{"gene":"GGCT","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2008,"finding":"C7orf24 (GGCT) was identified as gamma-glutamyl cyclotransferase, catalyzing the formation of 5-oxoproline (pyroglutamic acid) from gamma-glutamyl dipeptides. The crystal structure was solved at 1.7 Å resolution, revealing a homodimer of 20,994-Da subunits with a unique 'BtrG-like' fold. Active-site mutagenesis identified Glu98 as the catalytic general acid/base; mutation of Glu98 to Ala or Gln completely inactivated the enzyme without altering the overall fold.","method":"Recombinant protein expression, enzymatic assay, X-ray crystallography (1.7 Å), site-directed mutagenesis (E98A, E98Q)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure, in vitro enzymatic assay, and active-site mutagenesis all in one study; fully reconstituted activity with defined catalytic residue","pmids":["18515354"],"is_preprint":false},{"year":2007,"finding":"C7orf24 (GGCT) knockdown via siRNA in cancer cell lines produced significant antiproliferative effects (MTT assay), and overexpression in NIH3T3 cells increased growth rate, establishing a role for GGCT in cancer cell proliferation.","method":"siRNA knockdown, MTT proliferation assay, retroviral overexpression, growth rate assay","journal":"Proteomics. Clinical applications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function (siRNA) and gain-of-function (overexpression) with defined proliferative phenotype, single lab, two orthogonal approaches","pmids":["21136669"],"is_preprint":false},{"year":2011,"finding":"C7orf24 (GGCT) knockdown in osteosarcoma cell lines inhibited cell growth, motility, and invasion. Gene ontology analysis of differentially expressed genes after C7orf24 siRNA treatment implicated cell adhesion and protein transport pathways.","method":"siRNA knockdown, growth assay, motility and invasion assays, genome-wide gene expression profiling","journal":"Anticancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with multiple defined cellular phenotypes, single lab","pmids":["21508379"],"is_preprint":false},{"year":2011,"finding":"The human C7orf24 (GGCT) promoter is TATA-less and contains five CCAAT boxes. Three proximal CCAAT boxes are essential for basal transcription, and NF-Y (nuclear factor Y) specifically binds all three via its NF-YB subunit, driving C7orf24 transcription. Depletion of NF-YB in HeLa cells significantly reduced C7orf24 mRNA and protein levels. C7orf24 expression oscillates during the cell cycle, consistent with NF-Y-mediated cell cycle regulation.","method":"Luciferase reporter assay with 5'-deleted and site-directed mutant constructs, EMSA, chromatin immunoprecipitation (ChIP), NF-YB siRNA knockdown","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — multiple orthogonal methods (reporter assay, EMSA, ChIP, and RNAi knockdown) in single study establishing transcriptional mechanism","pmids":["21883928"],"is_preprint":false},{"year":2012,"finding":"In vivo knockdown of C7orf24 (GGCT) by needle-free jet injection of anti-C7orf24 siRNA into lung cancer-bearing mice significantly inhibited tumor growth, demonstrating an in vivo requirement for GGCT in tumor proliferation.","method":"In vivo siRNA delivery by needle-free jet injection, tumor volume measurement, immunohistochemistry for C7orf24 protein levels in tumor tissue","journal":"Cancer gene therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo loss-of-function with defined tumor growth phenotype, single lab","pmids":["22653386"],"is_preprint":false},{"year":2016,"finding":"GGCT knockdown (lentiviral shRNA) in gastric cancer cells inhibited cell proliferation, reduced colony formation, arrested the cell cycle at G2/M phase, and induced late apoptosis, establishing GGCT as required for gastric cancer cell proliferation and survival.","method":"Lentivirus-mediated shRNA knockdown, MTT assay, colony formation assay, flow cytometry (cell cycle and apoptosis)","journal":"BMC biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with multiple orthogonal phenotypic readouts, single lab","pmids":["27905872"],"is_preprint":false},{"year":2016,"finding":"N-glutaryl-L-alanine was identified as the most potent inhibitor of recombinant human GGCT among 18 N-acyl-L-alanine analogues tested, defining substrate-mimetic inhibitor requirements for the GGCT active site.","method":"In vitro inhibition assay with recombinant human GGCT protein, structure-activity relationship analysis of 18 synthetic analogues","journal":"Chemical & pharmaceutical bulletin","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro enzymatic inhibition assay with recombinant protein, single lab, SAR study","pmids":["27373633"],"is_preprint":false},{"year":2019,"finding":"GGCT was identified as a downstream effector of oncogenic Ras. GGCT is required for oncogenic Ras-induced primary mouse cell proliferation and transformation and in vivo lung cancer formation in the LSL-KrasG12D mouse model. GGCT regulates a glutathione (GSH)-reactive oxygen species (ROS) metabolic pathway to alleviate oncogenic stress. GGCT deficiency is compatible with normal mouse development.","method":"LSL-KrasG12D mouse model, primary mouse cell transformation assays, in vivo lung cancer model, GSH/ROS measurement, genetic knockout","journal":"iScience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (Ras→GGCT pathway) validated in primary cells and in vivo mouse model with defined metabolic phenotype, single lab but multiple orthogonal approaches","pmids":["31400748"],"is_preprint":false},{"year":2009,"finding":"C7orf24 (GGCT) mRNA is broadly expressed in rat tissues, with highest levels in liver and kidney (hepatocytes and renal tubules), as determined by RT-PCR, quantitative RT-PCR, and in situ hybridization histochemistry.","method":"RT-PCR, quantitative RT-PCR, in situ hybridization histochemistry","journal":"The journal of histochemistry and cytochemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization by in situ hybridization across multiple tissues, single lab, no functional consequence linked","pmids":["19687470"],"is_preprint":false},{"year":2020,"finding":"GGCT knockdown inhibited migration and invasion of colorectal cancer cells and regulated EMT-associated genes (N-cadherin, Vimentin, Snail1, Snail2), placing GGCT upstream of EMT in colorectal cancer.","method":"siRNA knockdown, migration and invasion assays, Western blot for EMT markers","journal":"Oncology letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single knockdown approach with EMT marker readout, no rescue or pathway epistasis","pmids":["32724344"],"is_preprint":false},{"year":2021,"finding":"Ggct deletion in mice causes splenomegaly and progressive anaemia due to elevated oxidative damage and shortened red blood cell (RBC) lifespan. Ggct-/- RBCs have increased ROS, are more sensitive to H2O2-induced damage, and have decreased glutathione (GSH) and GSH precursor l-cysteine, establishing a critical physiological function for Ggct in RBC redox balance through GSH metabolism.","method":"Ggct knockout mouse model, complete blood count, spleen histology, ROS measurement, H2O2 sensitivity assay, GSH and l-cysteine quantification","journal":"British journal of haematology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic knockout with multiple orthogonal biochemical and cellular phenotypes definitively linking GGCT to GSH metabolism and RBC survival","pmids":["34409610"],"is_preprint":false},{"year":2022,"finding":"GGCT interacts physically with CD44 in papillary thyroid cancer (PTC) cells, stabilizing CD44 protein. miR-205-5p binds the 3'-UTR of GGCT (confirmed by dual-luciferase reporter and RNA-RNA pull-down assays) and suppresses GGCT expression, thereby reversing GGCT-driven pro-malignant effects including EMT and CD44 stabilization.","method":"Co-immunoprecipitation, dual-luciferase reporter assay, RNA-RNA pull-down, siRNA knockdown, in vitro and in vivo tumor assays","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and validated miRNA-3'UTR interaction, single lab, multiple orthogonal approaches for GGCT-CD44 interaction and upstream regulation","pmids":["35213720"],"is_preprint":false},{"year":2022,"finding":"GGCT physically interacts with MRPL9 (mitochondrial ribosomal protein L9) in PTC cells, as demonstrated by co-immunoprecipitation and immunofluorescence. Knockdown of GGCT or MRPL9 inhibited the MAPK/ERK signaling pathway, suppressed cell proliferation and migration in vitro, and inhibited subcutaneous xenograft growth and lung metastasis in vivo.","method":"Co-immunoprecipitation, immunofluorescence, lentiviral knockdown, in vitro proliferation and migration assays, in vivo xenograft and lung metastasis models, Western blot for MAPK/ERK pathway","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and immunofluorescence for interaction, in vivo and in vitro functional readouts, single lab","pmids":["36233293"],"is_preprint":false},{"year":2024,"finding":"Myc directly upregulates Ggct transcription by binding to the Ggct promoter. Deletion of the Myc binding site in the Ggct promoter by genome editing attenuated the tumorigenic potential of p53-deficient osteosarcoma cells. Ggct deletion suppressed p53-deficient osteosarcomagenesis in mice, placing GGCT downstream of Myc in a pro-tumorigenic pathway.","method":"ChIP (Myc binding to Ggct promoter), CRISPR-Cas9 genome editing of Myc binding site, Ggct knockout mouse model of osteosarcoma, tumorigenic assays","journal":"Cancer science","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — ChIP defines direct transcriptional regulation, genome editing confirms functional Myc binding site, in vivo genetic knockout establishes pathway position; single lab but multiple rigorous methods","pmids":["38924236"],"is_preprint":false},{"year":2025,"finding":"GGCT-derived pyroglutamic acid (a byproduct of GGCT enzymatic activity) can bind aggregating proteins; genetic and pharmacological inhibition of GGCT prevents protein aggregation in drug-resistant glioblastoma cells. Increased GGCT expression and pyroglutamic acid staining were found in recurrent GBM patient samples.","method":"Genetic GGCT inhibition (knockdown), pharmacological GGCT inhibitor (Pro-GA), protein aggregation assays, immunostaining for pyroglutamic acid and GGCT in patient samples","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — both genetic and pharmacological loss-of-function with defined biochemical phenotype (protein aggregation), single lab, mechanistic link to GGCT enzymatic byproduct","pmids":["39949960"],"is_preprint":false},{"year":2025,"finding":"GGCT interacts with RPS15A by co-immunoprecipitation (confirmed by IP + LC-MS/MS), and promotes RPS15A protein stability. GGCT knockdown inhibited GSH synthesis and promoted ferroptosis in PTC cells by reducing SLC7A11 expression via a RPS15A→p53 axis. miR-205-5p targets the 3'UTR of GGCT to inhibit GGCT-mediated ferroptosis resistance.","method":"Co-immunoprecipitation, LC-MS/MS, siRNA knockdown, GSH/ROS/MDA measurements, ferroptosis assays, dual-luciferase reporter assay for miR-205-5p/GGCT 3'UTR, in vivo xenograft tumor formation","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP-MS identifies RPS15A interaction, multiple downstream readouts, single lab with several orthogonal methods","pmids":["40044122"],"is_preprint":false},{"year":2024,"finding":"GGCT silencing in glioma cells inhibited proliferation, migration, and induced apoptosis. Mechanistically, GGCT downregulated REST expression; REST in turn inhibited miR-34a-5p, which suppresses GGCT via its 3'UTR, forming a GGCT/REST/miR-34a-5p positive feedback loop. In vivo, REST overexpression reversed the repression of xenograft tumor formation induced by GGCT knockdown.","method":"siRNA/shRNA knockdown, CCK-8, Transwell, wound healing, flow cytometry, RNA-seq, dual luciferase reporter assay, in vivo xenograft","journal":"Translational oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with multiple phenotypic readouts and validated feedback loop by reporter assay and rescue experiment, single lab","pmids":["39128259"],"is_preprint":false}],"current_model":"GGCT (C7orf24) is a homodimeric gamma-glutamyl cyclotransferase enzyme—structurally unique, with Glu98 as the catalytic general acid/base—that converts gamma-glutamyl dipeptides to 5-oxoproline and free amino acids, thereby regulating glutathione (GSH) homeostasis; in normal physiology it is essential for RBC redox balance and survival (Ggct-/- mice develop haemolytic anaemia), while in cancer it acts downstream of oncogenic Ras and Myc to alleviate oxidative/oncogenic stress through GSH-ROS regulation, and interacts with binding partners including CD44, MRPL9, and RPS15A to promote tumour cell proliferation, migration, and ferroptosis resistance via MAPK/ERK and p53/SLC7A11 pathways; its transcription is driven by NF-Y binding to proximal CCAAT boxes and oscillates with the cell cycle."},"narrative":{"mechanistic_narrative":"GGCT (C7orf24) is a gamma-glutamyl cyclotransferase that converts gamma-glutamyl dipeptides to 5-oxoproline (pyroglutamic acid) and free amino acids, functioning as a homodimer with a unique BtrG-like fold and Glu98 as its catalytic general acid/base [PMID:18515354]. Through this enzymatic activity it governs glutathione (GSH) homeostasis and redox balance: Ggct-null mice develop splenomegaly and progressive haemolytic anaemia, with red blood cells showing elevated ROS, increased H2O2 sensitivity, and depleted GSH and its precursor l-cysteine, establishing GGCT as essential for erythrocyte redox balance and survival [PMID:34409610]. The same GSH-ROS regulatory function is co-opted in cancer, where GGCT acts downstream of oncogenic Ras to alleviate oncogenic stress and is required for Ras-driven transformation and lung tumorigenesis [PMID:31400748], and downstream of Myc, which directly binds the Ggct promoter to drive a pro-tumorigenic program in p53-deficient osteosarcoma [PMID:38924236]. Across multiple tumour types GGCT knockdown suppresses proliferation, migration, invasion, and survival [PMID:21136669, PMID:21508379, PMID:27905872], and in papillary thyroid cancer it physically interacts with CD44, MRPL9, and RPS15A to stabilize partner proteins and signal through MAPK/ERK and an RPS15A→p53→SLC7A11 axis that confers ferroptosis resistance [PMID:35213720, PMID:36233293, PMID:40044122]. Its transcription is TATA-less and CCAAT-dependent, driven by NF-Y binding to proximal CCAAT boxes via the NF-YB subunit, with expression oscillating across the cell cycle [PMID:21883928]. Substrate-mimetic active-site inhibitors and the enzymatic byproduct pyroglutamic acid have additionally been linked to protein-aggregation phenotypes in glioblastoma [PMID:27373633, PMID:39949960].","teleology":[{"year":2007,"claim":"Established that GGCT is functionally required for cancer cell proliferation, motivating mechanistic dissection of an otherwise uncharacterized open reading frame.","evidence":"siRNA knockdown and retroviral overexpression with proliferation assays in cancer cell lines and NIH3T3","pmids":["21136669"],"confidence":"Medium","gaps":["No molecular mechanism for the proliferative effect","Enzymatic identity not yet known","Single lab, two phenotypic readouts only"]},{"year":2008,"claim":"Defined the molecular identity of C7orf24 as a gamma-glutamyl cyclotransferase and resolved its catalytic mechanism, converting a phenotypic gene into a defined enzyme.","evidence":"Recombinant enzymatic assay, 1.7 Å X-ray crystallography, and active-site mutagenesis (E98A/E98Q)","pmids":["18515354"],"confidence":"High","gaps":["Did not connect enzymatic activity to the cellular proliferative phenotype","In vivo physiological substrate spectrum not addressed","No link to GSH metabolism established yet"]},{"year":2009,"claim":"Mapped baseline tissue expression, showing GGCT is broadly expressed with enrichment in metabolically active liver and kidney.","evidence":"RT-PCR, qRT-PCR, and in situ hybridization across rat tissues","pmids":["19687470"],"confidence":"Medium","gaps":["No functional consequence tied to tissue distribution","Subcellular localization not resolved"]},{"year":2011,"claim":"Identified the transcriptional control of GGCT, showing NF-Y drives basal expression through proximal CCAAT boxes and couples expression to the cell cycle.","evidence":"Luciferase reporter deletion/mutation, EMSA, ChIP, and NF-YB siRNA in HeLa cells","pmids":["21883928"],"confidence":"High","gaps":["Did not link transcriptional control to oncogenic signalling inputs","Cell-cycle oscillation mechanism not detailed"]},{"year":2011,"claim":"Extended the proliferative requirement to invasive phenotypes, showing GGCT supports growth, motility, and invasion in osteosarcoma.","evidence":"siRNA knockdown with growth/motility/invasion assays and genome-wide expression profiling","pmids":["21508379"],"confidence":"Medium","gaps":["Implicated adhesion/transport pathways not mechanistically validated","No rescue or epistasis"]},{"year":2012,"claim":"Demonstrated an in vivo requirement for GGCT in tumour growth, supporting therapeutic targeting.","evidence":"Needle-free jet injection of anti-C7orf24 siRNA into lung cancer-bearing mice with tumour volume and IHC readouts","pmids":["22653386"],"confidence":"Medium","gaps":["No mechanistic pathway tied to the in vivo effect","Single delivery model"]},{"year":2016,"claim":"Refined the cellular phenotype, showing GGCT loss arrests cells at G2/M and triggers apoptosis, and separately defined substrate-mimetic inhibitor requirements.","evidence":"Lentiviral shRNA with flow cytometry in gastric cancer cells; in vitro SAR inhibition assay of 18 N-acyl-L-alanine analogues on recombinant GGCT","pmids":["27905872","27373633"],"confidence":"Medium","gaps":["Connection between cell-cycle arrest and enzymatic activity not established","Inhibitor potency not tested in cells"]},{"year":2019,"claim":"Placed GGCT genetically downstream of oncogenic Ras and tied its function to GSH-ROS metabolism in alleviating oncogenic stress.","evidence":"LSL-KrasG12D mouse model, primary cell transformation, in vivo lung cancer, GSH/ROS measurement, and genetic knockout","pmids":["31400748"],"confidence":"High","gaps":["Molecular link between cyclotransferase activity and GSH pool not fully resolved","Did not address non-Ras tumour contexts"]},{"year":2020,"claim":"Linked GGCT to EMT regulation in colorectal cancer, broadening its role in metastatic phenotypes.","evidence":"siRNA knockdown with migration/invasion assays and Western blot of EMT markers","pmids":["32724344"],"confidence":"Low","gaps":["No rescue or pathway epistasis","Single knockdown approach","EMT regulation mechanism unknown"]},{"year":2021,"claim":"Defined the essential physiological role of GGCT in erythrocyte redox balance via GSH metabolism, explaining the consequences of its loss in normal tissue.","evidence":"Ggct knockout mouse with blood counts, spleen histology, ROS/H2O2 sensitivity, and GSH/l-cysteine quantification","pmids":["34409610"],"confidence":"High","gaps":["Mechanism linking GGCT cyclotransferase output to GSH precursor levels not fully delineated","Other tissues' dependence not characterized"]},{"year":2022,"claim":"Identified direct protein partners (CD44, MRPL9) and upstream miRNA control, expanding GGCT into a protein-stabilizing scaffold acting through MAPK/ERK.","evidence":"Co-IP, immunofluorescence, dual-luciferase reporter, RNA pull-down, and in vivo xenograft/metastasis models in papillary thyroid cancer","pmids":["35213720","36233293"],"confidence":"Medium","gaps":["Whether protein stabilization depends on enzymatic activity unknown","Direct binding interface not mapped","Single lab"]},{"year":2024,"claim":"Established Myc as a direct transcriptional driver of GGCT in tumorigenesis and identified a REST/miR-34a-5p feedback loop, integrating GGCT into oncogenic transcriptional circuits.","evidence":"ChIP and CRISPR deletion of the Myc binding site, Ggct knockout osteosarcoma mouse model; separately siRNA/RNA-seq and reporter assays defining a GGCT/REST/miR-34a-5p loop in glioma","pmids":["38924236","39128259"],"confidence":"High","gaps":["How GGCT downregulates REST mechanistically unresolved","Crosstalk between Myc and NF-Y inputs not addressed"]},{"year":2025,"claim":"Connected GGCT to ferroptosis resistance through an RPS15A→p53→SLC7A11 axis and linked its enzymatic byproduct pyroglutamic acid to protein aggregation in glioblastoma.","evidence":"Co-IP/LC-MS/MS, GSH/ROS/MDA and ferroptosis assays, reporter assays, and xenografts in PTC; genetic and pharmacological (Pro-GA) GGCT inhibition with aggregation assays and patient samples in GBM","pmids":["40044122","39949960"],"confidence":"Medium","gaps":["Mechanism by which RPS15A stabilization activates p53 axis incompletely defined","Whether pyroglutamic acid aggregation effect generalizes beyond GBM unknown","Single lab per finding"]},{"year":null,"claim":"It remains unresolved how GGCT's defined cyclotransferase activity mechanistically connects its protein-stabilizing interactions (CD44, MRPL9, RPS15A) and its scaffold/signalling roles to its core GSH-ROS metabolic function.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of GGCT bound to any protein partner","Whether partner stabilization requires catalytic activity untested","Physiological substrate spectrum in vivo not fully defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016853","term_label":"isomerase activity","supporting_discovery_ids":[0]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0,6]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[12]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[10,7]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[10,7,15]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[3,13]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[7,13]}],"complexes":[],"partners":["CD44","MRPL9","RPS15A","NF-YB","MYC"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O75223","full_name":"Gamma-glutamylcyclotransferase","aliases":["Cytochrome c-releasing factor 21"],"length_aa":188,"mass_kda":21.0,"function":"Catalyzes the formation of 5-oxoproline from gamma-glutamyl dipeptides and may play a significant role in glutathione homeostasis (PubMed:18515354). Induces release of cytochrome c from mitochondria with resultant induction of apoptosis (PubMed:16765912)","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/O75223/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GGCT","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"KRAS","stoichiometry":0.2},{"gene":"RBBP4","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/GGCT","total_profiled":1310},"omim":[{"mim_id":"614587","title":"CHAC GLUTATHIONE-SPECIFIC GAMMA-GLUTAMYLCYCLOTRANSFERASE 1; CHAC1","url":"https://www.omim.org/entry/614587"},{"mim_id":"613378","title":"AIG2-LIKE DOMAIN-CONTAINING PROTEIN 1; A2LD1","url":"https://www.omim.org/entry/613378"},{"mim_id":"260005","title":"5-@OXOPROLINASE DEFICIENCY; OPLAHD","url":"https://www.omim.org/entry/260005"},{"mim_id":"137170","title":"GAMMA-GLUTAMYL CYCLOTRANSFERASE; GGCT","url":"https://www.omim.org/entry/137170"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/GGCT"},"hgnc":{"alias_symbol":["MGC3077","CRF21","Ggc"],"prev_symbol":["C7orf24","GCTG"]},"alphafold":{"accession":"O75223","domains":[{"cath_id":"3.10.490.10","chopping":"17-177","consensus_level":"high","plddt":97.444,"start":17,"end":177}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75223","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75223-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75223-F1-predicted_aligned_error_v6.png","plddt_mean":93.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GGCT","jax_strain_url":"https://www.jax.org/strain/search?query=GGCT"},"sequence":{"accession":"O75223","fasta_url":"https://rest.uniprot.org/uniprotkb/O75223.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75223/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75223"}},"corpus_meta":[{"pmid":"31332381","id":"PMC_31332381","title":"Long-read sequencing identifies GGC repeat expansions in NOTCH2NLC associated with neuronal intranuclear inclusion disease.","date":"2019","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31332381","citation_count":402,"is_preprint":false},{"pmid":"7728763","id":"PMC_7728763","title":"The CAG and GGC microsatellites of the androgen receptor gene are in linkage disequilibrium in men with prostate cancer.","date":"1995","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/7728763","citation_count":369,"is_preprint":false},{"pmid":"31819945","id":"PMC_31819945","title":"Expansion of GGC repeat in the human-specific NOTCH2NLC gene is associated with essential tremor.","date":"2020","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/31819945","citation_count":164,"is_preprint":false},{"pmid":"20080938","id":"PMC_20080938","title":"Variant CCG and GGC repeats within the CTG expansion dramatically modify mutational dynamics and likely contribute toward unusual symptoms in some myotonic dystrophy type 1 patients.","date":"2010","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20080938","citation_count":133,"is_preprint":false},{"pmid":"33887199","id":"PMC_33887199","title":"Translation of GGC repeat expansions into a toxic polyglycine protein in NIID defines a novel class of human genetic disorders: The polyG diseases.","date":"2021","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/33887199","citation_count":127,"is_preprint":false},{"pmid":"32413282","id":"PMC_32413282","title":"Expansion of GGC Repeat in GIPC1 Is Associated with Oculopharyngodistal Myopathy.","date":"2020","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/32413282","citation_count":118,"is_preprint":false},{"pmid":"18515354","id":"PMC_18515354","title":"The identification and structural characterization of C7orf24 as gamma-glutamyl cyclotransferase. 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Malaysia","url":"https://pubmed.ncbi.nlm.nih.gov/20954559","citation_count":4,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51350,"output_tokens":4425,"usd":0.110213,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12502,"output_tokens":4165,"usd":0.083318,"stage2_stop_reason":"end_turn"},"total_usd":0.193531,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"C7orf24 (GGCT) was identified as gamma-glutamyl cyclotransferase, catalyzing the formation of 5-oxoproline (pyroglutamic acid) from gamma-glutamyl dipeptides. The crystal structure was solved at 1.7 Å resolution, revealing a homodimer of 20,994-Da subunits with a unique 'BtrG-like' fold. Active-site mutagenesis identified Glu98 as the catalytic general acid/base; mutation of Glu98 to Ala or Gln completely inactivated the enzyme without altering the overall fold.\",\n      \"method\": \"Recombinant protein expression, enzymatic assay, X-ray crystallography (1.7 Å), site-directed mutagenesis (E98A, E98Q)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure, in vitro enzymatic assay, and active-site mutagenesis all in one study; fully reconstituted activity with defined catalytic residue\",\n      \"pmids\": [\"18515354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"C7orf24 (GGCT) knockdown via siRNA in cancer cell lines produced significant antiproliferative effects (MTT assay), and overexpression in NIH3T3 cells increased growth rate, establishing a role for GGCT in cancer cell proliferation.\",\n      \"method\": \"siRNA knockdown, MTT proliferation assay, retroviral overexpression, growth rate assay\",\n      \"journal\": \"Proteomics. Clinical applications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function (siRNA) and gain-of-function (overexpression) with defined proliferative phenotype, single lab, two orthogonal approaches\",\n      \"pmids\": [\"21136669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"C7orf24 (GGCT) knockdown in osteosarcoma cell lines inhibited cell growth, motility, and invasion. Gene ontology analysis of differentially expressed genes after C7orf24 siRNA treatment implicated cell adhesion and protein transport pathways.\",\n      \"method\": \"siRNA knockdown, growth assay, motility and invasion assays, genome-wide gene expression profiling\",\n      \"journal\": \"Anticancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with multiple defined cellular phenotypes, single lab\",\n      \"pmids\": [\"21508379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The human C7orf24 (GGCT) promoter is TATA-less and contains five CCAAT boxes. Three proximal CCAAT boxes are essential for basal transcription, and NF-Y (nuclear factor Y) specifically binds all three via its NF-YB subunit, driving C7orf24 transcription. Depletion of NF-YB in HeLa cells significantly reduced C7orf24 mRNA and protein levels. C7orf24 expression oscillates during the cell cycle, consistent with NF-Y-mediated cell cycle regulation.\",\n      \"method\": \"Luciferase reporter assay with 5'-deleted and site-directed mutant constructs, EMSA, chromatin immunoprecipitation (ChIP), NF-YB siRNA knockdown\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple orthogonal methods (reporter assay, EMSA, ChIP, and RNAi knockdown) in single study establishing transcriptional mechanism\",\n      \"pmids\": [\"21883928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In vivo knockdown of C7orf24 (GGCT) by needle-free jet injection of anti-C7orf24 siRNA into lung cancer-bearing mice significantly inhibited tumor growth, demonstrating an in vivo requirement for GGCT in tumor proliferation.\",\n      \"method\": \"In vivo siRNA delivery by needle-free jet injection, tumor volume measurement, immunohistochemistry for C7orf24 protein levels in tumor tissue\",\n      \"journal\": \"Cancer gene therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo loss-of-function with defined tumor growth phenotype, single lab\",\n      \"pmids\": [\"22653386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"GGCT knockdown (lentiviral shRNA) in gastric cancer cells inhibited cell proliferation, reduced colony formation, arrested the cell cycle at G2/M phase, and induced late apoptosis, establishing GGCT as required for gastric cancer cell proliferation and survival.\",\n      \"method\": \"Lentivirus-mediated shRNA knockdown, MTT assay, colony formation assay, flow cytometry (cell cycle and apoptosis)\",\n      \"journal\": \"BMC biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with multiple orthogonal phenotypic readouts, single lab\",\n      \"pmids\": [\"27905872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"N-glutaryl-L-alanine was identified as the most potent inhibitor of recombinant human GGCT among 18 N-acyl-L-alanine analogues tested, defining substrate-mimetic inhibitor requirements for the GGCT active site.\",\n      \"method\": \"In vitro inhibition assay with recombinant human GGCT protein, structure-activity relationship analysis of 18 synthetic analogues\",\n      \"journal\": \"Chemical & pharmaceutical bulletin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro enzymatic inhibition assay with recombinant protein, single lab, SAR study\",\n      \"pmids\": [\"27373633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"GGCT was identified as a downstream effector of oncogenic Ras. GGCT is required for oncogenic Ras-induced primary mouse cell proliferation and transformation and in vivo lung cancer formation in the LSL-KrasG12D mouse model. GGCT regulates a glutathione (GSH)-reactive oxygen species (ROS) metabolic pathway to alleviate oncogenic stress. GGCT deficiency is compatible with normal mouse development.\",\n      \"method\": \"LSL-KrasG12D mouse model, primary mouse cell transformation assays, in vivo lung cancer model, GSH/ROS measurement, genetic knockout\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (Ras→GGCT pathway) validated in primary cells and in vivo mouse model with defined metabolic phenotype, single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"31400748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"C7orf24 (GGCT) mRNA is broadly expressed in rat tissues, with highest levels in liver and kidney (hepatocytes and renal tubules), as determined by RT-PCR, quantitative RT-PCR, and in situ hybridization histochemistry.\",\n      \"method\": \"RT-PCR, quantitative RT-PCR, in situ hybridization histochemistry\",\n      \"journal\": \"The journal of histochemistry and cytochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization by in situ hybridization across multiple tissues, single lab, no functional consequence linked\",\n      \"pmids\": [\"19687470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"GGCT knockdown inhibited migration and invasion of colorectal cancer cells and regulated EMT-associated genes (N-cadherin, Vimentin, Snail1, Snail2), placing GGCT upstream of EMT in colorectal cancer.\",\n      \"method\": \"siRNA knockdown, migration and invasion assays, Western blot for EMT markers\",\n      \"journal\": \"Oncology letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single knockdown approach with EMT marker readout, no rescue or pathway epistasis\",\n      \"pmids\": [\"32724344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Ggct deletion in mice causes splenomegaly and progressive anaemia due to elevated oxidative damage and shortened red blood cell (RBC) lifespan. Ggct-/- RBCs have increased ROS, are more sensitive to H2O2-induced damage, and have decreased glutathione (GSH) and GSH precursor l-cysteine, establishing a critical physiological function for Ggct in RBC redox balance through GSH metabolism.\",\n      \"method\": \"Ggct knockout mouse model, complete blood count, spleen histology, ROS measurement, H2O2 sensitivity assay, GSH and l-cysteine quantification\",\n      \"journal\": \"British journal of haematology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic knockout with multiple orthogonal biochemical and cellular phenotypes definitively linking GGCT to GSH metabolism and RBC survival\",\n      \"pmids\": [\"34409610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"GGCT interacts physically with CD44 in papillary thyroid cancer (PTC) cells, stabilizing CD44 protein. miR-205-5p binds the 3'-UTR of GGCT (confirmed by dual-luciferase reporter and RNA-RNA pull-down assays) and suppresses GGCT expression, thereby reversing GGCT-driven pro-malignant effects including EMT and CD44 stabilization.\",\n      \"method\": \"Co-immunoprecipitation, dual-luciferase reporter assay, RNA-RNA pull-down, siRNA knockdown, in vitro and in vivo tumor assays\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and validated miRNA-3'UTR interaction, single lab, multiple orthogonal approaches for GGCT-CD44 interaction and upstream regulation\",\n      \"pmids\": [\"35213720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"GGCT physically interacts with MRPL9 (mitochondrial ribosomal protein L9) in PTC cells, as demonstrated by co-immunoprecipitation and immunofluorescence. Knockdown of GGCT or MRPL9 inhibited the MAPK/ERK signaling pathway, suppressed cell proliferation and migration in vitro, and inhibited subcutaneous xenograft growth and lung metastasis in vivo.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, lentiviral knockdown, in vitro proliferation and migration assays, in vivo xenograft and lung metastasis models, Western blot for MAPK/ERK pathway\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and immunofluorescence for interaction, in vivo and in vitro functional readouts, single lab\",\n      \"pmids\": [\"36233293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Myc directly upregulates Ggct transcription by binding to the Ggct promoter. Deletion of the Myc binding site in the Ggct promoter by genome editing attenuated the tumorigenic potential of p53-deficient osteosarcoma cells. Ggct deletion suppressed p53-deficient osteosarcomagenesis in mice, placing GGCT downstream of Myc in a pro-tumorigenic pathway.\",\n      \"method\": \"ChIP (Myc binding to Ggct promoter), CRISPR-Cas9 genome editing of Myc binding site, Ggct knockout mouse model of osteosarcoma, tumorigenic assays\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — ChIP defines direct transcriptional regulation, genome editing confirms functional Myc binding site, in vivo genetic knockout establishes pathway position; single lab but multiple rigorous methods\",\n      \"pmids\": [\"38924236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GGCT-derived pyroglutamic acid (a byproduct of GGCT enzymatic activity) can bind aggregating proteins; genetic and pharmacological inhibition of GGCT prevents protein aggregation in drug-resistant glioblastoma cells. Increased GGCT expression and pyroglutamic acid staining were found in recurrent GBM patient samples.\",\n      \"method\": \"Genetic GGCT inhibition (knockdown), pharmacological GGCT inhibitor (Pro-GA), protein aggregation assays, immunostaining for pyroglutamic acid and GGCT in patient samples\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — both genetic and pharmacological loss-of-function with defined biochemical phenotype (protein aggregation), single lab, mechanistic link to GGCT enzymatic byproduct\",\n      \"pmids\": [\"39949960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GGCT interacts with RPS15A by co-immunoprecipitation (confirmed by IP + LC-MS/MS), and promotes RPS15A protein stability. GGCT knockdown inhibited GSH synthesis and promoted ferroptosis in PTC cells by reducing SLC7A11 expression via a RPS15A→p53 axis. miR-205-5p targets the 3'UTR of GGCT to inhibit GGCT-mediated ferroptosis resistance.\",\n      \"method\": \"Co-immunoprecipitation, LC-MS/MS, siRNA knockdown, GSH/ROS/MDA measurements, ferroptosis assays, dual-luciferase reporter assay for miR-205-5p/GGCT 3'UTR, in vivo xenograft tumor formation\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP-MS identifies RPS15A interaction, multiple downstream readouts, single lab with several orthogonal methods\",\n      \"pmids\": [\"40044122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GGCT silencing in glioma cells inhibited proliferation, migration, and induced apoptosis. Mechanistically, GGCT downregulated REST expression; REST in turn inhibited miR-34a-5p, which suppresses GGCT via its 3'UTR, forming a GGCT/REST/miR-34a-5p positive feedback loop. In vivo, REST overexpression reversed the repression of xenograft tumor formation induced by GGCT knockdown.\",\n      \"method\": \"siRNA/shRNA knockdown, CCK-8, Transwell, wound healing, flow cytometry, RNA-seq, dual luciferase reporter assay, in vivo xenograft\",\n      \"journal\": \"Translational oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with multiple phenotypic readouts and validated feedback loop by reporter assay and rescue experiment, single lab\",\n      \"pmids\": [\"39128259\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GGCT (C7orf24) is a homodimeric gamma-glutamyl cyclotransferase enzyme—structurally unique, with Glu98 as the catalytic general acid/base—that converts gamma-glutamyl dipeptides to 5-oxoproline and free amino acids, thereby regulating glutathione (GSH) homeostasis; in normal physiology it is essential for RBC redox balance and survival (Ggct-/- mice develop haemolytic anaemia), while in cancer it acts downstream of oncogenic Ras and Myc to alleviate oxidative/oncogenic stress through GSH-ROS regulation, and interacts with binding partners including CD44, MRPL9, and RPS15A to promote tumour cell proliferation, migration, and ferroptosis resistance via MAPK/ERK and p53/SLC7A11 pathways; its transcription is driven by NF-Y binding to proximal CCAAT boxes and oscillates with the cell cycle.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GGCT (C7orf24) is a gamma-glutamyl cyclotransferase that converts gamma-glutamyl dipeptides to 5-oxoproline (pyroglutamic acid) and free amino acids, functioning as a homodimer with a unique BtrG-like fold and Glu98 as its catalytic general acid/base [#0]. Through this enzymatic activity it governs glutathione (GSH) homeostasis and redox balance: Ggct-null mice develop splenomegaly and progressive haemolytic anaemia, with red blood cells showing elevated ROS, increased H2O2 sensitivity, and depleted GSH and its precursor l-cysteine, establishing GGCT as essential for erythrocyte redox balance and survival [#10]. The same GSH-ROS regulatory function is co-opted in cancer, where GGCT acts downstream of oncogenic Ras to alleviate oncogenic stress and is required for Ras-driven transformation and lung tumorigenesis [#7], and downstream of Myc, which directly binds the Ggct promoter to drive a pro-tumorigenic program in p53-deficient osteosarcoma [#13]. Across multiple tumour types GGCT knockdown suppresses proliferation, migration, invasion, and survival [#1, #2, #5], and in papillary thyroid cancer it physically interacts with CD44, MRPL9, and RPS15A to stabilize partner proteins and signal through MAPK/ERK and an RPS15A\\u2192p53\\u2192SLC7A11 axis that confers ferroptosis resistance [#11, #12, #15]. Its transcription is TATA-less and CCAAT-dependent, driven by NF-Y binding to proximal CCAAT boxes via the NF-YB subunit, with expression oscillating across the cell cycle [#3]. Substrate-mimetic active-site inhibitors and the enzymatic byproduct pyroglutamic acid have additionally been linked to protein-aggregation phenotypes in glioblastoma [#6, #14].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established that GGCT is functionally required for cancer cell proliferation, motivating mechanistic dissection of an otherwise uncharacterized open reading frame.\",\n      \"evidence\": \"siRNA knockdown and retroviral overexpression with proliferation assays in cancer cell lines and NIH3T3\",\n      \"pmids\": [\"21136669\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular mechanism for the proliferative effect\", \"Enzymatic identity not yet known\", \"Single lab, two phenotypic readouts only\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined the molecular identity of C7orf24 as a gamma-glutamyl cyclotransferase and resolved its catalytic mechanism, converting a phenotypic gene into a defined enzyme.\",\n      \"evidence\": \"Recombinant enzymatic assay, 1.7 \\u00c5 X-ray crystallography, and active-site mutagenesis (E98A/E98Q)\",\n      \"pmids\": [\"18515354\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not connect enzymatic activity to the cellular proliferative phenotype\", \"In vivo physiological substrate spectrum not addressed\", \"No link to GSH metabolism established yet\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Mapped baseline tissue expression, showing GGCT is broadly expressed with enrichment in metabolically active liver and kidney.\",\n      \"evidence\": \"RT-PCR, qRT-PCR, and in situ hybridization across rat tissues\",\n      \"pmids\": [\"19687470\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional consequence tied to tissue distribution\", \"Subcellular localization not resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified the transcriptional control of GGCT, showing NF-Y drives basal expression through proximal CCAAT boxes and couples expression to the cell cycle.\",\n      \"evidence\": \"Luciferase reporter deletion/mutation, EMSA, ChIP, and NF-YB siRNA in HeLa cells\",\n      \"pmids\": [\"21883928\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not link transcriptional control to oncogenic signalling inputs\", \"Cell-cycle oscillation mechanism not detailed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Extended the proliferative requirement to invasive phenotypes, showing GGCT supports growth, motility, and invasion in osteosarcoma.\",\n      \"evidence\": \"siRNA knockdown with growth/motility/invasion assays and genome-wide expression profiling\",\n      \"pmids\": [\"21508379\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Implicated adhesion/transport pathways not mechanistically validated\", \"No rescue or epistasis\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated an in vivo requirement for GGCT in tumour growth, supporting therapeutic targeting.\",\n      \"evidence\": \"Needle-free jet injection of anti-C7orf24 siRNA into lung cancer-bearing mice with tumour volume and IHC readouts\",\n      \"pmids\": [\"22653386\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No mechanistic pathway tied to the in vivo effect\", \"Single delivery model\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Refined the cellular phenotype, showing GGCT loss arrests cells at G2/M and triggers apoptosis, and separately defined substrate-mimetic inhibitor requirements.\",\n      \"evidence\": \"Lentiviral shRNA with flow cytometry in gastric cancer cells; in vitro SAR inhibition assay of 18 N-acyl-L-alanine analogues on recombinant GGCT\",\n      \"pmids\": [\"27905872\", \"27373633\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Connection between cell-cycle arrest and enzymatic activity not established\", \"Inhibitor potency not tested in cells\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed GGCT genetically downstream of oncogenic Ras and tied its function to GSH-ROS metabolism in alleviating oncogenic stress.\",\n      \"evidence\": \"LSL-KrasG12D mouse model, primary cell transformation, in vivo lung cancer, GSH/ROS measurement, and genetic knockout\",\n      \"pmids\": [\"31400748\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between cyclotransferase activity and GSH pool not fully resolved\", \"Did not address non-Ras tumour contexts\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linked GGCT to EMT regulation in colorectal cancer, broadening its role in metastatic phenotypes.\",\n      \"evidence\": \"siRNA knockdown with migration/invasion assays and Western blot of EMT markers\",\n      \"pmids\": [\"32724344\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No rescue or pathway epistasis\", \"Single knockdown approach\", \"EMT regulation mechanism unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined the essential physiological role of GGCT in erythrocyte redox balance via GSH metabolism, explaining the consequences of its loss in normal tissue.\",\n      \"evidence\": \"Ggct knockout mouse with blood counts, spleen histology, ROS/H2O2 sensitivity, and GSH/l-cysteine quantification\",\n      \"pmids\": [\"34409610\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking GGCT cyclotransferase output to GSH precursor levels not fully delineated\", \"Other tissues' dependence not characterized\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified direct protein partners (CD44, MRPL9) and upstream miRNA control, expanding GGCT into a protein-stabilizing scaffold acting through MAPK/ERK.\",\n      \"evidence\": \"Co-IP, immunofluorescence, dual-luciferase reporter, RNA pull-down, and in vivo xenograft/metastasis models in papillary thyroid cancer\",\n      \"pmids\": [\"35213720\", \"36233293\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether protein stabilization depends on enzymatic activity unknown\", \"Direct binding interface not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established Myc as a direct transcriptional driver of GGCT in tumorigenesis and identified a REST/miR-34a-5p feedback loop, integrating GGCT into oncogenic transcriptional circuits.\",\n      \"evidence\": \"ChIP and CRISPR deletion of the Myc binding site, Ggct knockout osteosarcoma mouse model; separately siRNA/RNA-seq and reporter assays defining a GGCT/REST/miR-34a-5p loop in glioma\",\n      \"pmids\": [\"38924236\", \"39128259\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How GGCT downregulates REST mechanistically unresolved\", \"Crosstalk between Myc and NF-Y inputs not addressed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected GGCT to ferroptosis resistance through an RPS15A\\u2192p53\\u2192SLC7A11 axis and linked its enzymatic byproduct pyroglutamic acid to protein aggregation in glioblastoma.\",\n      \"evidence\": \"Co-IP/LC-MS/MS, GSH/ROS/MDA and ferroptosis assays, reporter assays, and xenografts in PTC; genetic and pharmacological (Pro-GA) GGCT inhibition with aggregation assays and patient samples in GBM\",\n      \"pmids\": [\"40044122\", \"39949960\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which RPS15A stabilization activates p53 axis incompletely defined\", \"Whether pyroglutamic acid aggregation effect generalizes beyond GBM unknown\", \"Single lab per finding\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how GGCT's defined cyclotransferase activity mechanistically connects its protein-stabilizing interactions (CD44, MRPL9, RPS15A) and its scaffold/signalling roles to its core GSH-ROS metabolic function.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of GGCT bound to any protein partner\", \"Whether partner stabilization requires catalytic activity untested\", \"Physiological substrate spectrum in vivo not fully defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016853\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [10, 7]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [10, 7, 15]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3, 13]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [7, 13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CD44\", \"MRPL9\", \"RPS15A\", \"NF-YB\", \"Myc\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}