{"gene":"TMPO","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":1995,"finding":"The single TMPO gene encodes three isoforms (alpha 75 kDa, beta 51 kDa, gamma 39 kDa) by alternative mRNA splicing. TMPO alpha is present diffusely throughout the nucleus, while TMPO beta and gamma are localized to the nuclear membrane. Exon 4 (spliced into TMPO alpha) encodes a putative basic nuclear localization motif; exon 8 (spliced into TMPO beta and gamma) encodes a hydrophobic putative membrane-spanning domain that targets these isoforms to the nuclear membrane. TMPO beta was identified as the human homologue of rat LAP2 (lamina-associated polypeptide 2).","method":"cDNA cloning, gene structure analysis, alternative splicing characterization, subcellular localization by inference from sequence and prior biochemical data","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gene structure and isoform characterization with sequence analysis plus prior biochemical localization data; single study but multiple orthogonal approaches","pmids":["8530026"],"is_preprint":false},{"year":2015,"finding":"The LAP2alpha-specific isoform of TMPO arose through co-option of a DIRS1-like retrotransposon sequence that was domesticated in mammals. The retrotransposon-derived sequence was alternatively spliced, allowing production of both the new LAP2alpha isoform and the original isoforms. The LAP2alpha domain-containing isoform of TMPO has been co-opted for important cellular roles and evolves under strong purifying selection.","method":"Comparative genomics and evolutionary sequence analysis of vertebrate TMPO loci; identification of retrotransposon-derived sequences via sequence similarity","journal":"Bioinformatics","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational/evolutionary analysis only, no direct functional experiment on the protein","pmids":["25735770"],"is_preprint":false},{"year":2019,"finding":"siRNA-mediated knockdown of TMPO in A549 lung cancer cells inhibited cell proliferation, induced cell cycle arrest at G2/M phase, and promoted apoptosis. TMPO knockdown was associated with downregulation of PCNA, Notch1, and mTOR proteins, and upregulation of cleaved caspase-3, indicating TMPO promotes proliferation via the Notch1/mTOR signaling pathway.","method":"siRNA knockdown, MTT proliferation assay, flow cytometry (cell cycle and apoptosis), Western blot for PCNA, cleaved caspase-3, Notch1, mTOR","journal":"Zhonghua zhong liu za zhi [Chinese journal of oncology]","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean KD with defined cellular phenotype and western blot pathway readout, single lab, single study","pmids":["31648495"],"is_preprint":false},{"year":2023,"finding":"Three novel rare TMPO heterozygous variants in cardiomyopathy patients were functionally characterized: (1) frameshift variant LAP2alpha p.(Gly395Glufs*11) caused haploinsufficiency, impeded cell proliferation, and produced a truncated protein mislocalized to the cytoplasm; (2) C-terminal missense variant LAP2alpha p.(Ala240Thr) reduced proximity interactions between LAP2alpha and the nucleosome-binding protein HMGN5; (3) LEM-domain missense variant p.(Leu124Phe) decreased associations of LAP2alpha/beta with chromatin-associated protein BAF and impaired inhibition of E2F1 transcription factor activity (known to be Rb-dependent, and LAP2alpha is a partner of Rb).","method":"Cellular models with variant expression, proximity ligation/co-IP for LAP2alpha-HMGN5, LAP2-BAF interactions, E2F1 reporter assays, immunofluorescence for localization, proliferation assays","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (co-IP, reporter assay, localization, proliferation) in a single study; single lab","pmids":["36672271"],"is_preprint":false},{"year":2022,"finding":"LAP2alpha polymorphism Arg690Cys (encoded by TMPO) was predicted by protein modeling to destabilize the LAP2alpha homodimer and impair lamin AC-LAP2alpha docking. In leukocytes from a patient heterozygous for both LMNA Ser431* and LAP2alpha Arg690Cys, the LAP2alpha Arg690Cys variant appeared to attenuate the nuclear morphology defects (decreased nuclear area, increased elongation) caused by the lamin AC truncating mutation, partially compensating for nuclear circularity defects.","method":"Protein modeling and docking, confocal microscopy of leukocyte nuclear morphology in family members with different genotype combinations","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — protein modeling plus morphological microscopy; small n, single family, no direct biochemical interaction assay","pmids":["36362411"],"is_preprint":false},{"year":2024,"finding":"5-FU treatment induced autolysosome-dependent degradation of TMPO protein in colon cancer cells, which subsequently triggered ERK-mediated phosphorylation of c-Fos, promoting cancer stemness and 5-FU resistance via NANOG transcription.","method":"Western blot for TMPO protein after 5-FU treatment, autophagy/lysosome inhibitor experiments, ERK phosphorylation assays, promoter binding assays for c-Fos on NANOG promoter, rescue experiments","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined degradation mechanism with pathway readouts (ERK phosphorylation, NANOG promoter binding) using multiple methods; single lab","pmids":["38233377"],"is_preprint":false},{"year":2021,"finding":"TMPO interacts with TMEM35A in bovine mammary epithelial cells. Co-immunoprecipitation detected an interaction between TMEM35A and TMPO. Knockdown of TMPO attenuated phosphorylated p65, p-p38, TNF-α, and iNOS levels. Overexpression of TMEM35A reversed the EC-mediated effects in TMPO knockdown cells, indicating TMEM35A-TMPO interaction inhibits MAPK and NF-κB pathways.","method":"CRISPR/Cas9-based knockdown, overexpression, co-immunoprecipitation, western blot for p-p65, p-p38, TNF-α, iNOS, RNA-seq, tandem mass tag proteomics","journal":"Journal of dairy science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus functional knockdown/overexpression with signaling readouts; single lab, bovine cell model","pmids":["34593235"],"is_preprint":false},{"year":2024,"finding":"TMPO expression is upregulated under high glucose conditions in diabetic foot ulcer models. TMPO knockdown in vitro promoted cell proliferation and migration while activating the TGF-β/Smad signaling pathway. In vivo, TMPO knockdown reduced inflammation, improved tissue regeneration, enhanced microvascular and collagen formation, and facilitated wound healing.","method":"In vitro cell knockdown under high glucose, TGF-β/Smad pathway western blot, in vivo wound healing mouse model, histology","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — defined pathway (TGF-β/Smad) with in vitro and in vivo KD experiments; single lab, single study","pmids":["41321624"],"is_preprint":false},{"year":2024,"finding":"TMPO (encoding LAP2/Lap2) is identified as a key driver of CTC heterogeneity in prostate cancer. TMPO promotes dissemination and metastasis in vivo by enhancing survival under conditions of metabolic stress. TMPO activity is upregulated in advanced human prostate tumors, metastases, and CTCs.","method":"Computational systems analysis of CTC organoids from GEMMs, in vivo dissemination/metastasis assays, metabolic stress survival assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vivo functional experiments with defined phenotype (metastasis under metabolic stress), systems analysis; preprint, single lab","pmids":["41509437"],"is_preprint":true},{"year":2024,"finding":"siRNA-mediated depletion of TMPO in triple-negative breast cancer (TNBC) cell lines induced aberrant nuclear morphology, decreased proliferation, and induced cell death. Minimal effects were observed in non-cancerous MCF10A cells, indicating a cancer-specific dependency. TMPO (as a Lem-D protein) is overexpressed in TNBC at both mRNA and protein levels.","method":"siRNA knockdown, immunoblotting, immunofluorescence for nuclear morphology, proliferation assays, apoptosis assays in TNBC cell panel vs. non-cancerous MCF10A cells","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean KD with multiple functional readouts and comparison to non-cancerous cells; single lab, single study","pmids":["38720803"],"is_preprint":false}],"current_model":"TMPO encodes the nuclear envelope protein LAP2 (lamina-associated polypeptide 2), produced as multiple isoforms (alpha, beta, gamma) by alternative splicing from a single gene; the alpha isoform localizes diffusely in the nucleus via a basic NLS sequence while beta and gamma are targeted to the inner nuclear membrane via a hydrophobic membrane-spanning domain, where they interact with lamin B1 and chromatin-associated proteins (BAF, HMGN5) and partner with Rb to regulate E2F1 transcription factor activity; loss of TMPO impairs cell proliferation and induces apoptosis partly through Notch1/mTOR signaling, while in cancer contexts TMPO undergoes autolysosome-dependent degradation in response to 5-FU that activates ERK-mediated c-Fos phosphorylation, and TMPO promotes metastatic dissemination under metabolic stress conditions."},"narrative":{"mechanistic_narrative":"TMPO encodes LAP2 (lamina-associated polypeptide 2), a nuclear protein expressed as three isoforms — alpha (75 kDa), beta (51 kDa) and gamma (39 kDa) — generated by alternative splicing of a single gene, with exon-encoded sequence determining localization: the alpha isoform is distributed diffusely throughout the nucleus via a basic localization motif, whereas beta and gamma are targeted to the nuclear membrane through a hydrophobic membrane-spanning domain [PMID:8530026]. At the molecular level, LAP2 isoforms engage chromatin-associated partners and the cell-cycle machinery: the LEM domain mediates association with BAF, the C-terminus contacts the nucleosome-binding protein HMGN5, and LAP2alpha partners with Rb to inhibit E2F1 transcriptional activity, with disease-associated TMPO variants disrupting each of these contacts and impairing proliferation [PMID:36672271]. Loss of TMPO restrains proliferation and triggers apoptosis — through downregulation of PCNA, Notch1 and mTOR and caspase-3 cleavage in lung cancer cells [PMID:31648495], and through aberrant nuclear morphology and cancer-selective cell death in triple-negative breast cancer [PMID:38720803]. In cancer, TMPO supports malignant phenotypes: 5-FU induces its autolysosome-dependent degradation, which activates ERK-mediated c-Fos phosphorylation and NANOG-driven stemness conferring drug resistance in colon cancer [PMID:38233377], and TMPO drives dissemination and metastasis by enhancing survival under metabolic stress [PMID:41509437]. Beyond these contexts, TMPO has been linked to inflammatory signaling via interaction with TMEM35A, restraining MAPK and NF-kB pathways [PMID:34593235], and to TGF-beta/Smad-dependent wound healing [PMID:41321624].","teleology":[{"year":1995,"claim":"Established that a single TMPO gene generates structurally and topologically distinct proteins, defining the isoform architecture that underlies all subsequent functional studies.","evidence":"cDNA cloning, gene structure and alternative splicing analysis with sequence-based localization assignment","pmids":["8530026"],"confidence":"Medium","gaps":["Localization inferred from sequence and prior data rather than direct imaging of each isoform","Molecular partners of each isoform not yet defined"]},{"year":2015,"claim":"Addressed the evolutionary origin of the alpha isoform, showing the LAP2alpha-specific domain arose by domestication of a DIRS1-like retrotransposon under purifying selection.","evidence":"Comparative genomics and evolutionary sequence analysis of vertebrate TMPO loci","pmids":["25735770"],"confidence":"Low","gaps":["Computational only; no functional experiment on the protein","Does not establish the cellular role of the co-opted domain"]},{"year":2019,"claim":"Demonstrated that TMPO is required for cancer cell proliferation, linking its loss to G2/M arrest and apoptosis via Notch1/mTOR signaling.","evidence":"siRNA knockdown in A549 lung cancer cells with proliferation, cell cycle, apoptosis assays and Western blot pathway readouts","pmids":["31648495"],"confidence":"Medium","gaps":["Single cell line, single lab","Mechanistic link between TMPO and Notch1/mTOR not shown to be direct"]},{"year":2021,"claim":"Identified TMEM35A as a physical interactor of TMPO and connected this interaction to suppression of MAPK and NF-kB inflammatory signaling.","evidence":"Co-IP, CRISPR knockdown/overexpression, RNA-seq and proteomics with signaling Western blots in bovine mammary epithelial cells","pmids":["34593235"],"confidence":"Medium","gaps":["Single non-human cell model","Reciprocal validation and interaction interface not defined","Direct versus indirect pathway regulation unresolved"]},{"year":2022,"claim":"Probed how a TMPO polymorphism modulates lamin interactions, suggesting Arg690Cys destabilizes the LAP2alpha homodimer and lamin AC docking with partial compensation of nuclear morphology defects.","evidence":"Protein modeling/docking and confocal nuclear morphology imaging in leukocytes from a single family","pmids":["36362411"],"confidence":"Low","gaps":["No direct biochemical interaction assay; modeling-based prediction","Single family, small n","Confounded by co-occurring LMNA mutation"]},{"year":2023,"claim":"Resolved molecular consequences of disease variants, mapping specific LAP2 contacts (BAF via LEM domain, HMGN5 at C-terminus, Rb/E2F1 regulation) and tying their disruption to impaired proliferation in cardiomyopathy.","evidence":"Variant expression cellular models with proximity ligation/co-IP, E2F1 reporter assays, immunofluorescence and proliferation assays","pmids":["36672271"],"confidence":"Medium","gaps":["Single lab","Causal link to cardiomyopathy pathophysiology not established in vivo","Quantitative contribution of each interaction not separated"]},{"year":2024,"claim":"Established TMPO as an actionable node in cancer therapy resistance, showing 5-FU-induced autolysosomal degradation activates ERK/c-Fos/NANOG to drive stemness and resistance.","evidence":"Western blot of TMPO after 5-FU, autophagy/lysosome inhibitors, ERK phosphorylation, NANOG promoter binding and rescue in colon cancer cells","pmids":["38233377"],"confidence":"Medium","gaps":["Single lab","Mechanism linking TMPO loss to ERK activation not fully defined","In vivo relevance untested"]},{"year":2024,"claim":"Defined a cancer-selective dependency, showing TMPO depletion causes aberrant nuclear morphology and death in TNBC cells but spares non-cancerous cells.","evidence":"siRNA knockdown with immunofluorescence, proliferation and apoptosis assays across a TNBC panel versus MCF10A","pmids":["38720803"],"confidence":"Medium","gaps":["Single lab","Basis of cancer selectivity unexplained","No in vivo validation"]},{"year":2024,"claim":"Extended TMPO function to fibrotic/regenerative contexts, showing high-glucose-induced TMPO restrains proliferation/migration via TGF-beta/Smad and impairs wound healing.","evidence":"In vitro knockdown under high glucose and in vivo diabetic wound healing mouse model with histology","pmids":["41321624"],"confidence":"Medium","gaps":["Single study","Connection between nuclear LAP2 function and TGF-beta/Smad signaling not mechanistically resolved"]},{"year":2024,"claim":"Implicated TMPO as a driver of metastatic heterogeneity, promoting prostate cancer dissemination by enhancing survival under metabolic stress.","evidence":"Computational systems analysis of CTC organoids from GEMMs with in vivo dissemination and metabolic stress survival assays (preprint)","pmids":["41509437"],"confidence":"Medium","gaps":["Preprint, single lab","Molecular mechanism of stress survival undefined","Isoform responsible not specified"]},{"year":null,"claim":"It remains unresolved how the distinct nuclear-envelope/chromatin functions of LAP2 isoforms mechanistically connect to the diverse cytoplasmic signaling outcomes (Notch1/mTOR, ERK/c-Fos, TGF-beta/Smad, MAPK/NF-kB) attributed to TMPO across tissues.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying mechanism linking nuclear architecture role to cytoplasmic signaling","Isoform-specific contributions to each phenotype not dissected","Structural model of LAP2 complexes absent from corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[3]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[3]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[3]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[0]}],"pathway":[],"complexes":[],"partners":["LMNB1","BAF","HMGN5","RB1","TMEM35A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P42166","full_name":"Lamina-associated polypeptide 2, isoform alpha","aliases":["Thymopoietin isoform alpha","TP alpha","Thymopoietin-related peptide isoform alpha","TPRP isoform alpha"],"length_aa":694,"mass_kda":75.5,"function":"May be involved in the structural organization of the nucleus and in the post-mitotic nuclear assembly. Plays an important role, together with LMNA, in the nuclear anchorage of RB1 TP and TP5 may play a role in T-cell development and function. TP5 is an immunomodulating pentapeptide","subcellular_location":"Nucleus; Chromosome","url":"https://www.uniprot.org/uniprotkb/P42166/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TMPO","classification":"Not Classified","n_dependent_lines":22,"n_total_lines":1208,"dependency_fraction":0.018211920529801324},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000120802","cell_line_id":"CID001498","localizations":[{"compartment":"nucleoplasm","grade":3},{"compartment":"chromatin","grade":2},{"compartment":"nuclear_membrane","grade":2},{"compartment":"cytoplasmic","grade":1}],"interactors":[{"gene":"DAD1","stoichiometry":10.0},{"gene":"DDOST","stoichiometry":4.0},{"gene":"RPN1","stoichiometry":4.0},{"gene":"RPN2","stoichiometry":4.0},{"gene":"ATG13","stoichiometry":0.2},{"gene":"CANX","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"CSNK2B","stoichiometry":0.2},{"gene":"EMC9","stoichiometry":0.2},{"gene":"ENY2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001498","total_profiled":1310},"omim":[{"mim_id":"618627","title":"GERM CELL-LESS 1, SPERMATOGENESIS-ASSOCIATED; GMCL1","url":"https://www.omim.org/entry/618627"},{"mim_id":"616312","title":"LEM DOMAIN-CONTAINING PROTEIN 2; LEMD2","url":"https://www.omim.org/entry/616312"},{"mim_id":"188380","title":"THYMOPOIETIN; TMPO","url":"https://www.omim.org/entry/188380"},{"mim_id":"115200","title":"CARDIOMYOPATHY, DILATED, 1A; CMD1A","url":"https://www.omim.org/entry/115200"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nuclear membrane","reliability":"Enhanced"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":130.2}],"url":"https://www.proteinatlas.org/search/TMPO"},"hgnc":{"alias_symbol":["TP","LAP2","LEMD4"],"prev_symbol":[]},"alphafold":{"accession":"P42166","domains":[{"cath_id":"1.10.720.40","chopping":"9-48","consensus_level":"high","plddt":88.587,"start":9,"end":48},{"cath_id":"1.10.287.3160","chopping":"461-469_496-501_518-687","consensus_level":"high","plddt":90.0176,"start":461,"end":687}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P42166","model_url":"https://alphafold.ebi.ac.uk/files/AF-P42166-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P42166-F1-predicted_aligned_error_v6.png","plddt_mean":60.09},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TMPO","jax_strain_url":"https://www.jax.org/strain/search?query=TMPO"},"sequence":{"accession":"P42166","fasta_url":"https://rest.uniprot.org/uniprotkb/P42166.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P42166/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P42166"}},"corpus_meta":[{"pmid":"8530026","id":"PMC_8530026","title":"Structure and mapping of the human thymopoietin (TMPO) gene and relationship of human TMPO beta to rat lamin-associated polypeptide 2.","date":"1995","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/8530026","citation_count":80,"is_preprint":false},{"pmid":"31501276","id":"PMC_31501276","title":"ESR1-Stabilizing Long Noncoding RNA TMPO-AS1 Promotes Hormone-Refractory Breast Cancer Progression.","date":"2019","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/31501276","citation_count":52,"is_preprint":false},{"pmid":"31230752","id":"PMC_31230752","title":"Long noncoding RNA TMPO-AS1 promotes progression of non-small cell lung cancer through regulating its natural antisense transcript TMPO.","date":"2019","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/31230752","citation_count":40,"is_preprint":false},{"pmid":"33295056","id":"PMC_33295056","title":"Long noncoding RNA TMPO-AS1/miR-126-5p/BRCC3 axis accelerates gastric cancer progression and angiogenesis via activating PI3K/Akt/mTOR pathway.","date":"2021","source":"Journal of gastroenterology and hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/33295056","citation_count":39,"is_preprint":false},{"pmid":"31483914","id":"PMC_31483914","title":"TMPO-AS1 promotes cervical cancer progression by upregulating RAB14 via sponging miR-577.","date":"2019","source":"The journal of gene medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31483914","citation_count":38,"is_preprint":false},{"pmid":"31680323","id":"PMC_31680323","title":"LncRNA TMPO-AS1 serves as a ceRNA to promote osteosarcoma tumorigenesis by regulating miR-199a-5p/WNT7B axis.","date":"2019","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31680323","citation_count":36,"is_preprint":false},{"pmid":"32062549","id":"PMC_32062549","title":"Long noncoding RNA TMPO-AS1 promotes lung adenocarcinoma progression and is negatively regulated by miR-383-5p.","date":"2020","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/32062549","citation_count":33,"is_preprint":false},{"pmid":"32437068","id":"PMC_32437068","title":"Proliferation-associated long noncoding RNA, TMPO-AS1, is a potential therapeutic target for triple-negative breast cancer.","date":"2020","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/32437068","citation_count":32,"is_preprint":false},{"pmid":"32087328","id":"PMC_32087328","title":"TMPO-AS1/miR-98-5p/EBF1 feedback loop contributes to the progression of bladder cancer.","date":"2020","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/32087328","citation_count":30,"is_preprint":false},{"pmid":"32462698","id":"PMC_32462698","title":"LncRNA TMPO-AS1 promotes hepatocellular carcinoma cell proliferation, migration and invasion through sponging miR-329-3p to stimulate FOXK1-mediated AKT/mTOR signaling pathway.","date":"2020","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32462698","citation_count":30,"is_preprint":false},{"pmid":"25735770","id":"PMC_25735770","title":"Alternative splicing and co-option of transposable elements: the case of TMPO/LAP2α and ZNF451 in mammals.","date":"2015","source":"Bioinformatics (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/25735770","citation_count":30,"is_preprint":false},{"pmid":"35760875","id":"PMC_35760875","title":"LncRNA TMPO-AS1 promotes esophageal squamous cell carcinoma progression by forming biomolecular condensates with FUS and p300 to regulate TMPO transcription.","date":"2022","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35760875","citation_count":27,"is_preprint":false},{"pmid":"38233377","id":"PMC_38233377","title":"c-Fos regulated by TMPO/ERK axis promotes 5-FU resistance via inducing NANOG transcription in colon 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Axis.","date":"2020","source":"The American journal of the medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32988599","citation_count":25,"is_preprint":false},{"pmid":"32184662","id":"PMC_32184662","title":"Long Non-Coding RNA TMPO-AS1 Promotes Cervical Cancer Cell Proliferation, Migration, and Invasion by Regulating miR-143-3p/ZEB1 Axis.","date":"2020","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/32184662","citation_count":25,"is_preprint":false},{"pmid":"32110100","id":"PMC_32110100","title":"Long Non-Coding RNA TMPO-AS1 Promotes Cell Migration and Invasion by Sponging miR-140-5p and Inducing SOX4-Mediated EMT in Gastric Cancer.","date":"2020","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/32110100","citation_count":23,"is_preprint":false},{"pmid":"31768869","id":"PMC_31768869","title":"Overexpression and Clinicopathological Correlation of Long Noncoding RNA TMPO-AS1 in Colorectal Cancer Patients.","date":"2020","source":"Journal of gastrointestinal cancer","url":"https://pubmed.ncbi.nlm.nih.gov/31768869","citation_count":22,"is_preprint":false},{"pmid":"32139259","id":"PMC_32139259","title":"LncRNA TMPO-AS1 up-regulates the expression of HIF-1α and promotes the malignant phenotypes of retinoblastoma cells via sponging miR-199a-5p.","date":"2020","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/32139259","citation_count":21,"is_preprint":false},{"pmid":"32497621","id":"PMC_32497621","title":"Roles of a TMPO-AS1/microRNA-200c/TMEFF2 ceRNA network in the malignant behaviors and 5-FU resistance of ovarian cancer cells.","date":"2020","source":"Experimental and molecular pathology","url":"https://pubmed.ncbi.nlm.nih.gov/32497621","citation_count":19,"is_preprint":false},{"pmid":"32753892","id":"PMC_32753892","title":"lncRNA TMPO-AS1 Exerts Oncogenic Roles in HCC Through Regulating miR-320a/SERBP1 Axis.","date":"2020","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/32753892","citation_count":18,"is_preprint":false},{"pmid":"32643321","id":"PMC_32643321","title":"Propofol suppresses hypoxia-induced esophageal cancer cell migration, invasion, and EMT through regulating lncRNA TMPO-AS1/miR-498 axis.","date":"2020","source":"Thoracic cancer","url":"https://pubmed.ncbi.nlm.nih.gov/32643321","citation_count":18,"is_preprint":false},{"pmid":"33981362","id":"PMC_33981362","title":"Long non-coding RNA TMPO-AS1 facilitates chemoresistance and invasion in breast cancer by modulating the miR-1179/TRIM37 axis.","date":"2021","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/33981362","citation_count":18,"is_preprint":false},{"pmid":"34593235","id":"PMC_34593235","title":"Anti-inflammation of epicatechin mediated by TMEM35A and TMPO in bovine mammary epithelial cell line cells and mouse mammary gland.","date":"2021","source":"Journal of dairy 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APJCP","url":"https://pubmed.ncbi.nlm.nih.gov/39205592","citation_count":4,"is_preprint":false},{"pmid":"38330619","id":"PMC_38330619","title":"Deciphering the oncogenic landscape: Unveiling the molecular machinery and clinical significance of LncRNA TMPO-AS1 in human cancers.","date":"2024","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/38330619","citation_count":3,"is_preprint":false},{"pmid":"36417294","id":"PMC_36417294","title":"Neuroinflammation after ischemic stroke involves INPP5D expression mediated by the TMPO-AS1-PU.1 complex.","date":"2022","source":"Neurological research","url":"https://pubmed.ncbi.nlm.nih.gov/36417294","citation_count":2,"is_preprint":false},{"pmid":"40439393","id":"PMC_40439393","title":"In Silico Analysis Revealed a Role for NUSAP1 in Lung Adenocarcinoma through E2F1/hsa-let-7b-5p/lncRNA-TMPO-AS1.","date":"2025","source":"Asian Pacific journal of cancer prevention : APJCP","url":"https://pubmed.ncbi.nlm.nih.gov/40439393","citation_count":2,"is_preprint":false},{"pmid":"34335680","id":"PMC_34335680","title":"Interaction of HLA Class II rs9272219 and TMPO rs17028450 (Arg690Cys) Variants Affects Neuromyelitis Optica Spectrum Disorder Susceptibility in an Admixed Mexican Population.","date":"2021","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34335680","citation_count":2,"is_preprint":false},{"pmid":"41321624","id":"PMC_41321624","title":"Cuproptosis-related gene TMPO affects the healing of diabetic foot ulcers through TGF-β/Smad signaling pathway.","date":"2025","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/41321624","citation_count":1,"is_preprint":false},{"pmid":"38937856","id":"PMC_38937856","title":"Long noncoding RNA TMPO-AS1 upregulates BCAT1 expression to promote cell proliferation in nasopharyngeal carcinoma via microRNA let-7c-5p.","date":"2024","source":"Genes and environment : the official journal of the Japanese Environmental Mutagen Society","url":"https://pubmed.ncbi.nlm.nih.gov/38937856","citation_count":1,"is_preprint":false},{"pmid":"41094477","id":"PMC_41094477","title":"Long noncoding RNA TMPO-AS1 upregulates chromosomal passenger complex expression to promote cell proliferation in lung cancer via sponging microRNA let-7b-5p.","date":"2025","source":"Cell division","url":"https://pubmed.ncbi.nlm.nih.gov/41094477","citation_count":1,"is_preprint":false},{"pmid":"38720803","id":"PMC_38720803","title":"The expression and role of the Lem-D proteins Ankle2, Emerin, Lemd2, and TMPO in triple-negative breast cancer cell growth.","date":"2024","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/38720803","citation_count":1,"is_preprint":false},{"pmid":"40242419","id":"PMC_40242419","title":"In smokers, the axis NCAPG/hsa-let-7b-5p/TMPO-AS1 promotes lung adenocarcinoma.","date":"2025","source":"Reports of practical oncology and radiotherapy : journal of Greatpoland Cancer Center in Poznan and Polish Society of Radiation Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40242419","citation_count":1,"is_preprint":false},{"pmid":"36362411","id":"PMC_36362411","title":"Leukocyte Nuclear Morphology Alterations in Dilated Cardiomyopathy Caused by a Lamin AC Truncating Mutation (LMNA/Ser431*) Are Modified by the Presence of a LAP2 Missense Polymorphism (TMPO/Arg690Cys).","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36362411","citation_count":1,"is_preprint":false},{"pmid":"41509437","id":"PMC_41509437","title":"TMPO promotes cellular dissemination and metastasis in circulating tumor cells.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41509437","citation_count":0,"is_preprint":false},{"pmid":"31648495","id":"PMC_31648495","title":"[Proliferation inhibition and apoptosis promotion induced by deletion of TMPO in 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cells.","date":"2026","source":"Archives of oral biology","url":"https://pubmed.ncbi.nlm.nih.gov/42166844","citation_count":0,"is_preprint":false},{"pmid":"41642421","id":"PMC_41642421","title":"LncRNA TMPO-AS1 aggravates the cisplatin resistance in cervical cancer via miR-140-5p/DNMT1 axis-mediated DNA methylation of KLK10.","date":"2026","source":"Medical oncology (Northwood, London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/41642421","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":38607,"output_tokens":2935,"usd":0.079923,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10353,"output_tokens":3408,"usd":0.068483,"stage2_stop_reason":"end_turn"},"total_usd":0.148406,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"The single TMPO gene encodes three isoforms (alpha 75 kDa, beta 51 kDa, gamma 39 kDa) by alternative mRNA splicing. TMPO alpha is present diffusely throughout the nucleus, while TMPO beta and gamma are localized to the nuclear membrane. Exon 4 (spliced into TMPO alpha) encodes a putative basic nuclear localization motif; exon 8 (spliced into TMPO beta and gamma) encodes a hydrophobic putative membrane-spanning domain that targets these isoforms to the nuclear membrane. TMPO beta was identified as the human homologue of rat LAP2 (lamina-associated polypeptide 2).\",\n      \"method\": \"cDNA cloning, gene structure analysis, alternative splicing characterization, subcellular localization by inference from sequence and prior biochemical data\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gene structure and isoform characterization with sequence analysis plus prior biochemical localization data; single study but multiple orthogonal approaches\",\n      \"pmids\": [\"8530026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The LAP2alpha-specific isoform of TMPO arose through co-option of a DIRS1-like retrotransposon sequence that was domesticated in mammals. The retrotransposon-derived sequence was alternatively spliced, allowing production of both the new LAP2alpha isoform and the original isoforms. The LAP2alpha domain-containing isoform of TMPO has been co-opted for important cellular roles and evolves under strong purifying selection.\",\n      \"method\": \"Comparative genomics and evolutionary sequence analysis of vertebrate TMPO loci; identification of retrotransposon-derived sequences via sequence similarity\",\n      \"journal\": \"Bioinformatics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational/evolutionary analysis only, no direct functional experiment on the protein\",\n      \"pmids\": [\"25735770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"siRNA-mediated knockdown of TMPO in A549 lung cancer cells inhibited cell proliferation, induced cell cycle arrest at G2/M phase, and promoted apoptosis. TMPO knockdown was associated with downregulation of PCNA, Notch1, and mTOR proteins, and upregulation of cleaved caspase-3, indicating TMPO promotes proliferation via the Notch1/mTOR signaling pathway.\",\n      \"method\": \"siRNA knockdown, MTT proliferation assay, flow cytometry (cell cycle and apoptosis), Western blot for PCNA, cleaved caspase-3, Notch1, mTOR\",\n      \"journal\": \"Zhonghua zhong liu za zhi [Chinese journal of oncology]\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean KD with defined cellular phenotype and western blot pathway readout, single lab, single study\",\n      \"pmids\": [\"31648495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Three novel rare TMPO heterozygous variants in cardiomyopathy patients were functionally characterized: (1) frameshift variant LAP2alpha p.(Gly395Glufs*11) caused haploinsufficiency, impeded cell proliferation, and produced a truncated protein mislocalized to the cytoplasm; (2) C-terminal missense variant LAP2alpha p.(Ala240Thr) reduced proximity interactions between LAP2alpha and the nucleosome-binding protein HMGN5; (3) LEM-domain missense variant p.(Leu124Phe) decreased associations of LAP2alpha/beta with chromatin-associated protein BAF and impaired inhibition of E2F1 transcription factor activity (known to be Rb-dependent, and LAP2alpha is a partner of Rb).\",\n      \"method\": \"Cellular models with variant expression, proximity ligation/co-IP for LAP2alpha-HMGN5, LAP2-BAF interactions, E2F1 reporter assays, immunofluorescence for localization, proliferation assays\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (co-IP, reporter assay, localization, proliferation) in a single study; single lab\",\n      \"pmids\": [\"36672271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LAP2alpha polymorphism Arg690Cys (encoded by TMPO) was predicted by protein modeling to destabilize the LAP2alpha homodimer and impair lamin AC-LAP2alpha docking. In leukocytes from a patient heterozygous for both LMNA Ser431* and LAP2alpha Arg690Cys, the LAP2alpha Arg690Cys variant appeared to attenuate the nuclear morphology defects (decreased nuclear area, increased elongation) caused by the lamin AC truncating mutation, partially compensating for nuclear circularity defects.\",\n      \"method\": \"Protein modeling and docking, confocal microscopy of leukocyte nuclear morphology in family members with different genotype combinations\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — protein modeling plus morphological microscopy; small n, single family, no direct biochemical interaction assay\",\n      \"pmids\": [\"36362411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"5-FU treatment induced autolysosome-dependent degradation of TMPO protein in colon cancer cells, which subsequently triggered ERK-mediated phosphorylation of c-Fos, promoting cancer stemness and 5-FU resistance via NANOG transcription.\",\n      \"method\": \"Western blot for TMPO protein after 5-FU treatment, autophagy/lysosome inhibitor experiments, ERK phosphorylation assays, promoter binding assays for c-Fos on NANOG promoter, rescue experiments\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined degradation mechanism with pathway readouts (ERK phosphorylation, NANOG promoter binding) using multiple methods; single lab\",\n      \"pmids\": [\"38233377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TMPO interacts with TMEM35A in bovine mammary epithelial cells. Co-immunoprecipitation detected an interaction between TMEM35A and TMPO. Knockdown of TMPO attenuated phosphorylated p65, p-p38, TNF-α, and iNOS levels. Overexpression of TMEM35A reversed the EC-mediated effects in TMPO knockdown cells, indicating TMEM35A-TMPO interaction inhibits MAPK and NF-κB pathways.\",\n      \"method\": \"CRISPR/Cas9-based knockdown, overexpression, co-immunoprecipitation, western blot for p-p65, p-p38, TNF-α, iNOS, RNA-seq, tandem mass tag proteomics\",\n      \"journal\": \"Journal of dairy science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus functional knockdown/overexpression with signaling readouts; single lab, bovine cell model\",\n      \"pmids\": [\"34593235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TMPO expression is upregulated under high glucose conditions in diabetic foot ulcer models. TMPO knockdown in vitro promoted cell proliferation and migration while activating the TGF-β/Smad signaling pathway. In vivo, TMPO knockdown reduced inflammation, improved tissue regeneration, enhanced microvascular and collagen formation, and facilitated wound healing.\",\n      \"method\": \"In vitro cell knockdown under high glucose, TGF-β/Smad pathway western blot, in vivo wound healing mouse model, histology\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — defined pathway (TGF-β/Smad) with in vitro and in vivo KD experiments; single lab, single study\",\n      \"pmids\": [\"41321624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TMPO (encoding LAP2/Lap2) is identified as a key driver of CTC heterogeneity in prostate cancer. TMPO promotes dissemination and metastasis in vivo by enhancing survival under conditions of metabolic stress. TMPO activity is upregulated in advanced human prostate tumors, metastases, and CTCs.\",\n      \"method\": \"Computational systems analysis of CTC organoids from GEMMs, in vivo dissemination/metastasis assays, metabolic stress survival assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vivo functional experiments with defined phenotype (metastasis under metabolic stress), systems analysis; preprint, single lab\",\n      \"pmids\": [\"41509437\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"siRNA-mediated depletion of TMPO in triple-negative breast cancer (TNBC) cell lines induced aberrant nuclear morphology, decreased proliferation, and induced cell death. Minimal effects were observed in non-cancerous MCF10A cells, indicating a cancer-specific dependency. TMPO (as a Lem-D protein) is overexpressed in TNBC at both mRNA and protein levels.\",\n      \"method\": \"siRNA knockdown, immunoblotting, immunofluorescence for nuclear morphology, proliferation assays, apoptosis assays in TNBC cell panel vs. non-cancerous MCF10A cells\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean KD with multiple functional readouts and comparison to non-cancerous cells; single lab, single study\",\n      \"pmids\": [\"38720803\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TMPO encodes the nuclear envelope protein LAP2 (lamina-associated polypeptide 2), produced as multiple isoforms (alpha, beta, gamma) by alternative splicing from a single gene; the alpha isoform localizes diffusely in the nucleus via a basic NLS sequence while beta and gamma are targeted to the inner nuclear membrane via a hydrophobic membrane-spanning domain, where they interact with lamin B1 and chromatin-associated proteins (BAF, HMGN5) and partner with Rb to regulate E2F1 transcription factor activity; loss of TMPO impairs cell proliferation and induces apoptosis partly through Notch1/mTOR signaling, while in cancer contexts TMPO undergoes autolysosome-dependent degradation in response to 5-FU that activates ERK-mediated c-Fos phosphorylation, and TMPO promotes metastatic dissemination under metabolic stress conditions.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TMPO encodes LAP2 (lamina-associated polypeptide 2), a nuclear protein expressed as three isoforms — alpha (75 kDa), beta (51 kDa) and gamma (39 kDa) — generated by alternative splicing of a single gene, with exon-encoded sequence determining localization: the alpha isoform is distributed diffusely throughout the nucleus via a basic localization motif, whereas beta and gamma are targeted to the nuclear membrane through a hydrophobic membrane-spanning domain [#0]. At the molecular level, LAP2 isoforms engage chromatin-associated partners and the cell-cycle machinery: the LEM domain mediates association with BAF, the C-terminus contacts the nucleosome-binding protein HMGN5, and LAP2alpha partners with Rb to inhibit E2F1 transcriptional activity, with disease-associated TMPO variants disrupting each of these contacts and impairing proliferation [#3]. Loss of TMPO restrains proliferation and triggers apoptosis — through downregulation of PCNA, Notch1 and mTOR and caspase-3 cleavage in lung cancer cells [#2], and through aberrant nuclear morphology and cancer-selective cell death in triple-negative breast cancer [#9]. In cancer, TMPO supports malignant phenotypes: 5-FU induces its autolysosome-dependent degradation, which activates ERK-mediated c-Fos phosphorylation and NANOG-driven stemness conferring drug resistance in colon cancer [#5], and TMPO drives dissemination and metastasis by enhancing survival under metabolic stress [#8]. Beyond these contexts, TMPO has been linked to inflammatory signaling via interaction with TMEM35A, restraining MAPK and NF-kB pathways [#6], and to TGF-beta/Smad-dependent wound healing [#7].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established that a single TMPO gene generates structurally and topologically distinct proteins, defining the isoform architecture that underlies all subsequent functional studies.\",\n      \"evidence\": \"cDNA cloning, gene structure and alternative splicing analysis with sequence-based localization assignment\",\n      \"pmids\": [\"8530026\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Localization inferred from sequence and prior data rather than direct imaging of each isoform\", \"Molecular partners of each isoform not yet defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Addressed the evolutionary origin of the alpha isoform, showing the LAP2alpha-specific domain arose by domestication of a DIRS1-like retrotransposon under purifying selection.\",\n      \"evidence\": \"Comparative genomics and evolutionary sequence analysis of vertebrate TMPO loci\",\n      \"pmids\": [\"25735770\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Computational only; no functional experiment on the protein\", \"Does not establish the cellular role of the co-opted domain\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated that TMPO is required for cancer cell proliferation, linking its loss to G2/M arrest and apoptosis via Notch1/mTOR signaling.\",\n      \"evidence\": \"siRNA knockdown in A549 lung cancer cells with proliferation, cell cycle, apoptosis assays and Western blot pathway readouts\",\n      \"pmids\": [\"31648495\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single cell line, single lab\", \"Mechanistic link between TMPO and Notch1/mTOR not shown to be direct\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified TMEM35A as a physical interactor of TMPO and connected this interaction to suppression of MAPK and NF-kB inflammatory signaling.\",\n      \"evidence\": \"Co-IP, CRISPR knockdown/overexpression, RNA-seq and proteomics with signaling Western blots in bovine mammary epithelial cells\",\n      \"pmids\": [\"34593235\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single non-human cell model\", \"Reciprocal validation and interaction interface not defined\", \"Direct versus indirect pathway regulation unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Probed how a TMPO polymorphism modulates lamin interactions, suggesting Arg690Cys destabilizes the LAP2alpha homodimer and lamin AC docking with partial compensation of nuclear morphology defects.\",\n      \"evidence\": \"Protein modeling/docking and confocal nuclear morphology imaging in leukocytes from a single family\",\n      \"pmids\": [\"36362411\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct biochemical interaction assay; modeling-based prediction\", \"Single family, small n\", \"Confounded by co-occurring LMNA mutation\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Resolved molecular consequences of disease variants, mapping specific LAP2 contacts (BAF via LEM domain, HMGN5 at C-terminus, Rb/E2F1 regulation) and tying their disruption to impaired proliferation in cardiomyopathy.\",\n      \"evidence\": \"Variant expression cellular models with proximity ligation/co-IP, E2F1 reporter assays, immunofluorescence and proliferation assays\",\n      \"pmids\": [\"36672271\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Causal link to cardiomyopathy pathophysiology not established in vivo\", \"Quantitative contribution of each interaction not separated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established TMPO as an actionable node in cancer therapy resistance, showing 5-FU-induced autolysosomal degradation activates ERK/c-Fos/NANOG to drive stemness and resistance.\",\n      \"evidence\": \"Western blot of TMPO after 5-FU, autophagy/lysosome inhibitors, ERK phosphorylation, NANOG promoter binding and rescue in colon cancer cells\",\n      \"pmids\": [\"38233377\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Mechanism linking TMPO loss to ERK activation not fully defined\", \"In vivo relevance untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a cancer-selective dependency, showing TMPO depletion causes aberrant nuclear morphology and death in TNBC cells but spares non-cancerous cells.\",\n      \"evidence\": \"siRNA knockdown with immunofluorescence, proliferation and apoptosis assays across a TNBC panel versus MCF10A\",\n      \"pmids\": [\"38720803\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Basis of cancer selectivity unexplained\", \"No in vivo validation\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended TMPO function to fibrotic/regenerative contexts, showing high-glucose-induced TMPO restrains proliferation/migration via TGF-beta/Smad and impairs wound healing.\",\n      \"evidence\": \"In vitro knockdown under high glucose and in vivo diabetic wound healing mouse model with histology\",\n      \"pmids\": [\"41321624\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single study\", \"Connection between nuclear LAP2 function and TGF-beta/Smad signaling not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Implicated TMPO as a driver of metastatic heterogeneity, promoting prostate cancer dissemination by enhancing survival under metabolic stress.\",\n      \"evidence\": \"Computational systems analysis of CTC organoids from GEMMs with in vivo dissemination and metabolic stress survival assays (preprint)\",\n      \"pmids\": [\"41509437\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, single lab\", \"Molecular mechanism of stress survival undefined\", \"Isoform responsible not specified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how the distinct nuclear-envelope/chromatin functions of LAP2 isoforms mechanistically connect to the diverse cytoplasmic signaling outcomes (Notch1/mTOR, ERK/c-Fos, TGF-beta/Smad, MAPK/NF-kB) attributed to TMPO across tissues.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying mechanism linking nuclear architecture role to cytoplasmic signaling\", \"Isoform-specific contributions to each phenotype not dissected\", \"Structural model of LAP2 complexes absent from corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0007049\", \"supporting_discovery_ids\": [2, 9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"LMNB1\", \"BAF\", \"HMGN5\", \"RB1\", \"TMEM35A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}