{"gene":"RORC","run_date":"2026-06-10T06:43:37","timeline":{"discoveries":[{"year":1997,"finding":"The mouse ROR gamma (RORC) gene has a complex genomic structure consisting of 11 exons separated by 10 introns spanning more than 21 kb of genomic DNA. The DNA-binding domain is encoded by two exons (3 and 4), each encoding one zinc finger, with splice site organization identical to that found in RAR and TR3 receptors. ROR gamma is expressed as two mRNAs (2.3 and 3.0 kb) derived by alternative polyadenylation. Mouse Rorc maps to chromosome 3 (band 3F2.1-2.2) and human RORC maps to chromosome region 1q21, syntenic regions.","method":"Genomic cloning of P1 vector clones, exon mapping, fluorescence in situ hybridization (FISH)","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct genomic sequencing and FISH with defined structural outcome; foundational structural characterization replicated across species","pmids":["9403063"],"is_preprint":false},{"year":2014,"finding":"RORγt (encoded by RORC) directly binds the Ptger2 promoter region (the gene encoding prostaglandin receptor EP2) in Th17 cells, as demonstrated by ChIP-seq, and RORC knockdown in human Th17 cells restored EP2 expression. This establishes RORC as a direct transcriptional repressor of PTGER2 in Th17 cells, controlling the cellular response to PGE2.","method":"Chromatin immunoprecipitation followed by DNA sequencing (ChIP-seq), RORC knockdown with measurement of EP2 expression","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal ChIP-seq and loss-of-function knockdown with defined molecular readout in both mouse and human cells","pmids":["24812667"],"is_preprint":false},{"year":2019,"finding":"NFAT proteins bind to regulatory elements at the human RORC locus in CD4+ T cells and promote RORγt transcription in cooperation with NF-κB. T cell receptor stimulation induces cyclosporine A-sensitive histone modifications and P300/CBP acetylase recruitment at these regulatory elements. CRISPR/Cas9-guided deletion of these RORC locus regulatory elements confirmed their role in RORγt expression.","method":"CRISPR/Cas9-guided deletion of genomic regulatory elements, chromatin immunoprecipitation, cyclosporine A inhibition (mechanistic), identification of P300/CBP recruitment","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (CRISPR deletion, ChIP, pharmacological inhibition) in a single study definitively establishing NFAT as an upstream activator of RORC transcription","pmids":["31619674"],"is_preprint":false},{"year":2022,"finding":"RORα cooperatively binds with RORγt to a previously unidentified cis-regulatory element at the Rorc locus. Although RORα is dispensable for initial Th17 cell differentiation, it is required for maintaining RORγt expression levels and Th17 effector function in peripheral tissues. Loss of RORα in T cells reduced both RORγt expression and Th17 effector function in vivo, placing RORα as a non-redundant co-regulator that reinforces the RORC transcriptional program through a positive feedback loop.","method":"Genetic deletion of RORα in T cells, identification of Rorc cis-regulatory element, cooperative binding analysis, in vivo Th17 response assays","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function with defined molecular mechanism (cooperative binding to Rorc cis-regulatory element) and in vivo phenotypic validation","pmids":["36243007"],"is_preprint":false},{"year":2022,"finding":"α-Synuclein promotes transcription of RORC (encoding RORγt) in CD4+ T cells including Tregs and Th17 cells, leading to increased Th17 differentiation and loss of Treg stability and function. Pharmacological inhibition of RORγt (GSK805) suppressed α-Syn-induced Th17 expansion and attenuated dopaminergic neuron apoptosis in MPTP-treated mice.","method":"In vitro α-Syn stimulation of CD4+ T cells, RORC mRNA quantification, RORγt inhibitor (GSK805) treatment in vivo in MPTP mouse model, flow cytometry for Th17/Treg populations","journal":"Brain, behavior, and immunity","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, mechanistic claim (RORC transcriptional upregulation by α-Syn) supported by pharmacological rescue but no direct binding or ChIP data; pathway placement inferred from inhibitor experiments","pmids":["36343753"],"is_preprint":false},{"year":2022,"finding":"Notch signaling promotes upregulation of RORC transcription in innate lymphoid cell precursors (ILCP), enabling acquisition of Group 1 (IFN-γ) and Group 3 (IL-17A, IL-22) effector functions. Interfering with RORC or signaling through its target IL-23R compromises ILC3 effector functions and suppresses ILC production from multi-potent ILCP, defining a Notch→RORC→IL-23R pathway in human ILC differentiation. Validation was provided by patient samples with rare RORC genetic deficiencies.","method":"Single cell cloning analyses, genetic deficiency patient samples (RORC-deficient), pharmacological interference with Notch and IL-23 signaling, functional cytokine assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic validation via RORC-deficient patients combined with in vitro clonal analysis, but pathway placement between Notch and RORC is primarily inferred from expression data and single lab","pmids":["35896601"],"is_preprint":false},{"year":2014,"finding":"RORC (encoding RORγt) is identified as a promising drug target whose ligand-binding domain can be modulated by small molecules. The structural biology of RORc supports inverse agonist binding that suppresses IL-17 production. Multiple pharmaceutical companies have disclosed RORc inhibitors with selectivity over other ROR family members.","method":"Structural biology of RORc LBD, cellular IL-17 reporter assays, medicinal chemistry SAR","journal":"Journal of medicinal chemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — review paper summarizing structural and pharmacological data without describing a single primary experiment; mechanistic claims are derived from multiple undescribed original sources","pmids":["24502334"],"is_preprint":false},{"year":2015,"finding":"Potent and selective imidazo[1,5-a]pyridine and -pyrimidine RORc inverse agonists were discovered that show >300-fold selectivity for RORc over other ROR family members, PPARγ, and other nuclear receptors in cellular assays, and potently suppress IL-17 production in human primary cells, confirming that RORc transcriptional activity directly drives IL-17 cytokine production.","method":"Cellular nuclear receptor selectivity panel, IL-17 production assay in human primary cells, medicinal chemistry","journal":"Bioorganic & medicinal chemistry letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition with selective tool compounds in human primary cells establishing RORc-dependent IL-17 production; selectivity data from cellular panel provides mechanistic specificity","pmids":["26048793"],"is_preprint":false}],"current_model":"RORC encodes the nuclear orphan receptor RORγt, a transcription factor with an 11-exon genomic structure that directly binds DNA response elements to drive target gene expression (including IL-17 and IL-23R) in Th17 cells and innate lymphoid cells; its transcription is activated at the RORC locus by NFAT proteins (in cooperation with NF-κB) in response to TCR stimulation, and reinforced by cooperative binding of RORα to a Rorc cis-regulatory element, while RORγt itself directly represses PTGER2 transcription in Th17 cells, and its activity is positioned downstream of Notch signaling in ILC differentiation."},"narrative":{"mechanistic_narrative":"RORC encodes the nuclear receptor RORγt, a DNA-binding transcription factor that directs the effector programs of Th17 cells and innate lymphoid cells [PMID:24812667, PMID:35896601]. The gene has a complex 11-exon structure in which the DNA-binding domain is encoded across two exons, each contributing a zinc finger [PMID:9403063]. RORγt transcriptional activity drives IL-17 cytokine production, and selective small-molecule inverse agonists targeting its ligand-binding domain suppress IL-17 output in human primary cells [PMID:26048793]. As a direct transcriptional regulator, RORγt binds the PTGER2 (EP2) promoter to repress prostaglandin receptor expression in Th17 cells, controlling the cellular response to PGE2 [PMID:24812667]. RORC transcription is itself tightly controlled: NFAT proteins acting cooperatively with NF-κB bind regulatory elements at the RORC locus to activate RORγt expression downstream of T cell receptor stimulation, with P300/CBP recruitment and acetylation marking these elements [PMID:31619674], and RORα cooperatively binds a Rorc cis-regulatory element to sustain RORγt expression and Th17 effector function through a positive feedback loop [PMID:36243007]. In innate lymphoid cell differentiation, Notch signaling upregulates RORC, which through its target IL-23R enables ILC3 effector functions [PMID:35896601].","teleology":[{"year":1997,"claim":"Established the foundational genomic architecture of RORC, defining it as a zinc-finger nuclear receptor with a DNA-binding domain split across two exons, anchoring it within the nuclear receptor structural framework.","evidence":"Genomic cloning of P1 vector clones, exon mapping, and FISH in mouse and human","pmids":["9403063"],"confidence":"High","gaps":["Does not address transcriptional targets or cellular function","No tissue-specific expression or isoform function defined"]},{"year":2014,"claim":"Identified RORγt as a direct transcriptional repressor of PTGER2 in Th17 cells, linking the receptor to control of the cellular PGE2 response rather than purely activating function.","evidence":"ChIP-seq for RORγt binding plus RORC knockdown with EP2 expression readout in human Th17 cells","pmids":["24812667"],"confidence":"High","gaps":["Mechanism of repression (cofactor recruitment) not defined","Does not establish the full target gene repertoire"]},{"year":2014,"claim":"Synthesized RORγt as a druggable nuclear receptor whose ligand-binding domain accommodates inverse agonists that suppress IL-17, framing its therapeutic tractability.","evidence":"Review summarizing RORc LBD structural biology, IL-17 reporter assays, and medicinal chemistry","pmids":["24502334"],"confidence":"Low","gaps":["Review without primary experiments; mechanistic claims drawn from undescribed sources","No single defined structural or binding dataset"]},{"year":2015,"claim":"Confirmed with selective tool compounds that RORc transcriptional activity directly drives IL-17 production, establishing a causal mechanistic link rather than correlation.","evidence":"Selective imidazopyridine/pyrimidine inverse agonists (>300-fold selectivity) in nuclear receptor panels and IL-17 assays in human primary cells","pmids":["26048793"],"confidence":"Medium","gaps":["Pharmacological inhibition; does not map direct IL-17 locus binding","Off-target contributions in primary cells not fully excluded"]},{"year":2019,"claim":"Defined the upstream control of RORC transcription, showing NFAT cooperates with NF-κB to activate the locus downstream of TCR signaling via chromatin remodeling.","evidence":"CRISPR/Cas9 deletion of RORC regulatory elements, ChIP, cyclosporine A inhibition, and P300/CBP recruitment analysis in CD4+ T cells","pmids":["31619674"],"confidence":"High","gaps":["Does not resolve how NFAT/NF-κB integrate with other Th17 cues","Quantitative contribution of each element to expression not partitioned"]},{"year":2022,"claim":"Revealed RORα as a non-redundant co-regulator that reinforces RORC expression through cooperative binding to a Rorc cis-regulatory element, defining a positive feedback loop sustaining Th17 effector function.","evidence":"Genetic deletion of RORα in T cells, identification of the cis-regulatory element, cooperative binding analysis, and in vivo Th17 assays","pmids":["36243007"],"confidence":"High","gaps":["Does not establish whether RORα binding alters local chromatin state","Tissue-specific dependence beyond peripheral effector sites unclear"]},{"year":2022,"claim":"Positioned RORC downstream of Notch signaling in human ILC differentiation, with the RORC→IL-23R axis required for ILC3 effector functions, extending RORγt biology beyond adaptive T cells.","evidence":"Single-cell clonal analysis, RORC-deficient patient samples, and pharmacological Notch/IL-23 interference with cytokine assays","pmids":["35896601"],"confidence":"Medium","gaps":["Notch→RORC step inferred from expression rather than direct binding evidence","Single lab; molecular link between Notch effectors and RORC locus undefined"]},{"year":2022,"claim":"Connected α-synuclein to RORC induction in CD4+ T cells, linking the receptor's transcriptional upregulation to Th17 expansion, Treg destabilization, and neurodegeneration in a Parkinson's model.","evidence":"In vitro α-Syn stimulation with RORC mRNA quantification and GSK805 RORγt inhibitor rescue in MPTP mice with flow cytometry","pmids":["36343753"],"confidence":"Medium","gaps":["No direct binding or ChIP data; transcriptional upregulation mechanism inferred from inhibitor rescue","Single lab; pathway placement of α-Syn relative to RORC indirect"]},{"year":null,"claim":"How RORγt selects between activating (IL-17, IL-23R) and repressive (PTGER2) target programs, and the full cofactor logic governing its locus regulation, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No comprehensive direct target map across cell types","Coactivator/corepressor switching mechanism undefined","Structural basis of ligand-dependent transcriptional output not integrated with target selection"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,2,3,5,7]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,1,3]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,2]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,2,3]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,5,7]}],"complexes":[],"partners":["RORA","NFAT","NFKB","EP300","CREBBP"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P51449","full_name":"Nuclear receptor ROR-gamma","aliases":["Nuclear receptor RZR-gamma","Nuclear receptor subfamily 1 group F member 3","RAR-related orphan receptor C","Retinoid-related orphan receptor-gamma"],"length_aa":518,"mass_kda":58.2,"function":"Nuclear receptor that binds DNA as a monomer to ROR response elements (RORE) containing a single core motif half-site 5'-AGGTCA-3' preceded by a short A-T-rich sequence. Key regulator of cellular differentiation, immunity, peripheral circadian rhythm as well as lipid, steroid, xenobiotics and glucose metabolism (PubMed:19381306, PubMed:19965867, PubMed:20203100, PubMed:22789990, PubMed:26160376). Considered to have intrinsic transcriptional activity, have some natural ligands like oxysterols that act as agonists (25-hydroxycholesterol) or inverse agonists (7-oxygenated sterols), enhancing or repressing the transcriptional activity, respectively (PubMed:19965867, PubMed:22789990). Recruits distinct combinations of cofactors to target gene regulatory regions to modulate their transcriptional expression, depending on the tissue, time and promoter contexts. Regulates the circadian expression of clock genes such as CRY1, BMAL1 and NR1D1 in peripheral tissues and in a tissue-selective manner. Competes with NR1D1 for binding to their shared DNA response element on some clock genes such as BMAL1, CRY1 and NR1D1 itself, resulting in NR1D1-mediated repression or RORC-mediated activation of the expression, leading to the circadian pattern of clock genes expression. Therefore influences the period length and stability of the clock. Involved in the regulation of the rhythmic expression of genes involved in glucose and lipid metabolism, including PLIN2 and AVPR1A (PubMed:19965867). Negative regulator of adipocyte differentiation through the regulation of early phase genes expression, such as MMP3. Controls adipogenesis as well as adipocyte size and modulates insulin sensitivity in obesity. In liver, has specific and redundant functions with RORA as positive or negative modulator of expression of genes encoding phase I and Phase II proteins involved in the metabolism of lipids, steroids and xenobiotics, such as SULT1E1. Also plays a role in the regulation of hepatocyte glucose metabolism through the regulation of G6PC1 and PCK1 (PubMed:19965867). Regulates the rhythmic expression of PROX1 and promotes its nuclear localization (PubMed:19381306, PubMed:19965867, PubMed:20203100, PubMed:22789990, PubMed:26160376). Plays an indispensable role in the induction of IFN-gamma dependent anti-mycobacterial systemic immunity (PubMed:26160376) Nuclear receptor essential for thymopoiesis and the development of several secondary lymphoid tissues, including lymph nodes and Peyer's patches (PubMed:21499262). Required for the generation of LTi (lymphoid tissue inducer) cells (By similarity). Regulates thymocyte survival through DNA-binding on ROREs of target gene promoter regions and recruitment of coactivaros via the AF-2 (By similarity). Also plays a key role, downstream of IL6 and TGFB and synergistically with RORA, for lineage specification of uncommitted CD4(+) T-helper (T(H)) cells into T(H)17 cells, antagonizing the T(H)1 program (PubMed:21499262). Probably regulates IL17 and IL17F expression on T(H) by binding to the essential enhancer conserved non-coding sequence 2 (CNS2) in the IL17-IL17F locus (PubMed:21499262). Plays a key role in tolerance to gut microbiota and foreign antigens in food by mediating differentiation of peripherally-induced regulatory T-cells (pTreg), which suppress inflammatory responses to commensal microorganisms and food proteins (By similarity). Specifically expressed in antigen-presenting cell populations, such as (1) type 3 innate lymphoid cells (ILC3s), which are required for tolerance to gut microbiota, (2) Thetis cells, also named Janus cells, which are enriched in gut lymph nodes during early life and are required for oral tolerance, and (3) a subset of dendritic cells (By similarity). Following activation by an unknown ligand in antigen-presenting cells, promotes recruitment of transcription regulators, such as PRDM16 or ZBTB46, and drives differentiation of pTreg cells, which maintain immune tolerance and prevent autoimmune diseases (By similarity). May also play a role in the pre-TCR activation cascade leading to the maturation of alpha/beta T-cells and may participate in the regulation of DNA accessibility in the TCR-J(alpha) locus (By similarity)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P51449/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RORC","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":[],"url":"https://opencell.sf.czbiohub.org/search/RORC","total_profiled":1310},"omim":[{"mim_id":"621004","title":"AUTOIMMUNE DISEASE, MULTISYSTEM, INFANTILE-ONSET, 4; ADMIO4","url":"https://www.omim.org/entry/621004"},{"mim_id":"616622","title":"IMMUNODEFICIENCY 42; IMD42","url":"https://www.omim.org/entry/616622"},{"mim_id":"614995","title":"INTERLEUKIN 17 RECEPTOR E; IL17RE","url":"https://www.omim.org/entry/614995"},{"mim_id":"614397","title":"MAJOR FACILITATOR SUPERFAMILY DOMAIN-CONTAINING PROTEIN 2A; MFSD2A","url":"https://www.omim.org/entry/614397"},{"mim_id":"612476","title":"BASIC LEUCINE ZIPPER TRANSCRIPTION FACTOR, ATF-LIKE; BATF","url":"https://www.omim.org/entry/612476"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear bodies","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"skeletal muscle","ntpm":100.2}],"url":"https://www.proteinatlas.org/search/RORC"},"hgnc":{"alias_symbol":["RZRG","RORG","NR1F3","TOR"],"prev_symbol":[]},"alphafold":{"accession":"P51449","domains":[{"cath_id":"3.30.50.10","chopping":"20-123","consensus_level":"high","plddt":86.335,"start":20,"end":123},{"cath_id":"1.10.565.10","chopping":"266-505","consensus_level":"high","plddt":95.179,"start":266,"end":505}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P51449","model_url":"https://alphafold.ebi.ac.uk/files/AF-P51449-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P51449-F1-predicted_aligned_error_v6.png","plddt_mean":74.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RORC","jax_strain_url":"https://www.jax.org/strain/search?query=RORC"},"sequence":{"accession":"P51449","fasta_url":"https://rest.uniprot.org/uniprotkb/P51449.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P51449/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P51449"}},"corpus_meta":[{"pmid":"16469695","id":"PMC_16469695","title":"TOR signaling in growth and metabolism.","date":"2006","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/16469695","citation_count":4650,"is_preprint":false},{"pmid":"11057898","id":"PMC_11057898","title":"TOR, a central controller of cell growth.","date":"2000","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/11057898","citation_count":1631,"is_preprint":false},{"pmid":"15094765","id":"PMC_15094765","title":"Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression.","date":"2004","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/15094765","citation_count":1022,"is_preprint":false},{"pmid":"10995454","id":"PMC_10995454","title":"Tor-mediated induction of autophagy via an Apg1 protein kinase complex.","date":"2000","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/10995454","citation_count":944,"is_preprint":false},{"pmid":"32130880","id":"PMC_32130880","title":"AMPK and TOR: The Yin and Yang of Cellular Nutrient Sensing and Growth Control.","date":"2020","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/32130880","citation_count":622,"is_preprint":false},{"pmid":"23542588","id":"PMC_23542588","title":"Glucose-TOR signalling reprograms the transcriptome and activates meristems.","date":"2013","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/23542588","citation_count":619,"is_preprint":false},{"pmid":"28096180","id":"PMC_28096180","title":"Nutrient sensing and TOR signaling in yeast and mammals.","date":"2017","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/28096180","citation_count":580,"is_preprint":false},{"pmid":"20519118","id":"PMC_20519118","title":"With TOR, less is more: a key role for the conserved nutrient-sensing TOR pathway in aging.","date":"2010","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/20519118","citation_count":507,"is_preprint":false},{"pmid":"24828042","id":"PMC_24828042","title":"The metabolite α-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR.","date":"2014","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/24828042","citation_count":500,"is_preprint":false},{"pmid":"11416184","id":"PMC_11416184","title":"The target of rapamycin (TOR) proteins.","date":"2001","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/11416184","citation_count":485,"is_preprint":false},{"pmid":"12563289","id":"PMC_12563289","title":"Tor signalling in bugs, brain and brawn.","date":"2003","source":"Nature reviews. Molecular cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/12563289","citation_count":479,"is_preprint":false},{"pmid":"9425342","id":"PMC_9425342","title":"TOR signalling and control of cell growth.","date":"1997","source":"Current opinion in cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/9425342","citation_count":416,"is_preprint":false},{"pmid":"15780592","id":"PMC_15780592","title":"The expanding TOR signaling network.","date":"2005","source":"Current opinion in cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/15780592","citation_count":403,"is_preprint":false},{"pmid":"14607085","id":"PMC_14607085","title":"Rheb fills a GAP between TSC and TOR.","date":"2003","source":"Trends in biochemical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/14607085","citation_count":393,"is_preprint":false},{"pmid":"26905651","id":"PMC_26905651","title":"TOR Signaling and Nutrient Sensing.","date":"2016","source":"Annual review of plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/26905651","citation_count":317,"is_preprint":false},{"pmid":"18971624","id":"PMC_18971624","title":"Aging: ROS or TOR.","date":"2008","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/18971624","citation_count":311,"is_preprint":false},{"pmid":"18670193","id":"PMC_18670193","title":"The role of TOR in autophagy regulation from yeast to plants and mammals.","date":"2008","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/18670193","citation_count":303,"is_preprint":false},{"pmid":"12456783","id":"PMC_12456783","title":"Elucidating TOR signaling and rapamycin action: lessons from Saccharomyces cerevisiae.","date":"2002","source":"Microbiology and molecular biology reviews : MMBR","url":"https://pubmed.ncbi.nlm.nih.gov/12456783","citation_count":287,"is_preprint":false},{"pmid":"11266435","id":"PMC_11266435","title":"The TOR kinases link nutrient sensing to cell growth.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11266435","citation_count":284,"is_preprint":false},{"pmid":"9843498","id":"PMC_9843498","title":"The TOR nutrient signalling pathway phosphorylates NPR1 and inhibits turnover of the tryptophan permease.","date":"1998","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/9843498","citation_count":271,"is_preprint":false},{"pmid":"19539012","id":"PMC_19539012","title":"The TOR pathway comes of age.","date":"2009","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/19539012","citation_count":265,"is_preprint":false},{"pmid":"14668532","id":"PMC_14668532","title":"TOR signaling.","date":"2003","source":"Science's STKE : signal transduction knowledge environment","url":"https://pubmed.ncbi.nlm.nih.gov/14668532","citation_count":249,"is_preprint":false},{"pmid":"22134914","id":"PMC_22134914","title":"Rapamycin and glucose-target of rapamycin (TOR) protein signaling in plants.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22134914","citation_count":220,"is_preprint":false},{"pmid":"19875293","id":"PMC_19875293","title":"TOR complex 2: a signaling pathway of its own.","date":"2009","source":"Trends in biochemical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/19875293","citation_count":214,"is_preprint":false},{"pmid":"20006481","id":"PMC_20006481","title":"TOR-dependent control of autophagy: biting the hand that feeds.","date":"2009","source":"Current opinion in cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/20006481","citation_count":207,"is_preprint":false},{"pmid":"21548787","id":"PMC_21548787","title":"Amino acid signaling in TOR activation.","date":"2011","source":"Annual review of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21548787","citation_count":181,"is_preprint":false},{"pmid":"22305521","id":"PMC_22305521","title":"Sensing nutrient and energy status by SnRK1 and TOR kinases.","date":"2012","source":"Current opinion in plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/22305521","citation_count":163,"is_preprint":false},{"pmid":"18215152","id":"PMC_18215152","title":"TOR regulation of AGC kinases in yeast and mammals.","date":"2008","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/18215152","citation_count":159,"is_preprint":false},{"pmid":"29986898","id":"PMC_29986898","title":"TOR signaling in plants: conservation and innovation.","date":"2018","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/29986898","citation_count":156,"is_preprint":false},{"pmid":"22575479","id":"PMC_22575479","title":"Organ size control by Hippo and TOR pathways.","date":"2012","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/22575479","citation_count":156,"is_preprint":false},{"pmid":"24502334","id":"PMC_24502334","title":"Modulators of the nuclear receptor retinoic acid receptor-related orphan receptor-γ (RORγ or RORc).","date":"2014","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24502334","citation_count":150,"is_preprint":false},{"pmid":"26546292","id":"PMC_26546292","title":"TOR Complexes and the Maintenance of Cellular Homeostasis.","date":"2015","source":"Trends in cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/26546292","citation_count":149,"is_preprint":false},{"pmid":"14560952","id":"PMC_14560952","title":"Autophagy in yeast: a TOR-mediated response to nutrient starvation.","date":"2004","source":"Current topics in microbiology and immunology","url":"https://pubmed.ncbi.nlm.nih.gov/14560952","citation_count":146,"is_preprint":false},{"pmid":"28027512","id":"PMC_28027512","title":"Shaping plant development through the SnRK1-TOR metabolic regulators.","date":"2016","source":"Current opinion in plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/28027512","citation_count":140,"is_preprint":false},{"pmid":"24684168","id":"PMC_24684168","title":"The TOR signaling pathway regulates vegetative development and virulence in Fusarium graminearum.","date":"2014","source":"The New phytologist","url":"https://pubmed.ncbi.nlm.nih.gov/24684168","citation_count":125,"is_preprint":false},{"pmid":"23246968","id":"PMC_23246968","title":"The evolution of the TOR pathway and its role in cancer.","date":"2012","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/23246968","citation_count":123,"is_preprint":false},{"pmid":"30715492","id":"PMC_30715492","title":"Integration of nutrient, energy, light, and hormone signalling via TOR in plants.","date":"2019","source":"Journal of experimental botany","url":"https://pubmed.ncbi.nlm.nih.gov/30715492","citation_count":118,"is_preprint":false},{"pmid":"31594908","id":"PMC_31594908","title":"TOR Signaling in Caenorhabditis elegans Development, Metabolism, and Aging.","date":"2019","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31594908","citation_count":114,"is_preprint":false},{"pmid":"22057117","id":"PMC_22057117","title":"Evolution of the TOR pathway.","date":"2011","source":"Journal of molecular evolution","url":"https://pubmed.ncbi.nlm.nih.gov/22057117","citation_count":109,"is_preprint":false},{"pmid":"26476687","id":"PMC_26476687","title":"Novel links in the plant TOR kinase signaling network.","date":"2015","source":"Current opinion in plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/26476687","citation_count":108,"is_preprint":false},{"pmid":"15209374","id":"PMC_15209374","title":"PI3-kinase and TOR: PIKTORing cell growth.","date":"2004","source":"Seminars in cell & developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/15209374","citation_count":108,"is_preprint":false},{"pmid":"17046229","id":"PMC_17046229","title":"Thinking globally and acting locally with TOR.","date":"2006","source":"Current opinion in cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/17046229","citation_count":108,"is_preprint":false},{"pmid":"33658715","id":"PMC_33658715","title":"The TOR-EIN2 axis mediates nuclear signalling to modulate plant growth.","date":"2021","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/33658715","citation_count":108,"is_preprint":false},{"pmid":"30010338","id":"PMC_30010338","title":"Combating Autoimmune Diseases With Retinoic Acid Receptor-Related Orphan Receptor-γ (RORγ or RORc) Inhibitors: Hits and Misses.","date":"2018","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30010338","citation_count":104,"is_preprint":false},{"pmid":"16740339","id":"PMC_16740339","title":"Regulation of chemotaxis by the orchestrated activation of Ras, PI3K, and TOR.","date":"2006","source":"European journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/16740339","citation_count":104,"is_preprint":false},{"pmid":"21428920","id":"PMC_21428920","title":"A longer and healthier life with TOR down-regulation: genetics and drugs.","date":"2011","source":"Biochemical Society transactions","url":"https://pubmed.ncbi.nlm.nih.gov/21428920","citation_count":103,"is_preprint":false},{"pmid":"21925855","id":"PMC_21925855","title":"TOR in the immune system.","date":"2011","source":"Current opinion in cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/21925855","citation_count":102,"is_preprint":false},{"pmid":"29104218","id":"PMC_29104218","title":"Evolutionary Conservation of the Components in the TOR Signaling Pathways.","date":"2017","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/29104218","citation_count":98,"is_preprint":false},{"pmid":"28971552","id":"PMC_28971552","title":"TOR-mediated regulation of metabolism in aging.","date":"2017","source":"Aging cell","url":"https://pubmed.ncbi.nlm.nih.gov/28971552","citation_count":93,"is_preprint":false},{"pmid":"28485389","id":"PMC_28485389","title":"EGFR-dependent TOR-independent endocycles support Drosophila gut epithelial regeneration.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/28485389","citation_count":93,"is_preprint":false},{"pmid":"20385253","id":"PMC_20385253","title":"TOR signaling never gets old: aging, longevity and TORC1 activity.","date":"2010","source":"Ageing research reviews","url":"https://pubmed.ncbi.nlm.nih.gov/20385253","citation_count":92,"is_preprint":false},{"pmid":"32051250","id":"PMC_32051250","title":"TOR dynamically regulates plant cell-cell transport.","date":"2020","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/32051250","citation_count":91,"is_preprint":false},{"pmid":"22240970","id":"PMC_22240970","title":"Regulation of TOR by small GTPases.","date":"2012","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/22240970","citation_count":88,"is_preprint":false},{"pmid":"17081107","id":"PMC_17081107","title":"Mitochondrial signaling, TOR, and life span.","date":"2006","source":"Biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17081107","citation_count":88,"is_preprint":false},{"pmid":"36104568","id":"PMC_36104568","title":"Glucose-driven TOR-FIE-PRC2 signalling controls plant development.","date":"2022","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/36104568","citation_count":86,"is_preprint":false},{"pmid":"36243007","id":"PMC_36243007","title":"Transcription factor RORα enforces stability of the Th17 cell effector program by binding to a Rorc cis-regulatory element.","date":"2022","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/36243007","citation_count":81,"is_preprint":false},{"pmid":"21930774","id":"PMC_21930774","title":"Review series: TOR kinase complexes and cell migration.","date":"2011","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/21930774","citation_count":70,"is_preprint":false},{"pmid":"16980405","id":"PMC_16980405","title":"Nitrogen availability and TOR regulate the Snf1 protein kinase in Saccharomyces cerevisiae.","date":"2006","source":"Eukaryotic cell","url":"https://pubmed.ncbi.nlm.nih.gov/16980405","citation_count":70,"is_preprint":false},{"pmid":"26195783","id":"PMC_26195783","title":"Regulation of ribosomal DNA amplification by the TOR pathway.","date":"2015","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/26195783","citation_count":67,"is_preprint":false},{"pmid":"26251442","id":"PMC_26251442","title":"TOR signalling in plants.","date":"2015","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/26251442","citation_count":66,"is_preprint":false},{"pmid":"35787039","id":"PMC_35787039","title":"ABA represses TOR and root meristem activity through nuclear exit of the SnRK1 kinase.","date":"2022","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/35787039","citation_count":66,"is_preprint":false},{"pmid":"17679098","id":"PMC_17679098","title":"Structure of TOR and its complex with KOG1.","date":"2007","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/17679098","citation_count":66,"is_preprint":false},{"pmid":"18756382","id":"PMC_18756382","title":"TOR signaling in fission yeast.","date":"2008","source":"Critical reviews in biochemistry and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18756382","citation_count":60,"is_preprint":false},{"pmid":"21367463","id":"PMC_21367463","title":"RORC and Foxp3 axis in cerebrospinal fluid of patients with neuro-Behçet's disease.","date":"2011","source":"Journal of neuroimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/21367463","citation_count":60,"is_preprint":false},{"pmid":"21210909","id":"PMC_21210909","title":"Activating mutations of TOR (target of rapamycin).","date":"2011","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/21210909","citation_count":60,"is_preprint":false},{"pmid":"21428923","id":"PMC_21428923","title":"Regulation of plant growth and metabolism by the TOR kinase.","date":"2011","source":"Biochemical Society transactions","url":"https://pubmed.ncbi.nlm.nih.gov/21428923","citation_count":59,"is_preprint":false},{"pmid":"33309324","id":"PMC_33309324","title":"A Tour of TOR Complex Signaling in Plants.","date":"2020","source":"Trends in biochemical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33309324","citation_count":59,"is_preprint":false},{"pmid":"21981278","id":"PMC_21981278","title":"Mammalian TOR signaling to the AGC kinases.","date":"2011","source":"Critical reviews in biochemistry and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/21981278","citation_count":59,"is_preprint":false},{"pmid":"24567496","id":"PMC_24567496","title":"Balancing act: matching growth with environment by the TOR signalling pathway.","date":"2014","source":"Journal of experimental botany","url":"https://pubmed.ncbi.nlm.nih.gov/24567496","citation_count":59,"is_preprint":false},{"pmid":"9403063","id":"PMC_9403063","title":"Genomic structure and chromosomal mapping of the nuclear orphan receptor ROR gamma (RORC) gene.","date":"1997","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/9403063","citation_count":56,"is_preprint":false},{"pmid":"26024507","id":"PMC_26024507","title":"Activation of the TOR Signalling Pathway by Glutamine Regulates Insect Fecundity.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26024507","citation_count":56,"is_preprint":false},{"pmid":"14560949","id":"PMC_14560949","title":"The role of phosphatases in TOR signaling in yeast.","date":"2004","source":"Current topics in microbiology and immunology","url":"https://pubmed.ncbi.nlm.nih.gov/14560949","citation_count":52,"is_preprint":false},{"pmid":"33793860","id":"PMC_33793860","title":"TOR coordinates nucleotide availability with ribosome biogenesis in plants.","date":"2021","source":"The Plant cell","url":"https://pubmed.ncbi.nlm.nih.gov/33793860","citation_count":51,"is_preprint":false},{"pmid":"14560955","id":"PMC_14560955","title":"TOR action in mammalian cells and in Caenorhabditis elegans.","date":"2004","source":"Current topics in microbiology and immunology","url":"https://pubmed.ncbi.nlm.nih.gov/14560955","citation_count":50,"is_preprint":false},{"pmid":"23698095","id":"PMC_23698095","title":"Evolutionarily conserved regulation of TOR signalling.","date":"2013","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23698095","citation_count":50,"is_preprint":false},{"pmid":"34496244","id":"PMC_34496244","title":"Light regulates alternative splicing outcomes via the TOR kinase pathway.","date":"2021","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/34496244","citation_count":49,"is_preprint":false},{"pmid":"32117365","id":"PMC_32117365","title":"The Importance of TOR Kinase in Plant Development.","date":"2020","source":"Frontiers in plant science","url":"https://pubmed.ncbi.nlm.nih.gov/32117365","citation_count":48,"is_preprint":false},{"pmid":"26048793","id":"PMC_26048793","title":"Discovery of imidazo[1,5-a]pyridines and -pyrimidines as potent and selective RORc inverse agonists.","date":"2015","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/26048793","citation_count":46,"is_preprint":false},{"pmid":"22427692","id":"PMC_22427692","title":"TOR signaling regulates planarian stem cells and controls localized and organismal growth.","date":"2012","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/22427692","citation_count":44,"is_preprint":false},{"pmid":"29867948","id":"PMC_29867948","title":"\"Immune TOR-opathies,\" a Novel Disease Entity in Clinical Immunology.","date":"2018","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/29867948","citation_count":43,"is_preprint":false},{"pmid":"14560948","id":"PMC_14560948","title":"TOR: the first 10 years.","date":"2004","source":"Current topics in microbiology and immunology","url":"https://pubmed.ncbi.nlm.nih.gov/14560948","citation_count":41,"is_preprint":false},{"pmid":"27763256","id":"PMC_27763256","title":"Target of Rapamycin (TOR) Regulates Growth in Response to Nutritional Signals.","date":"2016","source":"Microbiology spectrum","url":"https://pubmed.ncbi.nlm.nih.gov/27763256","citation_count":41,"is_preprint":false},{"pmid":"33513917","id":"PMC_33513917","title":"TOR Signaling Pathway in Cardiac Aging and Heart Failure.","date":"2021","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/33513917","citation_count":37,"is_preprint":false},{"pmid":"31619674","id":"PMC_31619674","title":"NFAT primes the human RORC locus for RORγt expression in CD4+ T cells.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/31619674","citation_count":36,"is_preprint":false},{"pmid":"24812667","id":"PMC_24812667","title":"Decreased RORC-dependent silencing of prostaglandin receptor EP2 induces autoimmune Th17 cells.","date":"2014","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/24812667","citation_count":35,"is_preprint":false},{"pmid":"17245124","id":"PMC_17245124","title":"TOR-in(g) the nucleus.","date":"2007","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/17245124","citation_count":34,"is_preprint":false},{"pmid":"32393676","id":"PMC_32393676","title":"The flipside of the TOR coin - TORC2 and plasma membrane homeostasis at a glance.","date":"2020","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/32393676","citation_count":34,"is_preprint":false},{"pmid":"18493947","id":"PMC_18493947","title":"What controls TOR?","date":"2008","source":"IUBMB life","url":"https://pubmed.ncbi.nlm.nih.gov/18493947","citation_count":33,"is_preprint":false},{"pmid":"32759652","id":"PMC_32759652","title":"Structural Insights into TOR Signaling.","date":"2020","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/32759652","citation_count":33,"is_preprint":false},{"pmid":"17618850","id":"PMC_17618850","title":"TOR signaling and S6 kinase 1: Yeast catches up.","date":"2007","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/17618850","citation_count":33,"is_preprint":false},{"pmid":"36343753","id":"PMC_36343753","title":"α-Synuclein induces Th17 differentiation and impairs the function and stability of Tregs by promoting RORC transcription in Parkinson's disease.","date":"2022","source":"Brain, behavior, and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/36343753","citation_count":33,"is_preprint":false},{"pmid":"31063760","id":"PMC_31063760","title":"ROS Inhibits Cell Growth by Regulating 4EBP and S6K, Independent of TOR, during Development.","date":"2019","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/31063760","citation_count":33,"is_preprint":false},{"pmid":"35896601","id":"PMC_35896601","title":"Notch, RORC and IL-23 signals cooperate to promote multi-lineage human innate lymphoid cell differentiation.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/35896601","citation_count":32,"is_preprint":false},{"pmid":"22057328","id":"PMC_22057328","title":"Plant TOR signaling components.","date":"2011","source":"Plant signaling & behavior","url":"https://pubmed.ncbi.nlm.nih.gov/22057328","citation_count":32,"is_preprint":false},{"pmid":"30210580","id":"PMC_30210580","title":"ER Stress Activates the TOR Pathway through Atf6.","date":"2018","source":"Journal of molecular signaling","url":"https://pubmed.ncbi.nlm.nih.gov/30210580","citation_count":32,"is_preprint":false},{"pmid":"35204711","id":"PMC_35204711","title":"Interaction of TOR and PKA Signaling in S. cerevisiae.","date":"2022","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/35204711","citation_count":30,"is_preprint":false},{"pmid":"39952681","id":"PMC_39952681","title":"Target of Rapamycin (TOR): A Master Regulator in Plant Growth, Development, and Stress Responses.","date":"2025","source":"Annual review of plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/39952681","citation_count":30,"is_preprint":false},{"pmid":"32532005","id":"PMC_32532005","title":"Nuclear Functions of TOR: Impact on Transcription and the Epigenome.","date":"2020","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/32532005","citation_count":29,"is_preprint":false},{"pmid":"23524852","id":"PMC_23524852","title":"TOR tour to auxin.","date":"2013","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/23524852","citation_count":27,"is_preprint":false},{"pmid":"36831186","id":"PMC_36831186","title":"Interplays of AMPK and TOR in Autophagy Regulation in Yeast.","date":"2023","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/36831186","citation_count":25,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":34605,"output_tokens":2679,"usd":0.072,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9596,"output_tokens":2884,"usd":0.06004,"stage2_stop_reason":"end_turn"},"total_usd":0.13204,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify papers about RORC (the nuclear receptor RORγ/RORγt, also known as RZRG, RORG, NR1F3). The vast majority of papers (papers 1-32, 34-55, 57-63, 65-69, 71-83, 86-90, 92, 94-100) are about TOR/mTOR signaling — a completely different gene that shares the \"TOR\" alias used historically for RORC in some contexts, but these papers are clearly about the nutrient-sensing kinase, not the nuclear receptor. I will exclude those as symbol collisions.\n\nPapers directly about RORC (the nuclear orphan receptor):\n- Paper 31: RORc modulators review\n- Paper 44: RORc inhibitors review\n- Paper 56: RORα and RORC locus regulation\n- Paper 64: RORC expression in neuro-Behçet's (expression study)\n- Paper 70: Genomic structure of RORC\n- Paper 78: RORc inverse agonists (medicinal chemistry)\n- Paper 84: NFAT regulation of RORC locus\n- Paper 85: RORC silencing of EP2\n- Paper 91: α-Syn promotes RORC transcription\n- Paper 93: Notch/RORC in ILC differentiation\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"The mouse ROR gamma (RORC) gene has a complex genomic structure consisting of 11 exons separated by 10 introns spanning more than 21 kb of genomic DNA. The DNA-binding domain is encoded by two exons (3 and 4), each encoding one zinc finger, with splice site organization identical to that found in RAR and TR3 receptors. ROR gamma is expressed as two mRNAs (2.3 and 3.0 kb) derived by alternative polyadenylation. Mouse Rorc maps to chromosome 3 (band 3F2.1-2.2) and human RORC maps to chromosome region 1q21, syntenic regions.\",\n      \"method\": \"Genomic cloning of P1 vector clones, exon mapping, fluorescence in situ hybridization (FISH)\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct genomic sequencing and FISH with defined structural outcome; foundational structural characterization replicated across species\",\n      \"pmids\": [\"9403063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RORγt (encoded by RORC) directly binds the Ptger2 promoter region (the gene encoding prostaglandin receptor EP2) in Th17 cells, as demonstrated by ChIP-seq, and RORC knockdown in human Th17 cells restored EP2 expression. This establishes RORC as a direct transcriptional repressor of PTGER2 in Th17 cells, controlling the cellular response to PGE2.\",\n      \"method\": \"Chromatin immunoprecipitation followed by DNA sequencing (ChIP-seq), RORC knockdown with measurement of EP2 expression\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal ChIP-seq and loss-of-function knockdown with defined molecular readout in both mouse and human cells\",\n      \"pmids\": [\"24812667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NFAT proteins bind to regulatory elements at the human RORC locus in CD4+ T cells and promote RORγt transcription in cooperation with NF-κB. T cell receptor stimulation induces cyclosporine A-sensitive histone modifications and P300/CBP acetylase recruitment at these regulatory elements. CRISPR/Cas9-guided deletion of these RORC locus regulatory elements confirmed their role in RORγt expression.\",\n      \"method\": \"CRISPR/Cas9-guided deletion of genomic regulatory elements, chromatin immunoprecipitation, cyclosporine A inhibition (mechanistic), identification of P300/CBP recruitment\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (CRISPR deletion, ChIP, pharmacological inhibition) in a single study definitively establishing NFAT as an upstream activator of RORC transcription\",\n      \"pmids\": [\"31619674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RORα cooperatively binds with RORγt to a previously unidentified cis-regulatory element at the Rorc locus. Although RORα is dispensable for initial Th17 cell differentiation, it is required for maintaining RORγt expression levels and Th17 effector function in peripheral tissues. Loss of RORα in T cells reduced both RORγt expression and Th17 effector function in vivo, placing RORα as a non-redundant co-regulator that reinforces the RORC transcriptional program through a positive feedback loop.\",\n      \"method\": \"Genetic deletion of RORα in T cells, identification of Rorc cis-regulatory element, cooperative binding analysis, in vivo Th17 response assays\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function with defined molecular mechanism (cooperative binding to Rorc cis-regulatory element) and in vivo phenotypic validation\",\n      \"pmids\": [\"36243007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"α-Synuclein promotes transcription of RORC (encoding RORγt) in CD4+ T cells including Tregs and Th17 cells, leading to increased Th17 differentiation and loss of Treg stability and function. Pharmacological inhibition of RORγt (GSK805) suppressed α-Syn-induced Th17 expansion and attenuated dopaminergic neuron apoptosis in MPTP-treated mice.\",\n      \"method\": \"In vitro α-Syn stimulation of CD4+ T cells, RORC mRNA quantification, RORγt inhibitor (GSK805) treatment in vivo in MPTP mouse model, flow cytometry for Th17/Treg populations\",\n      \"journal\": \"Brain, behavior, and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, mechanistic claim (RORC transcriptional upregulation by α-Syn) supported by pharmacological rescue but no direct binding or ChIP data; pathway placement inferred from inhibitor experiments\",\n      \"pmids\": [\"36343753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Notch signaling promotes upregulation of RORC transcription in innate lymphoid cell precursors (ILCP), enabling acquisition of Group 1 (IFN-γ) and Group 3 (IL-17A, IL-22) effector functions. Interfering with RORC or signaling through its target IL-23R compromises ILC3 effector functions and suppresses ILC production from multi-potent ILCP, defining a Notch→RORC→IL-23R pathway in human ILC differentiation. Validation was provided by patient samples with rare RORC genetic deficiencies.\",\n      \"method\": \"Single cell cloning analyses, genetic deficiency patient samples (RORC-deficient), pharmacological interference with Notch and IL-23 signaling, functional cytokine assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic validation via RORC-deficient patients combined with in vitro clonal analysis, but pathway placement between Notch and RORC is primarily inferred from expression data and single lab\",\n      \"pmids\": [\"35896601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RORC (encoding RORγt) is identified as a promising drug target whose ligand-binding domain can be modulated by small molecules. The structural biology of RORc supports inverse agonist binding that suppresses IL-17 production. Multiple pharmaceutical companies have disclosed RORc inhibitors with selectivity over other ROR family members.\",\n      \"method\": \"Structural biology of RORc LBD, cellular IL-17 reporter assays, medicinal chemistry SAR\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — review paper summarizing structural and pharmacological data without describing a single primary experiment; mechanistic claims are derived from multiple undescribed original sources\",\n      \"pmids\": [\"24502334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Potent and selective imidazo[1,5-a]pyridine and -pyrimidine RORc inverse agonists were discovered that show >300-fold selectivity for RORc over other ROR family members, PPARγ, and other nuclear receptors in cellular assays, and potently suppress IL-17 production in human primary cells, confirming that RORc transcriptional activity directly drives IL-17 cytokine production.\",\n      \"method\": \"Cellular nuclear receptor selectivity panel, IL-17 production assay in human primary cells, medicinal chemistry\",\n      \"journal\": \"Bioorganic & medicinal chemistry letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition with selective tool compounds in human primary cells establishing RORc-dependent IL-17 production; selectivity data from cellular panel provides mechanistic specificity\",\n      \"pmids\": [\"26048793\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RORC encodes the nuclear orphan receptor RORγt, a transcription factor with an 11-exon genomic structure that directly binds DNA response elements to drive target gene expression (including IL-17 and IL-23R) in Th17 cells and innate lymphoid cells; its transcription is activated at the RORC locus by NFAT proteins (in cooperation with NF-κB) in response to TCR stimulation, and reinforced by cooperative binding of RORα to a Rorc cis-regulatory element, while RORγt itself directly represses PTGER2 transcription in Th17 cells, and its activity is positioned downstream of Notch signaling in ILC differentiation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"RORC encodes the nuclear receptor RORγt, a DNA-binding transcription factor that directs the effector programs of Th17 cells and innate lymphoid cells [#1, #5]. The gene has a complex 11-exon structure in which the DNA-binding domain is encoded across two exons, each contributing a zinc finger [#0]. RORγt transcriptional activity drives IL-17 cytokine production, and selective small-molecule inverse agonists targeting its ligand-binding domain suppress IL-17 output in human primary cells [#7]. As a direct transcriptional regulator, RORγt binds the PTGER2 (EP2) promoter to repress prostaglandin receptor expression in Th17 cells, controlling the cellular response to PGE2 [#1]. RORC transcription is itself tightly controlled: NFAT proteins acting cooperatively with NF-κB bind regulatory elements at the RORC locus to activate RORγt expression downstream of T cell receptor stimulation, with P300/CBP recruitment and acetylation marking these elements [#2], and RORα cooperatively binds a Rorc cis-regulatory element to sustain RORγt expression and Th17 effector function through a positive feedback loop [#3]. In innate lymphoid cell differentiation, Notch signaling upregulates RORC, which through its target IL-23R enables ILC3 effector functions [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established the foundational genomic architecture of RORC, defining it as a zinc-finger nuclear receptor with a DNA-binding domain split across two exons, anchoring it within the nuclear receptor structural framework.\",\n      \"evidence\": \"Genomic cloning of P1 vector clones, exon mapping, and FISH in mouse and human\",\n      \"pmids\": [\"9403063\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Does not address transcriptional targets or cellular function\",\n        \"No tissue-specific expression or isoform function defined\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified RORγt as a direct transcriptional repressor of PTGER2 in Th17 cells, linking the receptor to control of the cellular PGE2 response rather than purely activating function.\",\n      \"evidence\": \"ChIP-seq for RORγt binding plus RORC knockdown with EP2 expression readout in human Th17 cells\",\n      \"pmids\": [\"24812667\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism of repression (cofactor recruitment) not defined\",\n        \"Does not establish the full target gene repertoire\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Synthesized RORγt as a druggable nuclear receptor whose ligand-binding domain accommodates inverse agonists that suppress IL-17, framing its therapeutic tractability.\",\n      \"evidence\": \"Review summarizing RORc LBD structural biology, IL-17 reporter assays, and medicinal chemistry\",\n      \"pmids\": [\"24502334\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Review without primary experiments; mechanistic claims drawn from undescribed sources\",\n        \"No single defined structural or binding dataset\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Confirmed with selective tool compounds that RORc transcriptional activity directly drives IL-17 production, establishing a causal mechanistic link rather than correlation.\",\n      \"evidence\": \"Selective imidazopyridine/pyrimidine inverse agonists (>300-fold selectivity) in nuclear receptor panels and IL-17 assays in human primary cells\",\n      \"pmids\": [\"26048793\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Pharmacological inhibition; does not map direct IL-17 locus binding\",\n        \"Off-target contributions in primary cells not fully excluded\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined the upstream control of RORC transcription, showing NFAT cooperates with NF-κB to activate the locus downstream of TCR signaling via chromatin remodeling.\",\n      \"evidence\": \"CRISPR/Cas9 deletion of RORC regulatory elements, ChIP, cyclosporine A inhibition, and P300/CBP recruitment analysis in CD4+ T cells\",\n      \"pmids\": [\"31619674\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Does not resolve how NFAT/NF-κB integrate with other Th17 cues\",\n        \"Quantitative contribution of each element to expression not partitioned\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed RORα as a non-redundant co-regulator that reinforces RORC expression through cooperative binding to a Rorc cis-regulatory element, defining a positive feedback loop sustaining Th17 effector function.\",\n      \"evidence\": \"Genetic deletion of RORα in T cells, identification of the cis-regulatory element, cooperative binding analysis, and in vivo Th17 assays\",\n      \"pmids\": [\"36243007\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Does not establish whether RORα binding alters local chromatin state\",\n        \"Tissue-specific dependence beyond peripheral effector sites unclear\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Positioned RORC downstream of Notch signaling in human ILC differentiation, with the RORC→IL-23R axis required for ILC3 effector functions, extending RORγt biology beyond adaptive T cells.\",\n      \"evidence\": \"Single-cell clonal analysis, RORC-deficient patient samples, and pharmacological Notch/IL-23 interference with cytokine assays\",\n      \"pmids\": [\"35896601\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Notch→RORC step inferred from expression rather than direct binding evidence\",\n        \"Single lab; molecular link between Notch effectors and RORC locus undefined\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected α-synuclein to RORC induction in CD4+ T cells, linking the receptor's transcriptional upregulation to Th17 expansion, Treg destabilization, and neurodegeneration in a Parkinson's model.\",\n      \"evidence\": \"In vitro α-Syn stimulation with RORC mRNA quantification and GSK805 RORγt inhibitor rescue in MPTP mice with flow cytometry\",\n      \"pmids\": [\"36343753\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No direct binding or ChIP data; transcriptional upregulation mechanism inferred from inhibitor rescue\",\n        \"Single lab; pathway placement of α-Syn relative to RORC indirect\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RORγt selects between activating (IL-17, IL-23R) and repressive (PTGER2) target programs, and the full cofactor logic governing its locus regulation, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No comprehensive direct target map across cell types\",\n        \"Coactivator/corepressor switching mechanism undefined\",\n        \"Structural basis of ligand-dependent transcriptional output not integrated with target selection\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 2, 3, 5, 7]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 1, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 2, 3]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 5, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RORA\", \"NFAT\", \"NFKB\", \"EP300\", \"CREBBP\"],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}