{"gene":"LMNB2","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2015,"finding":"A homozygous missense mutation p.His157Tyr in the alpha-helical rod domain of lamin B2 causes a distinct defect in the assembly of highly ordered fibrous arrays typically formed by wild-type lamin B2, as demonstrated by in vitro assembly analysis of the mutant protein.","method":"In vitro lamin assembly assay comparing mutant (p.His157Tyr) vs wild-type lamin B2 protein","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro assembly assay with mutant protein, single lab, single method","pmids":["25954030"],"is_preprint":false},{"year":2021,"finding":"A missense mutation p.Arg234Trp in LMNB2 causes atypical aggregation of lamin B2 in the nucleoplasm, co-distributing with emerin and lamin A/C, and abnormal distribution of lamin A/C at the nuclear envelope; patient-derived fibroblasts showed nuclear shape abnormalities and premature senescence. siRNA-mediated reduction of lamin B2 expression decreased nuclear anomalies and senescence-associated beta-galactosidase, indicating the mutated protein drives these phenotypes.","method":"Patient-derived fibroblasts, immunofluorescence, siRNA knockdown, senescence-associated beta-galactosidase assay","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (immunofluorescence, siRNA rescue, senescence assay) in single lab","pmids":["35011612"],"is_preprint":false},{"year":2021,"finding":"LMNB2 promotes colorectal cancer cell proliferation by regulating the p21 promoter (as shown by ChIP analysis and luciferase reporter assay), suppressing p21 expression and driving cell cycle progression.","method":"ChIP analysis, luciferase reporter assay, CCK8, EdU, colony formation, cell cycle analysis, xenograft","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal mechanistic methods (ChIP + luciferase), single lab","pmids":["33782407"],"is_preprint":false},{"year":2022,"finding":"Loss-of-function of LMNB2 in human iPSC-derived cardiomyocytes, where LMNB2 normally represses cell cycle progression in primary cardiomyocytes in vivo, results in increased cardiomyocyte maturation characterized by transcriptional profiles related to myofibril structure and energy metabolism.","method":"LMNB2 inactivation in iPSC-derived cardiomyocytes, single-cell transcriptomic sequencing","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — loss-of-function with defined transcriptional phenotype, single lab, single method","pmids":["36518540"],"is_preprint":false},{"year":2025,"finding":"SPOP directly interacts with LMNB2 to mediate its ubiquitination and proteasomal degradation, thereby maintaining physiological PD-L1 expression levels; SPOP mutations or reduced SPOP expression cause LMNB2 accumulation and subsequent PD-L1 hyperactivation, facilitating immune escape in hepatocellular carcinoma.","method":"Co-immunoprecipitation (direct interaction), ubiquitination assay, proteasomal degradation assay, co-culture functional assay with Jurkat cells, in vivo xenograft","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction demonstrated with functional ubiquitination/degradation validation, single lab","pmids":["40483310"],"is_preprint":false},{"year":2025,"finding":"NOP2 catalyzes m5C methylation of LMNB2 mRNA, enhancing its stability and thereby elevating LMNB2 protein levels; overexpression of LMNB2 rescues the suppressed malignant phenotypes induced by NOP2 knockdown, confirming LMNB2 as a downstream effector of NOP2-mediated m5C modification in colorectal cancer.","method":"RIP-seq, MeRIP-seq, transcriptomic sequencing, rescue overexpression experiments, in vitro and in vivo tumor assays","journal":"Cancer medicine","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — multi-omics (MeRIP-seq, RIP-seq) plus functional rescue experiments, single lab","pmids":["40366008"],"is_preprint":false},{"year":2025,"finding":"Homozygous loss-of-function of LMNB2 in human patients causes complete absence of lamin B2 protein, accompanied by increased lamin B1, and alterations in alpha-tubulin and vimentin organisation, resulting in severe brain development abnormalities consistent with a role for lamin B2 in neuronal migration.","method":"Western blot and immunofluorescence on patient fibroblasts from newborns with homozygous LMNB2 loss-of-function variant","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct protein-level validation in patient cells with two orthogonal methods, single report","pmids":["40011009"],"is_preprint":false},{"year":2024,"finding":"Downregulation of LMNB2 in sarcoma cells impairs proliferation and cell cycle distribution; at the molecular level, LMNB2 acts as a regulator of cyclin D1 and cyclin E1 protein levels.","method":"MTT assay, flow cytometry (cell cycle), Western blot for cyclin D1 and cyclin E1","journal":"Aging","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, limited mechanistic depth, Western blot association only","pmids":["39774004"],"is_preprint":false},{"year":2025,"finding":"Silencing LMNB2 in esophageal carcinoma cells represses tumor cell stemness and the Warburg effect; in vitro experiments confirmed that LMNB2 regulates p38 phosphorylation in the MAPK signaling pathway, implicating this pathway as a downstream mediator of LMNB2's effects on sphere formation and glycolytic metabolism.","method":"Bioinformatics pathway analysis, Western blot for p38 phosphorylation, tumor sphere formation assay, xenograft model","journal":"Biochemical genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, limited mechanistic validation, pathway association mainly by bioinformatics","pmids":["41236686"],"is_preprint":false},{"year":2026,"finding":"LMNB2 knockdown in prostate cancer cell lines impairs proliferation, migration, invasion, and EMT; the Wnt/β-catenin pathway agonist SKL2001 rescues these effects, placing LMNB2 upstream of Wnt/β-catenin signaling in prostate cancer.","method":"LMNB2 knockdown, Wnt/β-catenin agonist rescue (SKL2001), proliferation/invasion/EMT assays, xenograft","journal":"Discover oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — epistasis via pharmacological rescue, single lab, no direct biochemical interaction shown","pmids":["42012624"],"is_preprint":false}],"current_model":"Lamin B2 (LMNB2) is a nuclear lamina protein whose rod domain mediates polymerization into fibrous arrays; pathogenic mutations disrupt this assembly and cause nuclear shape abnormalities, premature senescence, and defective neuronal migration leading to brain malformations and epilepsy. In proliferating cells, LMNB2 promotes cell cycle progression by suppressing p21 transcription (via chromatin occupancy at the p21 promoter) and by sustaining cyclin D1/E1 levels; its own protein stability is controlled by SPOP-mediated ubiquitination and proteasomal degradation, while NOP2-catalyzed m5C methylation of its mRNA enhances transcript stability and expression. Through these mechanisms, LMNB2 modulates PD-L1 transcription, Wnt/β-catenin signaling, and the p38 MAPK pathway in cancer contexts, and its loss-of-function in cardiomyocytes promotes maturation by relieving cell-cycle repression."},"narrative":{"mechanistic_narrative":"LMNB2 encodes a nuclear lamina protein whose alpha-helical rod domain drives polymerization into highly ordered fibrous arrays, and disruption of this assembly underlies its disease roles [PMID:25954030]. Pathogenic missense mutations cause aberrant nucleoplasmic aggregation of lamin B2 that co-distributes with emerin and lamin A/C, mislocalizes lamin A/C at the nuclear envelope, and drives nuclear shape abnormalities and premature senescence in patient fibroblasts [PMID:35011612]; homozygous loss-of-function abolishes the protein, elevates lamin B1, and perturbs alpha-tubulin and vimentin organization, producing severe brain malformations consistent with a role in neuronal migration [PMID:40011009]. Beyond structural functions, LMNB2 acts as a positive regulator of cell-cycle progression: it occupies the p21 promoter to suppress p21 transcription [PMID:33782407] and sustains cyclin D1 and cyclin E1 protein levels [PMID:39774004], such that its loss represses cell-cycle activity and promotes maturation, as seen in iPSC-derived cardiomyocytes where LMNB2 inactivation enhances myofibril and metabolic maturation [PMID:36518540]. LMNB2 abundance is set post-transcriptionally by NOP2-catalyzed m5C methylation that stabilizes its mRNA [PMID:40366008] and post-translationally by SPOP-mediated ubiquitination and proteasomal degradation, with loss of SPOP causing LMNB2 accumulation and PD-L1 hyperactivation that promotes immune escape [PMID:40483310]. In cancer contexts, downstream effectors of LMNB2 include p38 MAPK signaling [PMID:41236686] and Wnt/β-catenin signaling [PMID:42012624].","teleology":[{"year":2015,"claim":"Established that the lamin B2 rod domain is required for assembly into ordered fibrous arrays and that a point mutation specifically disrupts this polymerization, linking structural assembly to disease.","evidence":"In vitro lamin assembly assay comparing p.His157Tyr mutant vs wild-type lamin B2","pmids":["25954030"],"confidence":"Medium","gaps":["Single in vitro assay; cellular consequences of the assembly defect not shown","No structural model of the assembled array","Genotype-phenotype link inferred, not demonstrated in patient cells"]},{"year":2021,"claim":"Showed that a rod-domain mutation drives gain-of-function nucleoplasmic aggregation and senescence, with knockdown rescuing phenotypes, establishing the mutant protein as causal.","evidence":"Patient-derived fibroblasts, immunofluorescence, siRNA knockdown, SA-beta-gal assay","pmids":["35011612"],"confidence":"Medium","gaps":["Mechanism by which mislocalized lamin B2 triggers senescence unresolved","Single lab and limited patient material","Relationship between aggregation and lamin A/C mislocalization not mechanistically dissected"]},{"year":2021,"claim":"Identified a transcriptional cell-cycle function: LMNB2 occupies the p21 promoter to repress p21 and drive proliferation, distinguishing it from a purely structural role.","evidence":"ChIP and luciferase reporter assays plus proliferation and xenograft assays in colorectal cancer cells","pmids":["33782407"],"confidence":"Medium","gaps":["How a lamina protein achieves promoter-specific occupancy is unknown","No co-regulators identified at the p21 locus","Direct vs indirect chromatin engagement not resolved"]},{"year":2022,"claim":"Demonstrated that LMNB2 normally represses cardiomyocyte cell-cycle progression, so its loss promotes maturation, generalizing the cell-cycle role to a developmental context.","evidence":"LMNB2 inactivation in iPSC-derived cardiomyocytes with single-cell transcriptomics","pmids":["36518540"],"confidence":"Medium","gaps":["Molecular link between LMNB2 loss and maturation transcriptional programs not defined","Single method (transcriptomic)","Whether p21/cyclin axis mediates this effect untested here"]},{"year":2024,"claim":"Connected LMNB2 to cyclin control, showing it sustains cyclin D1 and cyclin E1 levels to maintain proliferation.","evidence":"Knockdown with MTT, flow cytometry, and Western blot for cyclins in sarcoma cells","pmids":["39774004"],"confidence":"Low","gaps":["Association only; direct regulation of cyclins not shown","No transcriptional vs post-translational distinction","Not independently confirmed"]},{"year":2025,"claim":"Defined post-translational control of LMNB2, showing SPOP directly ubiquitinates it for degradation and that loss of this control elevates PD-L1 and enables immune escape.","evidence":"Co-IP, ubiquitination and degradation assays, Jurkat co-culture, xenograft in hepatocellular carcinoma","pmids":["40483310"],"confidence":"Medium","gaps":["Mechanism linking LMNB2 to PD-L1 transcription not detailed","SPOP degron on LMNB2 not mapped","Single lab"]},{"year":2025,"claim":"Established post-transcriptional control, showing NOP2-catalyzed m5C methylation stabilizes LMNB2 mRNA, with LMNB2 overexpression rescuing NOP2-knockdown phenotypes.","evidence":"RIP-seq, MeRIP-seq, transcriptomics, rescue overexpression, tumor assays in colorectal cancer","pmids":["40366008"],"confidence":"Medium","gaps":["m5C site on LMNB2 mRNA and reader protein not identified","Whether this regulation operates outside colorectal cancer unknown","Single lab"]},{"year":2025,"claim":"Linked LMNB2 to p38 MAPK signaling as a downstream mediator of tumor stemness and the Warburg effect.","evidence":"Bioinformatics, Western blot for p38 phosphorylation, sphere formation, xenograft in esophageal carcinoma","pmids":["41236686"],"confidence":"Low","gaps":["Pathway link largely bioinformatic","No direct biochemical connection to p38 demonstrated","Single lab, limited mechanistic depth"]},{"year":2025,"claim":"Demonstrated complete absence of lamin B2 in homozygous loss-of-function patients, with cytoskeletal disorganization and brain malformation, establishing an essential developmental role in neuronal migration.","evidence":"Western blot and immunofluorescence on patient fibroblasts from newborns","pmids":["40011009"],"confidence":"Medium","gaps":["Mechanism linking lamin B2 loss to migration defect not shown","Functional significance of lamin B1 increase unclear","Single report"]},{"year":2026,"claim":"Placed LMNB2 upstream of Wnt/β-catenin signaling, with pharmacological agonist rescue of knockdown phenotypes in prostate cancer.","evidence":"Knockdown, SKL2001 rescue, proliferation/invasion/EMT assays, xenograft","pmids":["42012624"],"confidence":"Low","gaps":["Epistasis via pharmacology only; no direct biochemical interaction","How LMNB2 engages the Wnt pathway unknown","Single lab"]},{"year":null,"claim":"It remains unknown how a single nuclear lamina protein mechanistically bridges its structural assembly function to context-specific transcriptional (p21, PD-L1) and signaling (p38, Wnt) outputs.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unified model connecting lamina assembly to chromatin and signaling roles","Direct chromatin/DNA-binding mode at target promoters undefined","Tissue-specificity of the cell-cycle versus structural functions unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,6]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[1]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[2,3,7]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,6]}],"complexes":["nuclear lamina"],"partners":["SPOP","NOP2","EMERIN","LMNA"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q03252","full_name":"Lamin-B2","aliases":[],"length_aa":620,"mass_kda":69.9,"function":"Lamins are intermediate filament proteins that assemble into a filamentous meshwork, and which constitute the major components of the nuclear lamina, a fibrous layer on the nucleoplasmic side of the inner nuclear membrane (PubMed:33033404). Lamins provide a framework for the nuclear envelope, bridging the nuclear envelope and chromatin, thereby playing an important role in nuclear assembly, chromatin organization, nuclear membrane and telomere dynamics (PubMed:33033404). The structural integrity of the lamina is strictly controlled by the cell cycle, as seen by the disintegration and formation of the nuclear envelope in prophase and telophase, respectively (PubMed:33033404)","subcellular_location":"Nucleus lamina","url":"https://www.uniprot.org/uniprotkb/Q03252/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LMNB2","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ARL6IP5","stoichiometry":10.0},{"gene":"NOP10","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/search/LMNB2","total_profiled":1310},"omim":[{"mim_id":"619180","title":"MICROCEPHALY 27, PRIMARY, AUTOSOMAL DOMINANT; MCPH27","url":"https://www.omim.org/entry/619180"},{"mim_id":"616540","title":"EPILEPSY, PROGRESSIVE MYOCLONIC, 9; EPM9","url":"https://www.omim.org/entry/616540"},{"mim_id":"616136","title":"RING FINGER PROTEIN 220; RNF220","url":"https://www.omim.org/entry/616136"},{"mim_id":"613913","title":"LIPODYSTROPHY, PARTIAL, ACQUIRED, WITH LOW COMPLEMENT COMPONENT C3, WITH OR WITHOUT GLOMERULONEPHRITIS; APLDC3","url":"https://www.omim.org/entry/613913"},{"mim_id":"608709","title":"LIPODYSTROPHY, PARTIAL, ACQUIRED, SUSCEPTIBILITY TO; APLD","url":"https://www.omim.org/entry/608709"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear membrane","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/LMNB2"},"hgnc":{"alias_symbol":[],"prev_symbol":["LMN2"]},"alphafold":{"accession":"Q03252","domains":[{"cath_id":"2.60.40.1260","chopping":"464-581","consensus_level":"high","plddt":91.8553,"start":464,"end":581}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q03252","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q03252-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q03252-F1-predicted_aligned_error_v6.png","plddt_mean":79.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LMNB2","jax_strain_url":"https://www.jax.org/strain/search?query=LMNB2"},"sequence":{"accession":"Q03252","fasta_url":"https://rest.uniprot.org/uniprotkb/Q03252.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q03252/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q03252"}},"corpus_meta":[{"pmid":"16826530","id":"PMC_16826530","title":"Sequencing of the reannotated LMNB2 gene reveals novel mutations in patients with acquired partial lipodystrophy.","date":"2006","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16826530","citation_count":148,"is_preprint":false},{"pmid":"25954030","id":"PMC_25954030","title":"Mutation of the nuclear lamin gene LMNB2 in progressive myoclonus epilepsy with early ataxia.","date":"2015","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25954030","citation_count":45,"is_preprint":false},{"pmid":"33782407","id":"PMC_33782407","title":"LMNB2 promotes the progression of colorectal cancer by silencing p21 expression.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/33782407","citation_count":37,"is_preprint":false},{"pmid":"31558184","id":"PMC_31558184","title":"miR-122 Inhibits Hepatocarcinoma Cell Progression by Targeting LMNB2.","date":"2019","source":"Oncology research","url":"https://pubmed.ncbi.nlm.nih.gov/31558184","citation_count":33,"is_preprint":false},{"pmid":"22768673","id":"PMC_22768673","title":"A Chinese patient with acquired partial lipodystrophy caused by a novel mutation with LMNB2 gene.","date":"2012","source":"Journal of pediatric endocrinology & metabolism : JPEM","url":"https://pubmed.ncbi.nlm.nih.gov/22768673","citation_count":24,"is_preprint":false},{"pmid":"35435126","id":"PMC_35435126","title":"Plasmacytoma variant translocation 1 stabilized by EIF4A3 promoted malignant biological behaviors of lung adenocarcinoma by generating circular RNA LMNB2.","date":"2022","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/35435126","citation_count":13,"is_preprint":false},{"pmid":"34917510","id":"PMC_34917510","title":"Long Noncoding RNA SNHG1 Regulates LMNB2 Expression by Sponging miR-326 and Promotes Cancer Growth in Hepatocellular Carcinoma.","date":"2021","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34917510","citation_count":11,"is_preprint":false},{"pmid":"33783721","id":"PMC_33783721","title":"A novel missense variant in the LMNB2 gene causes progressive myoclonus epilepsy.","date":"2021","source":"Acta neurologica Belgica","url":"https://pubmed.ncbi.nlm.nih.gov/33783721","citation_count":11,"is_preprint":false},{"pmid":"33312362","id":"PMC_33312362","title":"ROR promotes the proliferation and migration of esophageal cancer through regulating miR-145/LMNB2 signal axis.","date":"2020","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/33312362","citation_count":11,"is_preprint":false},{"pmid":"36518540","id":"PMC_36518540","title":"Single-cell transcriptomic profiling reveals specific maturation signatures in human cardiomyocytes derived from LMNB2-inactivated induced pluripotent stem cells.","date":"2022","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/36518540","citation_count":7,"is_preprint":false},{"pmid":"40366008","id":"PMC_40366008","title":"NOP2-Mediated m5C Methylation Modification of LMNB2 mRNA Facilitates Colorectal Cancer Progression.","date":"2025","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40366008","citation_count":6,"is_preprint":false},{"pmid":"39774004","id":"PMC_39774004","title":"Comprehensive analysis of LMNB2 in pan-cancer and identification of its biological role in sarcoma.","date":"2024","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/39774004","citation_count":6,"is_preprint":false},{"pmid":"40483310","id":"PMC_40483310","title":"LMNB2-mediated high PD-L1 transcription triggers the immune escape of hepatocellular carcinoma.","date":"2025","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/40483310","citation_count":5,"is_preprint":false},{"pmid":"35011612","id":"PMC_35011612","title":"A Rare Mutation in LMNB2 Associated with Lipodystrophy Drives Premature Cell Senescence.","date":"2021","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/35011612","citation_count":5,"is_preprint":false},{"pmid":"37314513","id":"PMC_37314513","title":"miR-656-3p inhibits melanomas in vitro and in vivo by inducing senescence via inhibiting LMNB2.","date":"2023","source":"Journal of cancer research and clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/37314513","citation_count":2,"is_preprint":false},{"pmid":"41236686","id":"PMC_41236686","title":"LMNB2 Regulates Esophageal Carcinoma Stemness and Warburg Effect by Modulating the p38 MAPK Signaling Pathway.","date":"2025","source":"Biochemical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/41236686","citation_count":1,"is_preprint":false},{"pmid":"40011009","id":"PMC_40011009","title":"Homozygous loss of function variant in LMNB2 gene causes major brain malformation and perinatal death.","date":"2025","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/40011009","citation_count":0,"is_preprint":false},{"pmid":"42012624","id":"PMC_42012624","title":"LMNB2 promotes prostate cancer progression and epithelial-mesenchymal transition via the Wnt/β-catenin pathway.","date":"2026","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/42012624","citation_count":0,"is_preprint":false},{"pmid":"42065077","id":"PMC_42065077","title":"Retraction: miR-122 Inhibits Hepatocarcinoma Cell Progression by Targeting LMNB2.","date":"2026","source":"Oncology research","url":"https://pubmed.ncbi.nlm.nih.gov/42065077","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10944,"output_tokens":2448,"usd":0.034776,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9618,"output_tokens":3399,"usd":0.066532,"stage2_stop_reason":"end_turn"},"total_usd":0.101308,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"A homozygous missense mutation p.His157Tyr in the alpha-helical rod domain of lamin B2 causes a distinct defect in the assembly of highly ordered fibrous arrays typically formed by wild-type lamin B2, as demonstrated by in vitro assembly analysis of the mutant protein.\",\n      \"method\": \"In vitro lamin assembly assay comparing mutant (p.His157Tyr) vs wild-type lamin B2 protein\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro assembly assay with mutant protein, single lab, single method\",\n      \"pmids\": [\"25954030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A missense mutation p.Arg234Trp in LMNB2 causes atypical aggregation of lamin B2 in the nucleoplasm, co-distributing with emerin and lamin A/C, and abnormal distribution of lamin A/C at the nuclear envelope; patient-derived fibroblasts showed nuclear shape abnormalities and premature senescence. siRNA-mediated reduction of lamin B2 expression decreased nuclear anomalies and senescence-associated beta-galactosidase, indicating the mutated protein drives these phenotypes.\",\n      \"method\": \"Patient-derived fibroblasts, immunofluorescence, siRNA knockdown, senescence-associated beta-galactosidase assay\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (immunofluorescence, siRNA rescue, senescence assay) in single lab\",\n      \"pmids\": [\"35011612\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LMNB2 promotes colorectal cancer cell proliferation by regulating the p21 promoter (as shown by ChIP analysis and luciferase reporter assay), suppressing p21 expression and driving cell cycle progression.\",\n      \"method\": \"ChIP analysis, luciferase reporter assay, CCK8, EdU, colony formation, cell cycle analysis, xenograft\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal mechanistic methods (ChIP + luciferase), single lab\",\n      \"pmids\": [\"33782407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Loss-of-function of LMNB2 in human iPSC-derived cardiomyocytes, where LMNB2 normally represses cell cycle progression in primary cardiomyocytes in vivo, results in increased cardiomyocyte maturation characterized by transcriptional profiles related to myofibril structure and energy metabolism.\",\n      \"method\": \"LMNB2 inactivation in iPSC-derived cardiomyocytes, single-cell transcriptomic sequencing\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — loss-of-function with defined transcriptional phenotype, single lab, single method\",\n      \"pmids\": [\"36518540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SPOP directly interacts with LMNB2 to mediate its ubiquitination and proteasomal degradation, thereby maintaining physiological PD-L1 expression levels; SPOP mutations or reduced SPOP expression cause LMNB2 accumulation and subsequent PD-L1 hyperactivation, facilitating immune escape in hepatocellular carcinoma.\",\n      \"method\": \"Co-immunoprecipitation (direct interaction), ubiquitination assay, proteasomal degradation assay, co-culture functional assay with Jurkat cells, in vivo xenograft\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction demonstrated with functional ubiquitination/degradation validation, single lab\",\n      \"pmids\": [\"40483310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NOP2 catalyzes m5C methylation of LMNB2 mRNA, enhancing its stability and thereby elevating LMNB2 protein levels; overexpression of LMNB2 rescues the suppressed malignant phenotypes induced by NOP2 knockdown, confirming LMNB2 as a downstream effector of NOP2-mediated m5C modification in colorectal cancer.\",\n      \"method\": \"RIP-seq, MeRIP-seq, transcriptomic sequencing, rescue overexpression experiments, in vitro and in vivo tumor assays\",\n      \"journal\": \"Cancer medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multi-omics (MeRIP-seq, RIP-seq) plus functional rescue experiments, single lab\",\n      \"pmids\": [\"40366008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Homozygous loss-of-function of LMNB2 in human patients causes complete absence of lamin B2 protein, accompanied by increased lamin B1, and alterations in alpha-tubulin and vimentin organisation, resulting in severe brain development abnormalities consistent with a role for lamin B2 in neuronal migration.\",\n      \"method\": \"Western blot and immunofluorescence on patient fibroblasts from newborns with homozygous LMNB2 loss-of-function variant\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct protein-level validation in patient cells with two orthogonal methods, single report\",\n      \"pmids\": [\"40011009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Downregulation of LMNB2 in sarcoma cells impairs proliferation and cell cycle distribution; at the molecular level, LMNB2 acts as a regulator of cyclin D1 and cyclin E1 protein levels.\",\n      \"method\": \"MTT assay, flow cytometry (cell cycle), Western blot for cyclin D1 and cyclin E1\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, limited mechanistic depth, Western blot association only\",\n      \"pmids\": [\"39774004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Silencing LMNB2 in esophageal carcinoma cells represses tumor cell stemness and the Warburg effect; in vitro experiments confirmed that LMNB2 regulates p38 phosphorylation in the MAPK signaling pathway, implicating this pathway as a downstream mediator of LMNB2's effects on sphere formation and glycolytic metabolism.\",\n      \"method\": \"Bioinformatics pathway analysis, Western blot for p38 phosphorylation, tumor sphere formation assay, xenograft model\",\n      \"journal\": \"Biochemical genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, limited mechanistic validation, pathway association mainly by bioinformatics\",\n      \"pmids\": [\"41236686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"LMNB2 knockdown in prostate cancer cell lines impairs proliferation, migration, invasion, and EMT; the Wnt/β-catenin pathway agonist SKL2001 rescues these effects, placing LMNB2 upstream of Wnt/β-catenin signaling in prostate cancer.\",\n      \"method\": \"LMNB2 knockdown, Wnt/β-catenin agonist rescue (SKL2001), proliferation/invasion/EMT assays, xenograft\",\n      \"journal\": \"Discover oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — epistasis via pharmacological rescue, single lab, no direct biochemical interaction shown\",\n      \"pmids\": [\"42012624\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Lamin B2 (LMNB2) is a nuclear lamina protein whose rod domain mediates polymerization into fibrous arrays; pathogenic mutations disrupt this assembly and cause nuclear shape abnormalities, premature senescence, and defective neuronal migration leading to brain malformations and epilepsy. In proliferating cells, LMNB2 promotes cell cycle progression by suppressing p21 transcription (via chromatin occupancy at the p21 promoter) and by sustaining cyclin D1/E1 levels; its own protein stability is controlled by SPOP-mediated ubiquitination and proteasomal degradation, while NOP2-catalyzed m5C methylation of its mRNA enhances transcript stability and expression. Through these mechanisms, LMNB2 modulates PD-L1 transcription, Wnt/β-catenin signaling, and the p38 MAPK pathway in cancer contexts, and its loss-of-function in cardiomyocytes promotes maturation by relieving cell-cycle repression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LMNB2 encodes a nuclear lamina protein whose alpha-helical rod domain drives polymerization into highly ordered fibrous arrays, and disruption of this assembly underlies its disease roles [#0]. Pathogenic missense mutations cause aberrant nucleoplasmic aggregation of lamin B2 that co-distributes with emerin and lamin A/C, mislocalizes lamin A/C at the nuclear envelope, and drives nuclear shape abnormalities and premature senescence in patient fibroblasts [#1]; homozygous loss-of-function abolishes the protein, elevates lamin B1, and perturbs alpha-tubulin and vimentin organization, producing severe brain malformations consistent with a role in neuronal migration [#6]. Beyond structural functions, LMNB2 acts as a positive regulator of cell-cycle progression: it occupies the p21 promoter to suppress p21 transcription [#2] and sustains cyclin D1 and cyclin E1 protein levels [#7], such that its loss represses cell-cycle activity and promotes maturation, as seen in iPSC-derived cardiomyocytes where LMNB2 inactivation enhances myofibril and metabolic maturation [#3]. LMNB2 abundance is set post-transcriptionally by NOP2-catalyzed m5C methylation that stabilizes its mRNA [#5] and post-translationally by SPOP-mediated ubiquitination and proteasomal degradation, with loss of SPOP causing LMNB2 accumulation and PD-L1 hyperactivation that promotes immune escape [#4]. In cancer contexts, downstream effectors of LMNB2 include p38 MAPK signaling [#8] and Wnt/\\u03b2-catenin signaling [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Established that the lamin B2 rod domain is required for assembly into ordered fibrous arrays and that a point mutation specifically disrupts this polymerization, linking structural assembly to disease.\",\n      \"evidence\": \"In vitro lamin assembly assay comparing p.His157Tyr mutant vs wild-type lamin B2\",\n      \"pmids\": [\"25954030\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single in vitro assay; cellular consequences of the assembly defect not shown\", \"No structural model of the assembled array\", \"Genotype-phenotype link inferred, not demonstrated in patient cells\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed that a rod-domain mutation drives gain-of-function nucleoplasmic aggregation and senescence, with knockdown rescuing phenotypes, establishing the mutant protein as causal.\",\n      \"evidence\": \"Patient-derived fibroblasts, immunofluorescence, siRNA knockdown, SA-beta-gal assay\",\n      \"pmids\": [\"35011612\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which mislocalized lamin B2 triggers senescence unresolved\", \"Single lab and limited patient material\", \"Relationship between aggregation and lamin A/C mislocalization not mechanistically dissected\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified a transcriptional cell-cycle function: LMNB2 occupies the p21 promoter to repress p21 and drive proliferation, distinguishing it from a purely structural role.\",\n      \"evidence\": \"ChIP and luciferase reporter assays plus proliferation and xenograft assays in colorectal cancer cells\",\n      \"pmids\": [\"33782407\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How a lamina protein achieves promoter-specific occupancy is unknown\", \"No co-regulators identified at the p21 locus\", \"Direct vs indirect chromatin engagement not resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated that LMNB2 normally represses cardiomyocyte cell-cycle progression, so its loss promotes maturation, generalizing the cell-cycle role to a developmental context.\",\n      \"evidence\": \"LMNB2 inactivation in iPSC-derived cardiomyocytes with single-cell transcriptomics\",\n      \"pmids\": [\"36518540\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between LMNB2 loss and maturation transcriptional programs not defined\", \"Single method (transcriptomic)\", \"Whether p21/cyclin axis mediates this effect untested here\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected LMNB2 to cyclin control, showing it sustains cyclin D1 and cyclin E1 levels to maintain proliferation.\",\n      \"evidence\": \"Knockdown with MTT, flow cytometry, and Western blot for cyclins in sarcoma cells\",\n      \"pmids\": [\"39774004\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Association only; direct regulation of cyclins not shown\", \"No transcriptional vs post-translational distinction\", \"Not independently confirmed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined post-translational control of LMNB2, showing SPOP directly ubiquitinates it for degradation and that loss of this control elevates PD-L1 and enables immune escape.\",\n      \"evidence\": \"Co-IP, ubiquitination and degradation assays, Jurkat co-culture, xenograft in hepatocellular carcinoma\",\n      \"pmids\": [\"40483310\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking LMNB2 to PD-L1 transcription not detailed\", \"SPOP degron on LMNB2 not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established post-transcriptional control, showing NOP2-catalyzed m5C methylation stabilizes LMNB2 mRNA, with LMNB2 overexpression rescuing NOP2-knockdown phenotypes.\",\n      \"evidence\": \"RIP-seq, MeRIP-seq, transcriptomics, rescue overexpression, tumor assays in colorectal cancer\",\n      \"pmids\": [\"40366008\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"m5C site on LMNB2 mRNA and reader protein not identified\", \"Whether this regulation operates outside colorectal cancer unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked LMNB2 to p38 MAPK signaling as a downstream mediator of tumor stemness and the Warburg effect.\",\n      \"evidence\": \"Bioinformatics, Western blot for p38 phosphorylation, sphere formation, xenograft in esophageal carcinoma\",\n      \"pmids\": [\"41236686\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Pathway link largely bioinformatic\", \"No direct biochemical connection to p38 demonstrated\", \"Single lab, limited mechanistic depth\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated complete absence of lamin B2 in homozygous loss-of-function patients, with cytoskeletal disorganization and brain malformation, establishing an essential developmental role in neuronal migration.\",\n      \"evidence\": \"Western blot and immunofluorescence on patient fibroblasts from newborns\",\n      \"pmids\": [\"40011009\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking lamin B2 loss to migration defect not shown\", \"Functional significance of lamin B1 increase unclear\", \"Single report\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Placed LMNB2 upstream of Wnt/\\u03b2-catenin signaling, with pharmacological agonist rescue of knockdown phenotypes in prostate cancer.\",\n      \"evidence\": \"Knockdown, SKL2001 rescue, proliferation/invasion/EMT assays, xenograft\",\n      \"pmids\": [\"42012624\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Epistasis via pharmacology only; no direct biochemical interaction\", \"How LMNB2 engages the Wnt pathway unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how a single nuclear lamina protein mechanistically bridges its structural assembly function to context-specific transcriptional (p21, PD-L1) and signaling (p38, Wnt) outputs.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified model connecting lamina assembly to chromatin and signaling roles\", \"Direct chromatin/DNA-binding mode at target promoters undefined\", \"Tissue-specificity of the cell-cycle versus structural functions unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 6]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [2, 3, 7]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 6]}\n    ],\n    \"complexes\": [\"nuclear lamina\"],\n    \"partners\": [\"SPOP\", \"NOP2\", \"emerin\", \"LMNA\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":5,"faith_pct":80.0}}