human homologue and required for accurate mitotic chromosome segregation [PMID:8336709, PMID:7479798]. Structural and mutagenesis work defines the mechanism: cargo-free Cse1 adopts a closed HEAT-repeat ring that occludes RanGTP sites, and cargo binding drives a major conformational change at HEAT repeat 8 that couples importin-α and Ran contacts, with cooperative cNLS-cargo release in the nucleus requiring RanGTP and Nup2 [PMID:15866177, PMID:32734712]. This transport activity is biologically central: CSE1L mediates nuclear import of specific repressive cargo (HDAC1/2/8 and NOVA1), and its loss causes cytosolic mislocalization of these factors and genome-wide derepression of methylated genes without changing DNA methylation [PMID:29636421], while also driving nuclear accumulation of the coactivator TAZ/WWTR1 via importin-α5 and influencing RELA localization [PMID:34022224, PMID:33869740]. CSE1L is essential for early embryonic development and, cell-autonomously, for neural crest cell survival, where its ablation causes p53 elevation and massive apoptosis [PMID:11564884, PMID:41380931]. Beyond transport, CSE1L associates with microtubules and the mitotic spindle and with α/β-tubulin [PMID:8610099, PMID:18377724], participates in pathway-selective apoptosis [PMID:7479798, PMID:8639641], occupies p53 target promoters to control their transcription and local H3K27 methylation [PMID:17719542], and restrains homologous recombination by negatively regulating nuclear RAD51 [PMID:26123175]. An ERK-phosphorylated cytoplasmic pool, downstream of Ras, localizes to cytoplasmic vesicles and drives MMP-containing microvesicle biogenesis, secretion, and cancer cell invasion and metastasis [PMID:18597698, PMID:22952058], and a cytoplasmic form negatively regulates CFTR-dependent fluid secretion [PMID:20933420].","teleology":[{"year":1993,"claim":"Established the foundational role of the gene: the yeast ortholog is essential for accurate mitotic chromosome segregation, placing it in the chromosome segregation pathway.","evidence":"Conditional yeast mutant screen, complementation cloning, gene disruption","pmids":["8336709"],"confidence":"High","gaps":["Molecular mechanism connecting Cse1 to segregation not defined","No biochemical activity assigned at this stage"]},{"year":1995,"claim":"Identified human CSE1L (CAS) as the functional homologue of yeast CSE1 and implicated it in pathway-selective apoptosis, extending the gene's relevance to mammalian cell death.","evidence":"Expression/selection cloning, antisense cDNA knockdown across multiple toxin paradigms","pmids":["7479798","8639641"],"confidence":"Medium","gaps":["Selectivity for TNF/toxin pathways over staurosporine/etoposide unexplained mechanistically","No direct molecular target of CAS in apoptosis identified"]},{"year":1997,"claim":"Connected the human protein to the cell cycle: CAS depletion arrests cells at G2/M with elevated cyclin B, mirroring the yeast mitotic phenotype.","evidence":"Antisense CAS cDNA expression, flow cytometry, cyclin B western blot in HeLa","pmids":["9235994"],"confidence":"Medium","gaps":["Whether the effect is via transport function or a direct cyclin B role unclear","Single-lab antisense approach"]},{"year":1996,"claim":"Localized CAS to microtubules and the mitotic spindle, providing a cytoskeletal context distinct from its later-defined transport role.","evidence":"Immunofluorescence, cytoskeleton preparations, microtubule drug treatment","pmids":["8610099","18377724"],"confidence":"Medium","gaps":["Association is detergent-labile and non-integral; binding partners on the spindle undefined","Functional consequence of spindle association for transport unclear"]},{"year":2001,"claim":"Demonstrated in vivo essentiality: null knockout causes embryonic lethality by E5.5, showing CSE1L cannot be compensated during early development.","evidence":"Gene targeting in ES cells, mouse knockout, embryo analysis","pmids":["11564884"],"confidence":"High","gaps":["Earliest lethality precludes analysis of later tissue-specific roles","Molecular cause of lethality not resolved"]},{"year":2005,"claim":"Resolved the structural basis of the transport mechanism: cargo-free Cse1 forms a closed ring that occludes RanGTP, and cargo binding triggers a conformational change coupling importin-α and Ran sites.","evidence":"X-ray crystallography at 3.1 Å, structure comparison, site-directed mutagenesis","pmids":["15866177"],"confidence":"High","gaps":["Structure is of yeast Cse1; human-specific features not addressed","Dynamics of the conformational cycle in cells not measured"]},{"year":2007,"claim":"Revealed a chromatin/transcriptional role: hCAS/CSE1L occupies p53 target promoters in a p53-autonomous manner and controls their transcription and local H3K27 methylation.","evidence":"ChIP, siRNA knockdown, transcription assays, histone methylation analysis","pmids":["17719542"],"confidence":"High","gaps":["How a transport receptor associates with chromatin mechanistically unclear","Link between promoter occupancy and import function not directly tested"]},{"year":2008,"claim":"Identified PPM1H as a phosphatase that dephosphorylates CSE1L, providing an eraser for CSE1L phosphorylation and a regulatory handle on its activity.","evidence":"Co-IP/mass spectrometry, in vitro phosphatase assay, SDS-PAGE mobility shift","pmids":["18059182"],"confidence":"Medium","gaps":["Phosphosites on CSE1L not mapped","Functional consequence of dephosphorylation for transport vs vesicle roles not defined"]},{"year":2010,"claim":"Uncovered non-transport physiological roles in vertebrates: CSE1L negatively regulates CFTR-dependent fluid secretion and associates with E-cadherin in polarized epithelium.","evidence":"Zebrafish forward genetic screen with fluid secretion assays; GST pull-down and Co-IP with E-cadherin","pmids":["20933420","20734115"],"confidence":"High","gaps":["Mechanism linking CSE1L to CFTR regulation undefined","E-cadherin interaction (Low confidence) lacks mutagenesis/reconstitution"]},{"year":2012,"claim":"Defined the oncogenic cytoplasmic axis: Ras/ERK phosphorylates CSE1L to drive MMP-containing microvesicle biogenesis and metastasis, and AKT controls its nuclear localization to suppress proapoptotic RASSF1C.","evidence":"Ras/ERK and AKT manipulation, vesicle fractionation, MMP secretion and invasion assays, in vivo metastasis models, immunogold EM","pmids":["22952058","22389439","18597698","19383891"],"confidence":"Medium","gaps":["How phosphorylation switches CSE1L between transport and vesicle functions not resolved","Direct CSE1L cargo within microvesicles not fully defined"]},{"year":2013,"claim":"Linked nuclear CSE1L to invasion through AKT-dependent phospho-RanBP3 accumulation, coupling the transport machinery to a metastatic gene program.","evidence":"AKT inhibition, immunofluorescence, expression profiling after silencing, invasion/motility assays","pmids":["23948303"],"confidence":"Medium","gaps":["Direct cargo whose import drives the invasion program not pinpointed","Single cancer-cell context"]},{"year":2015,"claim":"Connected CSE1L to genome stability and to signaling crosstalk: it negatively regulates nuclear RAD51 and HR, and it links cAMP/PKA with Ras/ERK signaling.","evidence":"Co-IP, RAD51 focus and HR reporter assays, chromosomal stability assays; shRNA knockdown with pharmacological pathway activation and immunoblotting","pmids":["26123175","26331446"],"confidence":"Medium","gaps":["Whether RAD51 regulation reflects nuclear export/import function untested","Direct vs indirect control of ERK signaling unclear"]},{"year":2018,"claim":"Established the core mechanistic principle behind epigenetic silencing: CSE1L's nuclear import of HDAC1/2/8 and NOVA1 is required to maintain gene silencing, independent of DNA methylation.","evidence":"Genome-wide siRNA screen, reporter assays, DNA methylation analysis, subcellular fractionation, HDAC distribution western blots","pmids":["29636421"],"confidence":"High","gaps":["Why these specific cargoes depend on CSE1L not fully explained","Quantitative contribution of each cargo to derepression unresolved"]},{"year":2021,"claim":"Extended the import-cargo concept to oncogenic transcription factors: CSE1L promotes importin-α5-dependent TAZ nuclear import and influences RELA localization to drive proliferation/invasion.","evidence":"Affinity pull-down, in vitro Co-IP with a small-molecule modulator, fractionation, invasion/motility assays; Co-IP/MS and NF-κB pathway epistasis","pmids":["34022224","33869740","34773052"],"confidence":"Medium","gaps":["Selectivity of CSE1L for specific cargoes mechanistically undefined","Telomerase TLC1 import role (Low confidence) shown only in yeast"]},{"year":2023,"claim":"Tied CSE1L to p53-dependent tumor suppressor pathways: it negatively regulates the RB-DREAM pathway, and its loss is phenocopied by HDAC1/2 inhibition, reinforcing the HDAC-import link.","evidence":"siRNA knockdown, immunoblotting for DREAM components, viability assays, pharmacological HDAC inhibition","pmids":["37759078"],"confidence":"Medium","gaps":["Direct mechanism connecting CSE1L to RB/p21 unclear","Whether effect is purely via HDAC import not isolated"]},{"year":2025,"claim":"Demonstrated a cell-autonomous developmental requirement: neural crest-specific ablation causes p53 elevation and apoptosis, and CSE1L participates in cancer protein-stability and adhesion networks (TRIP13, DDX27, FAK).","evidence":"Conditional Cre/lox and CRISPR knockout with histology and p53/apoptosis readouts; Co-IP, ubiquitination assays, RNA-seq, and rescue experiments in cancer models","pmids":["41380931","41260444","38301874","39816536"],"confidence":"High","gaps":["Mechanism linking CSE1L loss to p53 elevation undefined","DDX27 and FAK links (Low confidence) lack direct binding/mechanistic detail"]},{"year":null,"claim":"How CSE1L phosphorylation by ERK and AKT-controlled localization mechanistically switches the protein between importin-α recycling, chromatin/transcriptional control, and cytoplasmic microvesicle biogenesis remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model integrating the transport, vesicular, and transcriptional pools","Phosphosite-resolved structure-function mapping in human CSE1L lacking","Determinants of cargo selectivity unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[6,20,22,23]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[3,9]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[7,16]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[18,30]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[16,20,23]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[20,16]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[3,9]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[10,11,15]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[11]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[6,20,22,23]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,4]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[7,20]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[1,2,16]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[18]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[5,31]}],"complexes":["CSE1L–importin-α–RanGTP export complex"],"partners":["IMPORTIN-Α","RANGTP","PPM1H","RAD51","WWTR1","RELA","TRIP13","E-CADHERIN"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P55060","full_name":"Exportin-2","aliases":["Cellular apoptosis susceptibility protein","Chromosome segregation 1-like protein","Importin-alpha re-exporter"],"length_aa":971,"mass_kda":110.4,"function":"Export receptor for importin-alpha. Mediates importin-alpha re-export from the nucleus to the cytoplasm after import substrates (cargos) have been released into the nucleoplasm. In the nucleus binds cooperatively to importin-alpha and to the GTPase Ran in its active GTP-bound form. Docking of this trimeric complex to the nuclear pore complex (NPC) is mediated through binding to nucleoporins. Upon transit of a nuclear export complex into the cytoplasm, disassembling of the complex and hydrolysis of Ran-GTP to Ran-GDP (induced by RANBP1 and RANGAP1, respectively) cause release of the importin-alpha from the export receptor. CSE1L/XPO2 then return to the nuclear compartment and mediate another round of transport. The directionality of nuclear export is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/P55060/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/CSE1L","classification":"Common Essential","n_dependent_lines":1207,"n_total_lines":1208,"dependency_fraction":0.9991721854304636},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000124207","cell_line_id":"CID001550","localizations":[{"compartment":"nucleoplasm","grade":2}],"interactors":[{"gene":"PRPF8","stoichiometry":10.0},{"gene":"KPNA1","stoichiometry":0.2},{"gene":"NUP50","stoichiometry":0.2},{"gene":"SRP54","stoichiometry":0.2},{"gene":"LMNB1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001550","total_profiled":1310},"omim":[{"mim_id":"601342","title":"CHROMOSOME SEGREGATION 1-LIKE; CSE1L","url":"https://www.omim.org/entry/601342"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CSE1L"},"hgnc":{"alias_symbol":["CAS","XPO2","CSE1"],"prev_symbol":[]},"alphafold":{"accession":"P55060","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P55060","model_url":"https://alphafold.ebi.ac.uk/files/AF-P55060-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P55060-F1-predicted_aligned_error_v6.png","plddt_mean":91.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CSE1L","jax_strain_url":"https://www.jax.org/strain/search?query=CSE1L"},"sequence":{"accession":"P55060","fasta_url":"https://rest.uniprot.org/uniprotkb/P55060.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P55060/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P55060"}},"corpus_meta":[{"pmid":"7479798","id":"PMC_7479798","title":"Cloning and characterization of a cellular apoptosis susceptibility gene, the human homologue to the yeast chromosome segregation 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of FAK phosphorylation.","date":"2024","source":"Translational cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/39816536","citation_count":2,"is_preprint":false},{"pmid":"35137271","id":"PMC_35137271","title":"Role of CSE1L expression in determining recurrence and survival of laryngeal tumors.","date":"2022","source":"European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery","url":"https://pubmed.ncbi.nlm.nih.gov/35137271","citation_count":2,"is_preprint":false},{"pmid":"37520736","id":"PMC_37520736","title":"The nuclear transport factor CSE1 drives macronuclear volume increase and macronuclear node coalescence in Stentor coeruleus.","date":"2023","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/37520736","citation_count":1,"is_preprint":false},{"pmid":"41260444","id":"PMC_41260444","title":"CSE1L regulates gastric cancer progression via molecular crosstalk with TRIP13.","date":"2025","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/41260444","citation_count":0,"is_preprint":false},{"pmid":"41380931","id":"PMC_41380931","title":"Cse1l is critical for cell survival, craniofacial and cardiac development.","date":"2025","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/41380931","citation_count":0,"is_preprint":false},{"pmid":"39469152","id":"PMC_39469152","title":"CSE1L Silencing Enhances Cytarabine-mediated Cytotoxicity in Acute Myeloid Leukemia.","date":"2024","source":"Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion","url":"https://pubmed.ncbi.nlm.nih.gov/39469152","citation_count":0,"is_preprint":false},{"pmid":"40654873","id":"PMC_40654873","title":"Cse1l Regulates Neural Crest Cell Survival and is Critical for Craniofacial and Cardiac 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Biobank","date":"2025-05-15","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.15.25327674","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":36292,"output_tokens":7440,"usd":0.110238,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16912,"output_tokens":5342,"usd":0.109055,"stage2_stop_reason":"end_turn"},"total_usd":0.219293,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1993,\n      \"finding\": \"Yeast CSE1 (ortholog of human CSE1L) is an essential gene required for accurate mitotic chromosome segregation; cse1 mutants accumulate large-budded cells with aberrant binucleate morphologies and show predominantly nondisjunction events, placing Cse1 in the chromosome segregation pathway.\",\n      \"method\": \"Conditional yeast mutant screen, complementation cloning, gene disruption\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — genetic complementation, loss-of-function mutant with defined mitotic phenotype, replicated across multiple alleles in a dedicated study\",\n      \"pmids\": [\"8336709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Human CSE1L (CAS) is the functional homologue of yeast CSE1 (59% overall protein homology, similar length); antisense reduction of CAS protein confers resistance to Pseudomonas exotoxin, diphtheria toxin, and TNF-mediated apoptosis, establishing CAS as a factor in selected apoptotic pathways.\",\n      \"method\": \"Expression/selection cloning, antisense cDNA, cDNA sequence analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — antisense knockdown with defined apoptosis phenotype, single lab but multiple toxin paradigms tested\",\n      \"pmids\": [\"7479798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"CAS reduction by antisense cDNA confers resistance to TNF-alpha, TNF-beta, Pseudomonas exotoxin, and diphtheria toxin-induced apoptosis but not to staurosporine, cycloheximide, or etoposide, indicating pathway-selective involvement of CAS in apoptosis.\",\n      \"method\": \"Antisense cDNA expression, cell viability and apoptosis assays\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined phenotypic selectivity, single lab, multiple apoptotic stimuli tested\",\n      \"pmids\": [\"8639641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"CAS protein localizes to microtubules and the mitotic spindle in proliferating cells; it shows microtubule-like distribution in interphase and labels the mitotic spindle, but is removed by mild detergent treatment and disperses in taxol/vincristine-treated cells, indicating it is associated with but not an integral part of microtubules.\",\n      \"method\": \"Immunofluorescence microscopy, cytoskeleton preparations, drug treatment\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by antibody staining with functional perturbation experiments, single lab\",\n      \"pmids\": [\"8610099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Antisense-mediated reduction of CAS protein in HeLa cells perturbs G2-to-G1 cell cycle progression and causes G2/M arrest, with elevated cyclin B levels, consistent with a role in mitosis and cyclin B degradation analogous to yeast Cse1.\",\n      \"method\": \"Antisense CAS cDNA expression, flow cytometry, cyclin B western blot\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cell-cycle phenotype, single lab, two orthogonal readouts (FACS and cyclin B)\",\n      \"pmids\": [\"9235994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Homozygous knockout of Cse1l in mice causes embryonic lethality by E5.5, demonstrating that CSE1L is essential for early embryonic development and cannot be compensated by other genes in vivo.\",\n      \"method\": \"Gene targeting in embryonic stem cells, mouse knockout, embryo analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — null knockout with clear lethal phenotype, statistical analysis, in vivo model\",\n      \"pmids\": [\"11564884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Crystal structure of cargo-free yeast Cse1 at 3.1 Å reveals a closed ring conformation formed by N- and C-terminal HEAT-repeat arches; comparison with cargo-bound Cse1 shows a major conformational change at HEAT repeat 8 upon cargo binding, where the insertion connects RanGTP and importin-α contact sites. In the closed state, RanGTP binding sites are occluded and importin-α sites are distorted. Mutations destabilizing the N-to-C interaction uncouple importin-α and Ran binding.\",\n      \"method\": \"X-ray crystallography (3.1 Å), structure comparison, site-directed mutagenesis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with mutagenesis validation in a single rigorous study\",\n      \"pmids\": [\"15866177\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"hCAS/CSE1L associates with a subset of p53 target promoters (including PIG3) in a p53-autonomous manner; its downregulation decreases transcription from those promoters and reduces apoptosis, and its silencing leads to increased methylation of histone H3 lysine 27 at the PIG3 gene, establishing a chromatin regulatory role.\",\n      \"method\": \"ChIP, siRNA knockdown, transcription assays, histone methylation analysis\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal ChIP and functional transcription assays, histone modification readout, published in Cell with multiple orthogonal methods\",\n      \"pmids\": [\"17719542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PPM1H (protein phosphatase 1H/PP2C family) physically associates with CSE1L as identified by co-immunoprecipitation/mass spectrometry; PPM1H dephosphorylates CSE1L in vitro and in cells (shown by altered SDS-PAGE mobility), identifying PPM1H as a phosphatase (eraser) for CSE1L phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation/mass spectrometry, in vitro phosphatase assay, SDS-PAGE mobility shift\",\n      \"journal\": \"Cancer biology & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP/MS plus in vitro dephosphorylation assay, single lab\",\n      \"pmids\": [\"18059182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CAS/CSE1L associates with alpha-tubulin and beta-tubulin, enhances tubulin heterodimer association, and its overexpression reduces paclitaxel-induced G2/M arrest and microtubule aster formation while enhancing apoptosis from other chemotherapeutic agents; knockdown produces opposite effects.\",\n      \"method\": \"Co-immunoprecipitation, flow cytometry, immunofluorescence, overexpression/knockdown\",\n      \"journal\": \"BMB reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP demonstrating tubulin interaction plus functional cell-cycle readouts, single lab\",\n      \"pmids\": [\"18377724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CAS/CSE1L overexpression enhances MMP-2 secretion and cancer cell invasion while failing to increase proliferation; CAS localizes to cytoplasmic vesicles and vesicle membranes (immunogold EM); CAS reduction inhibits B16-F10 melanoma metastasis in vivo by 56%.\",\n      \"method\": \"Overexpression/knockdown, Matrigel invasion assay, immunofluorescence, immunogold electron microscopy, animal metastasis model\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (EM localization, invasion assay, in vivo), single lab\",\n      \"pmids\": [\"18597698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CAS/CSE1L co-localizes with MMP-2 in vesicles at the cell membrane exterior; its C-terminal domain associates with MMP-2-containing vesicles; CAS is secreted and detected in conditioned medium and patient sera, establishing CAS as a secretory protein associated with vesicular MMP-2 trafficking.\",\n      \"method\": \"Co-localization (immunofluorescence), vesicle fractionation, immunoblotting of conditioned medium and sera\",\n      \"journal\": \"Cancer epidemiology, biomarkers & prevention\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-localization and biochemical fractionation, single lab, replicated in patient samples\",\n      \"pmids\": [\"19383891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CAS/CSE1L overexpression induces polarization of HT-29 colorectal cells, increases translocation of CAS-stained vesicles to the cell membrane/protrusions, and enhances secretion of CEA and cathepsin D, demonstrating a role in directed epithelial secretion.\",\n      \"method\": \"CAS overexpression, immunofluorescence, ELISA for secreted proteins\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single overexpression approach with secretion readout\",\n      \"pmids\": [\"19224336\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Loss-of-function mutation in zebrafish cse1l causes dramatic fluid accumulation in the gut due to uncontrolled CFTR channel activation; analyses in zebrafish larvae and mammalian cells confirmed that Cse1l is a negative regulator of CFTR-dependent fluid secretion.\",\n      \"method\": \"Forward genetic screen (zebrafish), mutant characterization, fluid secretion assays in zebrafish and mammalian cells\",\n      \"journal\": \"Current biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — forward genetic identification, vertebrate model, functional validation in two species with mechanistic readout\",\n      \"pmids\": [\"20933420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CSE1L associates with E-cadherin in GST pull-down and co-immunoprecipitation experiments; both proteins co-distribute basolaterally in polarized colorectal gland epithelium, linking CSE1L to E-cadherin-mediated epithelial polarity.\",\n      \"method\": \"GST pull-down, co-immunoprecipitation, immunohistochemistry\",\n      \"journal\": \"Journal of molecular histology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pull-down/Co-IP without mutagenesis or in vitro reconstitution\",\n      \"pmids\": [\"20734115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"v-H-Ras expression triggers ERK-dependent phosphorylation of CSE1L and induces microvesicle biogenesis; CSE1L overexpression triggers microvesicle generation; CSE1L knockdown reduces Ras-induced microvesicle biogenesis, MMP-2/MMP-9 secretion, and B16F10 melanoma metastasis, identifying CSE1L as a Ras/ERK-regulated microvesicle membrane protein.\",\n      \"method\": \"Ras overexpression, ERK inhibition, CSE1L knockdown/overexpression, vesicle fractionation, MMP secretion assay, animal metastasis model\",\n      \"journal\": \"Molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis (Ras→ERK→CSE1L) with multiple functional readouts, single lab\",\n      \"pmids\": [\"22952058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In ovarian cancer cells, nuclear localization of CSE1L depends on constitutively active AKT; AKT inactivation translocates CSE1L to the cytoplasm, and expression of constitutively active AKT forces cytoplasmic CSE1L into the nucleus. Nuclear CSE1L transcriptionally suppresses the proapoptotic RASSF1C gene, mediating ovarian cancer cell survival.\",\n      \"method\": \"AKT inhibition/activation, immunofluorescence, RNA interference, apoptosis assays, gene expression analysis\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis (AKT→CSE1L nuclear localization→RASSF1C suppression), multiple methods, single lab\",\n      \"pmids\": [\"22389439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"AKT-driven nuclear localization of CSE1L in ovarian cancer cells is associated with nuclear accumulation of phosphorylated RanBP3 (also AKT-dependent); nuclear CSE1L is required for expression of invasion/metastasis-promoting genes and for cell motility and invasiveness.\",\n      \"method\": \"AKT inhibition, immunofluorescence, expression profiling after CSE1L silencing, invasion/motility assays\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic epistasis with RanBP3, expression profiling, functional assays, single lab\",\n      \"pmids\": [\"23948303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"hCAS/CSE1L associates with RAD51 in human cells; under normal conditions, hCAS/CSE1L negatively regulates nuclear RAD51 levels and represses DNA damage-induced RAD51 focus formation and homologous recombination (HR) activity, thereby controlling chromosome stability.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, RAD51 focus formation assay, HR reporter assay, chromosomal stability assay\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional HR assays, single lab, multiple readouts\",\n      \"pmids\": [\"26123175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CSE1L regulates Ras-induced ERK1/2 phosphorylation and links cAMP/PKA and Ras/ERK pathways; IBMX (cAMP/PKA activator) induces CSE1L phosphorylation and augments Ras-induced ERK1/2 phosphorylation; CSE1L knockdown inhibits Ras-induced ERK1/2, phospho-CREB, MITF, and tyrosinase expression in melanoma cells.\",\n      \"method\": \"CSE1L shRNA knockdown, pharmacological pathway activation, immunoblotting\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis between cAMP/PKA and Ras/ERK through CSE1L, multiple downstream readouts, single lab\",\n      \"pmids\": [\"26331446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CSE1L depletion causes genome-wide derepression of methylated genes without altering DNA methylation; the silencing defect overlaps with that caused by HDAC inhibitors. CSE1L depletion mislocalizes HDAC1, HDAC2, HDAC8, and NOVA1 to the cytosol, demonstrating that CSE1L's nuclear import function for specific cargo proteins is required to maintain epigenetic gene silencing.\",\n      \"method\": \"Genome-wide siRNA screen, reporter gene assay, DNA methylation analysis, subcellular fractionation, western blot for nuclear/cytoplasmic HDAC distribution\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide siRNA screen plus mechanistic follow-up with multiple orthogonal methods (fractionation, DNA methylation, HDAC localization) in a single rigorous study\",\n      \"pmids\": [\"29636421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CSE1L silencing in gastric cancer cells decreases MITF expression and consequently reduces GPNMB expression, thereby regulating PI3K/Akt/mTOR and MEK/ERK signaling; GPNMB overexpression rescues the anti-tumor effects of CSE1L inhibition, establishing a CSE1L→MITF→GPNMB→PI3K-Akt/MEK-ERK axis.\",\n      \"method\": \"shRNA knockdown, overexpression rescue, immunoblotting, proliferation/invasion/apoptosis assays\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis confirmed by rescue experiment, multiple pathway readouts, single lab\",\n      \"pmids\": [\"31347172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In yeast, Cse1 and Nup2 function in concert with RanGTP to mediate cNLS-cargo release in the nucleus; reversing the charge of key residues in importin-α (Arg44) or Cse1 (Asp220) abolishes complex formation both in vitro and in vivo; Nup2 N-terminal basic residues are required for importin-α interaction and Nup2 function, establishing a mechanistic model of cooperative importin-α recycling.\",\n      \"method\": \"Structure-guided mutagenesis, in vitro binding assay, in vivo yeast functional assay, complex formation analysis\",\n      \"journal\": \"Traffic\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structure-guided mutagenesis validated in vitro and in vivo with multiple residues and complexes\",\n      \"pmids\": [\"32734712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CSE1L promotes nuclear accumulation of the transcriptional coactivator TAZ (WWTR1) by facilitating importin-α5-dependent nuclear import; in vitro Co-IP shows a compound (TI-4) strengthens CSE1L–importin-α5 interaction and blocks importin-α5 binding to TAZ. CSE1L silencing delays TAZ nuclear import, and TAZ silencing attenuates CSE1L-promoted colony formation, motility, and invasiveness.\",\n      \"method\": \"Affinity bead pull-down, in vitro co-immunoprecipitation, overexpression/silencing, subcellular fractionation, invasion/motility assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro Co-IP plus functional rescue/epistasis experiments, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"34022224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CSE1L interacts with RELA (p65) by co-immunoprecipitation/mass spectrometry and affects its nuclear localization; CSE1L promotes NSCLC cell proliferation and inhibits apoptosis through activation of the NF-κB/MAPK signaling pathway.\",\n      \"method\": \"Immunoprecipitation/mass spectrometry, gain- and loss-of-function experiments, in vitro and in vivo tumor models, pathway analysis\",\n      \"journal\": \"Molecular therapy oncolytics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP/MS for interaction, epistasis with NF-κB pathway, single lab\",\n      \"pmids\": [\"33869740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PHY34 treatment identifies CAS/CSE1L (via chemoproteomics pulldown) as a target in the nucleocytoplasmic transport pathway; CAS overexpression reduces PHY34-induced apoptosis; PHY34 also inhibits ATP6V0A2 (V-ATPase subunit) to block late-stage autophagy, while simultaneously altering CSE1L-dependent nuclear cargo localization.\",\n      \"method\": \"Mass spectrometry-based chemoproteomics pulldown, CAS overexpression, Annexin V/PARP cleavage apoptosis assays, ATP6V0A2 mutant cell lines\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — unbiased chemoproteomics identification with functional validation by overexpression and mutant resistance, single lab\",\n      \"pmids\": [\"35013112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CSE1L is a negative regulator of the RB-DREAM pathway; CSE1L knockdown in p53 wild-type NSCLC cells increases p21, activates RB1 and RBL2, and represses DREAM target genes, inducing toxicity in a p53-dependent manner; this effect can be phenocopied by the HDAC1/2 inhibitor mocetinostat.\",\n      \"method\": \"siRNA knockdown, immunoblotting for DREAM pathway components, cell viability assays, pharmacological HDAC inhibition\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with multiple pathway readouts and pharmacological validation, single lab\",\n      \"pmids\": [\"37759078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In zebrafish/yeast, Cse1 (yeast ortholog) participates in TLC1 telomerase RNA import into the nucleus and Sm-ring stabilization on TLC1; Cse1 mutation leads to Y' element amplification and elongated telomere ends, identifying Cse1 as a quality control factor in telomerase maturation.\",\n      \"method\": \"Yeast genetics, RNAi, telomere southern blot, RNA import assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — yeast model, novel non-canonical function, single lab, limited mechanistic follow-up\",\n      \"pmids\": [\"34773052\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CSE1L physically interacts with DDX27 (Co-IP confirmed) in oral cancer cells and acts as a downstream effector; CSE1L silencing impairs cell growth promoted by DDX27 overexpression, establishing CSE1L as a downstream target in the DDX27 oncogenic axis.\",\n      \"method\": \"Co-immunoprecipitation, shRNA knockdown, cell rescue experiments\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP and rescue experiment, single lab\",\n      \"pmids\": [\"38301874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CSE1L upregulates the focal adhesion pathway and p-FAK (Y397) in gastric cancer cells; CSE1L knockout reduces p-FAK(Y397) levels and enhances sensitivity to the FAK inhibitor defactinib, identifying CSE1L as a regulator of FAK phosphorylation.\",\n      \"method\": \"CSE1L knockout and overexpression, RNA-seq pathway analysis, western blot, immunofluorescence, drug sensitivity assay\",\n      \"journal\": \"Translational cancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, RNA-seq and western blot without direct binding evidence between CSE1L and FAK\",\n      \"pmids\": [\"39816536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CSE1L interacts with TRIP13 (co-immunoprecipitation); CSE1L represses TRIP13 ubiquitination-dependent degradation, stabilizing TRIP13 expression, while TRIP13 reciprocally regulates CSE1L protein stability, forming a bidirectional regulatory loop that promotes gastric cancer progression.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, knockdown/overexpression, in vitro and in vivo tumor models\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay demonstrating bidirectional regulation, single lab\",\n      \"pmids\": [\"41260444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Conditional neural crest-specific ablation of Cse1l (Wnt1-Cre2; Cse1l) causes severe forebrain/midbrain/hindbrain malformations, craniofacial hypoplasia, embryonic lethality by E11.5 from ventricular myocardium defects, and dramatically increased apoptosis with elevated p53 expression at E9.5, establishing a cell-autonomous requirement for CSE1L in neural crest cell survival.\",\n      \"method\": \"Conditional Cre/lox knockout, CRISPR-Cas9 null allele generation, histology, immunofluorescence for apoptosis and p53\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout with tissue-specific driver, complementation with CRISPR null, multiple phenotypic readouts including mechanistic p53 elevation\",\n      \"pmids\": [\"41380931\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CSE1L/CAS functions primarily as a nuclear export receptor that recycles importin-α from the nucleus to the cytoplasm (forming a ternary complex with RanGTP and importin-α that undergoes a major conformational change); this transport function is required for nuclear import of specific repressive cargo (e.g., HDAC1/2/8) that maintains epigenetic gene silencing, for nuclear accumulation of pro-oncogenic factors such as TAZ, and for DNA repair factor (RAD51) distribution. Beyond transport, CSE1L associates with microtubules and the mitotic spindle and is essential for mitosis and early embryonic development; it is phosphorylated by ERK downstream of Ras signaling and, when phosphorylated, localizes to cytoplasmic vesicles where it promotes MMP-containing microvesicle biogenesis and cancer cell invasion/metastasis; its nuclear localization—driven by AKT-mediated RanBP3 phosphorylation—additionally controls transcription of pro- and anti-apoptotic genes including suppression of RASSF1C and selective co-activation of p53 target promoters, while its cytoplasmic form negatively regulates CFTR-dependent fluid secretion.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CSE1L/CAS is an essential nuclear transport receptor that recycles importin-\\u03b1 from the nucleus to the cytoplasm, a function conserved from the essential yeast CSE1 gene to the human homologue and required for accurate mitotic chromosome segregation [#0, #1]. Structural and mutagenesis work defines the mechanism: cargo-free Cse1 adopts a closed HEAT-repeat ring that occludes RanGTP sites, and cargo binding drives a major conformational change at HEAT repeat 8 that couples importin-\\u03b1 and Ran contacts, with cooperative cNLS-cargo release in the nucleus requiring RanGTP and Nup2 [#6, #22]. This transport activity is biologically central: CSE1L mediates nuclear import of specific repressive cargo (HDAC1/2/8 and NOVA1), and its loss causes cytosolic mislocalization of these factors and genome-wide derepression of methylated genes without changing DNA methylation [#20], while also driving nuclear accumulation of the coactivator TAZ/WWTR1 via importin-\\u03b15 and influencing RELA localization [#23, #24]. CSE1L is essential for early embryonic development and, cell-autonomously, for neural crest cell survival, where its ablation causes p53 elevation and massive apoptosis [#5, #31]. Beyond transport, CSE1L associates with microtubules and the mitotic spindle and with \\u03b1/\\u03b2-tubulin [#3, #9], participates in pathway-selective apoptosis [#1, #2], occupies p53 target promoters to control their transcription and local H3K27 methylation [#7], and restrains homologous recombination by negatively regulating nuclear RAD51 [#18]. An ERK-phosphorylated cytoplasmic pool, downstream of Ras, localizes to cytoplasmic vesicles and drives MMP-containing microvesicle biogenesis, secretion, and cancer cell invasion and metastasis [#10, #15], and a cytoplasmic form negatively regulates CFTR-dependent fluid secretion [#13].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Established the foundational role of the gene: the yeast ortholog is essential for accurate mitotic chromosome segregation, placing it in the chromosome segregation pathway.\",\n      \"evidence\": \"Conditional yeast mutant screen, complementation cloning, gene disruption\",\n      \"pmids\": [\"8336709\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism connecting Cse1 to segregation not defined\", \"No biochemical activity assigned at this stage\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Identified human CSE1L (CAS) as the functional homologue of yeast CSE1 and implicated it in pathway-selective apoptosis, extending the gene's relevance to mammalian cell death.\",\n      \"evidence\": \"Expression/selection cloning, antisense cDNA knockdown across multiple toxin paradigms\",\n      \"pmids\": [\"7479798\", \"8639641\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Selectivity for TNF/toxin pathways over staurosporine/etoposide unexplained mechanistically\", \"No direct molecular target of CAS in apoptosis identified\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Connected the human protein to the cell cycle: CAS depletion arrests cells at G2/M with elevated cyclin B, mirroring the yeast mitotic phenotype.\",\n      \"evidence\": \"Antisense CAS cDNA expression, flow cytometry, cyclin B western blot in HeLa\",\n      \"pmids\": [\"9235994\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the effect is via transport function or a direct cyclin B role unclear\", \"Single-lab antisense approach\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Localized CAS to microtubules and the mitotic spindle, providing a cytoskeletal context distinct from its later-defined transport role.\",\n      \"evidence\": \"Immunofluorescence, cytoskeleton preparations, microtubule drug treatment\",\n      \"pmids\": [\"8610099\", \"18377724\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Association is detergent-labile and non-integral; binding partners on the spindle undefined\", \"Functional consequence of spindle association for transport unclear\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Demonstrated in vivo essentiality: null knockout causes embryonic lethality by E5.5, showing CSE1L cannot be compensated during early development.\",\n      \"evidence\": \"Gene targeting in ES cells, mouse knockout, embryo analysis\",\n      \"pmids\": [\"11564884\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Earliest lethality precludes analysis of later tissue-specific roles\", \"Molecular cause of lethality not resolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Resolved the structural basis of the transport mechanism: cargo-free Cse1 forms a closed ring that occludes RanGTP, and cargo binding triggers a conformational change coupling importin-\\u03b1 and Ran sites.\",\n      \"evidence\": \"X-ray crystallography at 3.1 \\u00c5, structure comparison, site-directed mutagenesis\",\n      \"pmids\": [\"15866177\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure is of yeast Cse1; human-specific features not addressed\", \"Dynamics of the conformational cycle in cells not measured\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Revealed a chromatin/transcriptional role: hCAS/CSE1L occupies p53 target promoters in a p53-autonomous manner and controls their transcription and local H3K27 methylation.\",\n      \"evidence\": \"ChIP, siRNA knockdown, transcription assays, histone methylation analysis\",\n      \"pmids\": [\"17719542\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a transport receptor associates with chromatin mechanistically unclear\", \"Link between promoter occupancy and import function not directly tested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified PPM1H as a phosphatase that dephosphorylates CSE1L, providing an eraser for CSE1L phosphorylation and a regulatory handle on its activity.\",\n      \"evidence\": \"Co-IP/mass spectrometry, in vitro phosphatase assay, SDS-PAGE mobility shift\",\n      \"pmids\": [\"18059182\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phosphosites on CSE1L not mapped\", \"Functional consequence of dephosphorylation for transport vs vesicle roles not defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Uncovered non-transport physiological roles in vertebrates: CSE1L negatively regulates CFTR-dependent fluid secretion and associates with E-cadherin in polarized epithelium.\",\n      \"evidence\": \"Zebrafish forward genetic screen with fluid secretion assays; GST pull-down and Co-IP with E-cadherin\",\n      \"pmids\": [\"20933420\", \"20734115\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking CSE1L to CFTR regulation undefined\", \"E-cadherin interaction (Low confidence) lacks mutagenesis/reconstitution\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined the oncogenic cytoplasmic axis: Ras/ERK phosphorylates CSE1L to drive MMP-containing microvesicle biogenesis and metastasis, and AKT controls its nuclear localization to suppress proapoptotic RASSF1C.\",\n      \"evidence\": \"Ras/ERK and AKT manipulation, vesicle fractionation, MMP secretion and invasion assays, in vivo metastasis models, immunogold EM\",\n      \"pmids\": [\"22952058\", \"22389439\", \"18597698\", \"19383891\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How phosphorylation switches CSE1L between transport and vesicle functions not resolved\", \"Direct CSE1L cargo within microvesicles not fully defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Linked nuclear CSE1L to invasion through AKT-dependent phospho-RanBP3 accumulation, coupling the transport machinery to a metastatic gene program.\",\n      \"evidence\": \"AKT inhibition, immunofluorescence, expression profiling after silencing, invasion/motility assays\",\n      \"pmids\": [\"23948303\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct cargo whose import drives the invasion program not pinpointed\", \"Single cancer-cell context\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Connected CSE1L to genome stability and to signaling crosstalk: it negatively regulates nuclear RAD51 and HR, and it links cAMP/PKA with Ras/ERK signaling.\",\n      \"evidence\": \"Co-IP, RAD51 focus and HR reporter assays, chromosomal stability assays; shRNA knockdown with pharmacological pathway activation and immunoblotting\",\n      \"pmids\": [\"26123175\", \"26331446\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether RAD51 regulation reflects nuclear export/import function untested\", \"Direct vs indirect control of ERK signaling unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established the core mechanistic principle behind epigenetic silencing: CSE1L's nuclear import of HDAC1/2/8 and NOVA1 is required to maintain gene silencing, independent of DNA methylation.\",\n      \"evidence\": \"Genome-wide siRNA screen, reporter assays, DNA methylation analysis, subcellular fractionation, HDAC distribution western blots\",\n      \"pmids\": [\"29636421\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why these specific cargoes depend on CSE1L not fully explained\", \"Quantitative contribution of each cargo to derepression unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended the import-cargo concept to oncogenic transcription factors: CSE1L promotes importin-\\u03b15-dependent TAZ nuclear import and influences RELA localization to drive proliferation/invasion.\",\n      \"evidence\": \"Affinity pull-down, in vitro Co-IP with a small-molecule modulator, fractionation, invasion/motility assays; Co-IP/MS and NF-\\u03baB pathway epistasis\",\n      \"pmids\": [\"34022224\", \"33869740\", \"34773052\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Selectivity of CSE1L for specific cargoes mechanistically undefined\", \"Telomerase TLC1 import role (Low confidence) shown only in yeast\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Tied CSE1L to p53-dependent tumor suppressor pathways: it negatively regulates the RB-DREAM pathway, and its loss is phenocopied by HDAC1/2 inhibition, reinforcing the HDAC-import link.\",\n      \"evidence\": \"siRNA knockdown, immunoblotting for DREAM components, viability assays, pharmacological HDAC inhibition\",\n      \"pmids\": [\"37759078\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mechanism connecting CSE1L to RB/p21 unclear\", \"Whether effect is purely via HDAC import not isolated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated a cell-autonomous developmental requirement: neural crest-specific ablation causes p53 elevation and apoptosis, and CSE1L participates in cancer protein-stability and adhesion networks (TRIP13, DDX27, FAK).\",\n      \"evidence\": \"Conditional Cre/lox and CRISPR knockout with histology and p53/apoptosis readouts; Co-IP, ubiquitination assays, RNA-seq, and rescue experiments in cancer models\",\n      \"pmids\": [\"41380931\", \"41260444\", \"38301874\", \"39816536\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking CSE1L loss to p53 elevation undefined\", \"DDX27 and FAK links (Low confidence) lack direct binding/mechanistic detail\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CSE1L phosphorylation by ERK and AKT-controlled localization mechanistically switches the protein between importin-\\u03b1 recycling, chromatin/transcriptional control, and cytoplasmic microvesicle biogenesis remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model integrating the transport, vesicular, and transcriptional pools\", \"Phosphosite-resolved structure-function mapping in human CSE1L lacking\", \"Determinants of cargo selectivity unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [6, 20, 22, 23]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [3, 9]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [7, 16]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [18, 30]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [16, 20, 23]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [20, 16]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [3, 9]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [10, 11, 15]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [6, 20, 22, 23]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [7, 20]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [1, 2, 16]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [18]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5, 31]}\n    ],\n    \"complexes\": [\n      \"CSE1L\\u2013importin-\\u03b1\\u2013RanGTP export complex\"\n    ],\n    \"partners\": [\n      \"importin-\\u03b1\",\n      \"RanGTP\",\n      \"PPM1H\",\n      \"RAD51\",\n      \"WWTR1\",\n      \"RELA\",\n      \"TRIP13\",\n      \"E-cadherin\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}