{"gene":"ODC1","run_date":"2026-04-29T11:37:57","timeline":{"discoveries":[{"year":1989,"finding":"A carboxyl-terminal domain of ODC (last 37 residues) is required for rapid intracellular degradation; truncation of these residues converts ODC from a short-lived protein (t½ ~1 h) to a stable protein retaining full activity for at least 4 hours.","method":"C-terminal truncation mutants expressed in mammalian cells; pulse-chase immunoprecipitation and gel electrophoresis","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 — direct mutagenesis with functional readout, foundational paper with 229 citations","pmids":["2928784"],"is_preprint":false},{"year":1993,"finding":"Antizyme (Az), induced by spermidine, binds to ODC and is essential for accelerated ODC degradation by the proteasome; this degradation is ubiquitin-independent and the rate correlates with antizyme levels in cell extracts. ODC is phosphorylated (likely at serine 303 in a PEST region), but antizyme promotes degradation of both phosphorylated and dephosphorylated ODC.","method":"In vitro ODC degradation system using cell extracts; immunodepletion of antizyme with anti-antizyme antibody; cycloheximide/actinomycin D experiments; pulse-chase","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with antibody depletion controls and multiple orthogonal methods","pmids":["8486633"],"is_preprint":false},{"year":2004,"finding":"In yeast, ODC antizyme (Oaz1) is itself subject to ubiquitin-mediated proteasomal degradation, and this degradation is inhibited by polyamines. Polyamines thus inhibit ODC biosynthesis by two mechanisms: inducing Oaz1 synthesis (via frameshifting) and inhibiting Oaz1 degradation. Degradation of yeast ODC by the proteasome is Oaz1-dependent.","method":"Genetic identification and characterization of yeast Oaz1; frameshifting assays; proteasome-dependent degradation assays in S. cerevisiae","journal":"The EMBO Journal","confidence":"High","confidence_rationale":"Tier 1–2 — reconstitution in yeast model with genetic and biochemical validation, ortholog of mammalian AZ system","pmids":["15538383"],"is_preprint":false},{"year":2005,"finding":"ODC undergoes ubiquitin-independent degradation by the 20S proteasome regulated by NAD(P)H quinone oxidoreductase 1 (NQO1), in addition to the antizyme-mediated ubiquitin-independent 26S proteasome pathway. The regulator antizyme (Az) is itself degraded in a ubiquitin-dependent manner, as is antizyme inhibitor (AzI).","method":"Review synthesizing biochemical and genetic studies on ODC degradation pathways","journal":"Cell Cycle","confidence":"Medium","confidence_rationale":"Tier 3 — review paper synthesizing prior experiments; underlying mechanistic findings replicated across labs","pmids":["16205122"],"is_preprint":false},{"year":2003,"finding":"Crystal structure of Trypanosoma brucei ODC bound to D-ornithine and G418 (2.5-Å resolution) shows D-ornithine forms a Schiff base with the PLP cofactor; the carboxylate binds on the si face of PLP. G418 binds at the boundary between two domains and disorders a 10-residue active-site loop (residues 392–401), providing a mechanism for allosteric inhibition.","method":"X-ray crystallography at 2.5-Å resolution with substrate analog and inhibitor","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with functional validation; trypanosomal ODC is a validated structural model for the enzyme mechanism","pmids":["12672797"],"is_preprint":false},{"year":2011,"finding":"In yeast ODC, an N-terminal unstructured domain (~45 residues, ODS) functions as a transplantable, ubiquitin-independent degron. The unstructured nature (not a specific sequence) is required; ODS can be functionally replaced by an unrelated unstructured domain. Oaz1 binding to ODC monomers is required to activate/expose ODS, and increasing the distance of ODS from the rest of ODC reduces Oaz1-dependence.","method":"Extensive mutagenesis; domain-swap experiments; proteasome degradation assays in S. cerevisiae; fusion protein stability assays","journal":"Journal of Molecular Biology","confidence":"High","confidence_rationale":"Tier 1 — reconstitution with extensive mutagenesis and multiple orthogonal experiments","pmids":["21295581"],"is_preprint":false},{"year":2010,"finding":"ZNF9 associates with actively translating ribosomes and activates cap-independent (IRES-mediated) translation of human ODC mRNA by directly binding the IRES in the 5′UTR of ODC mRNA. This activity is reduced in primary myoblasts from a DM2 patient.","method":"Polyribosome fractionation; direct RNA binding assay; IRES-reporter translation assay in primary human myoblasts including DM2 patient cells","journal":"PLoS ONE","confidence":"High","confidence_rationale":"Tier 2 — direct binding demonstrated with functional IRES assay, confirmed in disease-relevant primary cells","pmids":["20174632"],"is_preprint":false},{"year":1997,"finding":"c-Myc/Max heterodimers bind cooperatively to two adjacent E-box sequences (CACGTG) in the first intron of the rat ODC gene, with higher affinity than to a single E-box; cooperative binding of c-Myc/Max to these tandem E-boxes likely contributes to target gene specificity.","method":"In vitro DNA binding assay with vaccinia-virus-expressed c-Myc and Max proteins; electrophoretic mobility shift assay with the ODC gene fragment","journal":"Nucleic Acids Research","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro reconstituted binding with purified proteins, directly on natural ODC target sequence","pmids":["9162900"],"is_preprint":false},{"year":1997,"finding":"ODC-transformed cells display constitutive phosphorylation of Sos-1 and Raf-1 (detected as electrophoretic mobility shifts) and constitutive phosphorylation of c-Jun at serines 63 and 73, driven by a kinase distinct from Erk1/2. ODC-transformed cells also show loss of both PDGF α- and β-receptors.","method":"Immunoblotting/gel electrophoresis for mobility shifts in NIH3T3 and Rat-1 ODC-transformed cells; comparison with ras- and v-src-transformed cells","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 3 — single-lab biochemical characterization of signaling alterations in transformed cells","pmids":["9365242"],"is_preprint":false},{"year":1997,"finding":"Translation initiation factor eIF-4E is required for ODC mRNA translation in ras-transformed cells; antisense suppression of eIF-4E decreases ODC activity and also suppresses polyamine transporter activity, linking ras-induced malignancy to polyamine metabolism through eIF-4E.","method":"Antisense eIF-4E expression in CREFT24 ras-transformed rat embryo fibroblasts; measurement of ODC activity and polyamine uptake","journal":"Biochemical and Biophysical Research Communications","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with defined molecular and biochemical readouts","pmids":["9367873"],"is_preprint":false},{"year":1990,"finding":"Superinduction of ODC activity by actinomycin D is due to stimulation of ODC mRNA translation (increased rate of ODC protein synthesis), not to mRNA stabilization; steady-state ODC mRNA levels are unchanged while ODC synthesis rate increases, indicating translational regulation.","method":"[35S]methionine incorporation into immunoprecipitated ODC protein; ODC activity assays; RNA quantification in Ehrlich ascites tumor cells","journal":"FEBS Letters","confidence":"Medium","confidence_rationale":"Tier 2 — direct measurement of translation rate with metabolic labeling","pmids":["2384152"],"is_preprint":false},{"year":2018,"finding":"A de novo heterozygous gain-of-function nonsense mutation in ODC1 (c.1342 A>T) leads to a C-terminal truncation removing 14 amino acids; the truncated protein is resistant to normal proteasomal degradation, accumulates to high levels, and produces elevated putrescine in patient cells (RBCs and fibroblasts), causing a syndromic neurodevelopmental disorder.","method":"Whole-exome sequencing; Sanger sequencing confirmation; red blood cell ODC protein and polyamine level measurement; patient cell biochemistry","journal":"American Journal of Medical Genetics Part A","confidence":"High","confidence_rationale":"Tier 2 — human genetic variant with direct biochemical validation in patient-derived primary cells, consistent with known C-terminal degron mechanism","pmids":["30239107"],"is_preprint":false},{"year":2019,"finding":"Primary dermal fibroblasts from a patient with the ODC1 gain-of-function mutation (c.1342 A>T) show 12–17-fold elevated ODC enzyme activity and large accumulation of ODC protein and putrescine; the accumulated truncated ODC protein variant remains enzymatically active. DFMO treatment normalizes ODC activity and putrescine levels without cell toxicity.","method":"14C radioactive ODC enzyme activity assay; ODC protein quantification; putrescine measurement in primary patient-derived fibroblasts and RBCs; DFMO inhibitor treatment","journal":"The Biochemical Journal","confidence":"High","confidence_rationale":"Tier 1–2 — direct enzymatic assay in patient-derived cells with inhibitor rescue, multiple orthogonal readouts","pmids":["31249027"],"is_preprint":false},{"year":1999,"finding":"Ectopic expression of antizyme induces rapid decline in intracellular polyamines and cell death in both normal and transformed cell lines; antizyme blocks tumor formation in vivo in nude mice, demonstrating that antizyme exerts its anti-tumor activity through ODC inactivation and polyamine depletion.","method":"Inducible antizyme expression vector in transformed NIH3T3 cells; nude mouse tumor formation assay; polyamine measurement","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — in vivo and in vitro functional experiments with defined molecular mechanism","pmids":["9926931"],"is_preprint":false},{"year":1998,"finding":"In oral carcinogenesis, reduced/lost expression of ODC antizyme (ODC-Az) leads to elevated ODC mRNA, prolonged ODC protein half-life, and elevated ODC enzymatic activity, demonstrating that loss of antizyme function is a mechanism for ODC deregulation in tumor development.","method":"Subtractive hybridization; Northern blot; Southern blot (RFLP); direct ODC enzymatic activity measurement in hamster oral keratinocytes vs. malignant cells","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods comparing normal and malignant cells with direct enzymatic readout","pmids":["9692545"],"is_preprint":false},{"year":2021,"finding":"ODC-dependent putrescine synthesis in macrophages maintains basal expression of MerTK (MER tyrosine-protein kinase) via a histone methylation-dependent transcriptional mechanism; lower basal MerTK in ODC-deficient macrophages impairs MerTK-Erk1/2-dependent IL-10 production upon apoptotic cell exposure, reducing inflammation resolution.","method":"RNA-seq of ODC-deficient macrophages; myeloid-specific ODC deletion; zymosan peritonitis model; nanoparticle-mediated ODC silencing; putrescine rescue experiments; Western blotting for MerTK and Erk1/2 signaling","journal":"Arteriosclerosis, Thrombosis, and Vascular Biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal in vivo and in vitro methods with defined downstream pathway","pmids":["33406854"],"is_preprint":false},{"year":2006,"finding":"Antizyme overexpression in K14-MEK transgenic skin dramatically delays tumor incidence and reduces tumor multiplicity, primarily by inhibiting putrescine accumulation (putrescine decreased in MEK/AZ tumors while spermidine/spermine unaffected); the mechanism involves slowing cell growth by increasing G2/M transit time rather than inducing apoptosis.","method":"Cross-breeding of MEK and antizyme transgenic mice; polyamine measurement; S-phase and mitotic index analysis; TUNEL assay","journal":"Carcinogenesis","confidence":"High","confidence_rationale":"Tier 2 — in vivo genetic epistasis with biochemical and cell-cycle mechanistic readouts","pmids":["16400186"],"is_preprint":false},{"year":2020,"finding":"FATS (fragile-site associated tumour suppressor) binds to ERβ and translocates to the cytosol, leading to ODC protein degradation; FATS suppresses ODC at both protein and mRNA levels in an ERβ-dependent manner, thereby inhibiting polyamine biosynthesis in NSCLC cells.","method":"Co-immunoprecipitation (FATS-ERβ binding); subcellular fractionation; Western blot; ODC mRNA quantification; functional apoptosis assays in NSCLC cells","journal":"Cell Death & Disease","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, Co-IP with functional follow-up but limited mechanistic detail on degradation","pmids":["33037185"],"is_preprint":false},{"year":2024,"finding":"Long-term knockdown of astrocytic Odc1 in APP/PS1 Alzheimer's disease mice completely clears Aβ plaques in the hippocampus and switches astrocytes from a reactive to a regenerative active state (characterized by proBDNF expression); ODC1 acts as a bridge between the astrocytic urea cycle and the putrescine-to-GABA conversion pathway.","method":"Viral-mediated Odc1 knockdown in astrocytes of APP/PS1 mice; Aβ plaque immunostaining; transcriptomic analysis; proBDNF western blot","journal":"Molecular Brain","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo loss-of-function with defined cellular and molecular phenotype, single lab","pmids":["38216963"],"is_preprint":false},{"year":1995,"finding":"Two sites of transcription arrest in the murine ODC gene downstream of the transcription start site are identified: Attenuator 1 (Att.1) at +220 near two USF/Myc-Max binding E-boxes (acts as transient pause) and Attenuator 2 (Att.2) at +1590 near a T-stretch (more prolonged arrest); both are modulated by elongation factor TFIIS. Att.2 recognition is an intrinsic property of RNA Pol II, while Att.1 requires an auxiliary factor.","method":"In vitro transcription in HeLa nuclear extract; isolated transcription complex elongation assays; promoter-independent transcription with purified RNA Pol II","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstituted transcription assays with mechanistic dissection","pmids":["7537363"],"is_preprint":false},{"year":2001,"finding":"NF-κB directly transactivates the ODC gene in HGF-treated tumor cells, as demonstrated by transient transfection of two ODC gene reporter constructs.","method":"Transient transfection of ODC promoter-reporter constructs; NF-κB manipulation in HGF-treated carcinoma cell lines","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 — reporter assay with direct promoter readout, replicated across two reporter constructs","pmids":["15240510"],"is_preprint":false},{"year":2006,"finding":"Prolactin induces ODC activity through a protein kinase C delta (PKCδ) pathway without changing ODC mRNA or protein levels; ODC activity in turn upregulates Bcl-2 expression (blocked by DFMO, rescued by putrescine), contributing to anti-apoptotic effects. Bcl-2 does not affect ODC activity or protein levels.","method":"PKCδ inhibitor (rottlerin) treatment; ODC activity assay; Western blot for ODC and Bcl-2; DFMO and putrescine rescue experiments in HL-60 cells","journal":"Apoptosis","confidence":"Medium","confidence_rationale":"Tier 2 — inhibitor dissection with rescue experiment, multiple readouts, single lab","pmids":["16520895"],"is_preprint":false},{"year":2020,"finding":"siRNA-mediated knockdown of ODC1 in primary cultured uroepithelial cells causes genome-wide LINE-1 demethylation, induction of LINE-1 transcripts, double-strand DNA breaks, and decreased cell viability, indicating that ODC1 activity is required to maintain DNA methylation homeostasis.","method":"siRNA knockdown; LINE-1 methylation assay; LINE-1 RT-qPCR; γH2AX (DSB marker) immunostaining; cell viability assay in primary uroepithelial cells","journal":"Scientific Reports","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with multiple orthogonal epigenetic and DNA damage readouts","pmids":["32123240"],"is_preprint":false}],"current_model":"ODC1 (ornithine decarboxylase 1) is the rate-limiting pyridoxal-5'-phosphate-dependent enzyme that catalyzes the decarboxylation of L-ornithine to putrescine, thereby controlling polyamine biosynthesis; its activity is tightly regulated by rapid ubiquitin-independent proteasomal degradation mediated through a C-terminal degron and through interaction with antizyme (which is itself induced by polyamines via ribosomal frameshifting and stabilized by polyamines), while its translation is regulated cap-independently via an IRES, its transcription is activated by c-Myc/Max binding to tandem E-boxes and by NF-κB, and downstream putrescine production drives cell proliferation, modulates inflammation resolution via MerTK/Erk1/2/IL-10, and maintains DNA methylation homeostasis."},"narrative":{"teleology":[{"year":1989,"claim":"Identification of the C-terminal degron established that ODC's notoriously short half-life is encoded in its last 37 residues, separating catalytic function from protein stability control.","evidence":"C-terminal truncation mutants in mammalian cells with pulse-chase immunoprecipitation","pmids":["2928784"],"confidence":"High","gaps":["The trans-acting factor(s) recognizing the C-terminal degron were not identified","Whether additional degron elements exist elsewhere in ODC was unknown"]},{"year":1993,"claim":"Demonstration that antizyme is required for accelerated ODC degradation and that this process is ubiquitin-independent resolved the mechanism by which polyamines feed back to eliminate ODC protein.","evidence":"In vitro degradation reconstitution with antizyme immunodepletion; cycloheximide chase in mammalian cell extracts","pmids":["8486633"],"confidence":"High","gaps":["How antizyme physically presents ODC to the proteasome was not defined","Role of ODC phosphorylation at Ser303 in degradation kinetics remained unclear"]},{"year":1995,"claim":"Discovery of two transcriptional attenuator sites in the ODC gene revealed an elongation-level regulatory checkpoint, showing that ODC output is controlled not only at initiation but also by RNA Pol II pausing.","evidence":"In vitro transcription in HeLa nuclear extract with purified RNA Pol II and elongation factor TFIIS","pmids":["7537363"],"confidence":"High","gaps":["In vivo relevance of both attenuators was not demonstrated","Identity of the auxiliary factor required for Att.1 recognition was unknown"]},{"year":1997,"claim":"Showing that c-Myc/Max binds cooperatively to tandem E-boxes in ODC intron 1 established ODC as a direct Myc target and explained how Myc-driven proliferation channels through polyamine synthesis.","evidence":"Electrophoretic mobility shift assay with purified vaccinia-expressed c-Myc and Max on the native ODC genomic fragment","pmids":["9162900"],"confidence":"High","gaps":["Functional consequence of tandem versus single E-box occupancy on ODC transcription in vivo was not measured","Whether Myc/Max binding is sufficient or requires co-activators was unresolved"]},{"year":1997,"claim":"Connecting ODC-mediated transformation to Sos-1/Raf-1 phosphorylation and eIF-4E-dependent ODC mRNA translation placed ODC downstream of Ras signaling and upstream of growth factor receptor remodeling.","evidence":"Immunoblotting in ODC- and ras-transformed NIH3T3 cells; antisense eIF-4E in ras-transformed fibroblasts","pmids":["9365242","9367873"],"confidence":"Medium","gaps":["Direct versus indirect effects of ODC overexpression on Sos-1/Raf-1 were not delineated","The kinase responsible for c-Jun phosphorylation in ODC-transformed cells was not identified"]},{"year":1999,"claim":"Antizyme overexpression was shown to be sufficient to kill transformed cells and block tumor formation in vivo, validating the ODC–antizyme axis as a druggable node in cancer.","evidence":"Inducible antizyme expression in NIH3T3 cells; nude mouse tumorigenicity assay with polyamine measurements","pmids":["9926931"],"confidence":"High","gaps":["Whether antizyme exerts ODC-independent anti-proliferative effects was not excluded","Therapeutic delivery of antizyme was not explored"]},{"year":2003,"claim":"The crystal structure of trypanosomal ODC with D-ornithine and the inhibitor G418 revealed the Schiff-base catalytic mechanism and an allosteric inhibition site involving active-site loop disordering.","evidence":"X-ray crystallography at 2.5 Å resolution of T. brucei ODC with substrate analog and inhibitor","pmids":["12672797"],"confidence":"High","gaps":["Structure of mammalian ODC in complex with antizyme was not determined","The allosteric site's druggability for human ODC was not assessed"]},{"year":2004,"claim":"Establishing that antizyme itself is degraded by ubiquitin-dependent proteolysis inhibited by polyamines completed the feedback circuit: polyamines both induce antizyme synthesis and stabilize antizyme protein.","evidence":"Genetic identification of yeast Oaz1; frameshifting and proteasome-dependent degradation assays in S. cerevisiae","pmids":["15538383"],"confidence":"High","gaps":["The E3 ligase ubiquitinating antizyme was not identified","Quantitative contribution of antizyme stabilization versus synthesis to polyamine homeostasis was unmeasured"]},{"year":2006,"claim":"In vivo genetic epistasis showed that antizyme delays Ras/MEK-driven skin tumorigenesis primarily by depleting putrescine and prolonging G2/M rather than inducing apoptosis, dissecting the cell-cycle mechanism downstream of ODC.","evidence":"MEK × antizyme double-transgenic mice; polyamine quantification; S-phase/mitotic index; TUNEL assay","pmids":["16400186"],"confidence":"High","gaps":["Molecular target linking putrescine to G2/M transit was not identified","Whether spermidine/spermine contribute independently was not resolved"]},{"year":2010,"claim":"Demonstration that ZNF9 binds the ODC 5′UTR IRES and activates cap-independent translation provided the first trans-acting factor for IRES-mediated ODC regulation, with relevance to myotonic dystrophy type 2.","evidence":"Polyribosome fractionation; direct RNA binding; IRES-reporter assay in human myoblasts including DM2 patient cells","pmids":["20174632"],"confidence":"High","gaps":["Whether ZNF9 is the sole IRES trans-acting factor for ODC mRNA was unknown","Structural basis of ZNF9–IRES interaction was not determined"]},{"year":2011,"claim":"Identifying an N-terminal unstructured degron (ODS) in yeast ODC that is activated by antizyme binding unified the C-terminal and N-terminal degron models: antizyme monomerizes ODC to expose the N-terminal unstructured initiation site for proteasomal threading.","evidence":"Domain-swap and extensive mutagenesis; fusion protein stability assays in S. cerevisiae","pmids":["21295581"],"confidence":"High","gaps":["Whether mammalian ODC uses the same N-terminal unstructured degron was not tested","Structural details of antizyme-induced conformational change were lacking"]},{"year":2018,"claim":"Discovery that a heterozygous C-terminal truncating ODC1 mutation causes a human neurodevelopmental syndrome (Bachmann–Bupp syndrome) via protein stabilization and putrescine accumulation provided the first Mendelian disease link and validated the degron mechanism in human disease.","evidence":"Whole-exome sequencing; Sanger validation; RBC and fibroblast ODC protein and polyamine quantification","pmids":["30239107"],"confidence":"High","gaps":["Genotype–phenotype correlation across different truncation mutations was not established","CNS-specific consequences of putrescine excess were not mechanistically defined"]},{"year":2019,"claim":"Quantifying 12–17-fold elevated ODC activity in patient fibroblasts and demonstrating normalization by DFMO established proof-of-concept for therapeutic inhibition in Bachmann–Bupp syndrome.","evidence":"14C radioactive ODC activity assay; putrescine measurement; DFMO rescue in patient-derived fibroblasts","pmids":["31249027"],"confidence":"High","gaps":["In vivo efficacy and safety of DFMO in patients was not demonstrated","Whether DFMO fully rescues neurodevelopmental phenotypes was unknown"]},{"year":2020,"claim":"Linking ODC1 knockdown to genome-wide LINE-1 demethylation and DNA double-strand breaks revealed a previously unrecognized role for polyamine metabolism in maintaining epigenomic integrity.","evidence":"siRNA knockdown in primary uroepithelial cells; LINE-1 methylation assay; γH2AX immunostaining","pmids":["32123240"],"confidence":"Medium","gaps":["Which polyamine species (putrescine, spermidine, or spermine) mediates the methylation effect was not determined","Whether ODC1 loss affects methylation at loci beyond LINE-1 was not systematically assessed"]},{"year":2021,"claim":"Showing that macrophage ODC-derived putrescine sustains MerTK expression via histone methylation and thereby enables Erk1/2-dependent IL-10 production during efferocytosis connected polyamine biosynthesis to innate immune resolution of inflammation.","evidence":"Myeloid-specific ODC deletion; zymosan peritonitis; RNA-seq; nanoparticle-mediated silencing; putrescine rescue; Western blot for MerTK/Erk1/2","pmids":["33406854"],"confidence":"High","gaps":["The specific histone methyltransferase downstream of putrescine was not identified","Relevance to chronic inflammatory diseases beyond peritonitis models was not tested"]},{"year":2024,"claim":"Astrocytic ODC1 knockdown cleared amyloid plaques and switched astrocytes to a regenerative state in an Alzheimer's model, positioning ODC1 as a bridge between the urea cycle and GABA production in neurodegeneration.","evidence":"Viral-mediated Odc1 knockdown in astrocytes of APP/PS1 mice; Aβ plaque immunostaining; transcriptomics; proBDNF Western blot","pmids":["38216963"],"confidence":"Medium","gaps":["Whether plaque clearance is due to reduced putrescine, reduced GABA, or another metabolite was not resolved","Behavioral and cognitive rescue was not reported","Single mouse model without independent replication"]},{"year":null,"claim":"A high-resolution structure of mammalian ODC in complex with antizyme, the identity of the E3 ligase that ubiquitinates antizyme, the specific histone methyltransferases mediating putrescine's epigenomic effects, and in vivo clinical outcomes of DFMO in Bachmann–Bupp syndrome remain to be established.","evidence":"","pmids":[],"confidence":"Low","gaps":["No mammalian ODC–antizyme co-crystal structure exists","The E3 ligase for antizyme ubiquitination is unidentified","Clinical trial data for DFMO in Bachmann–Bupp syndrome are unavailable in the primary mechanism literature"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016829","term_label":"lyase activity","supporting_discovery_ids":[4,12]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,12]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,1,4,12,15]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[16]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[7,19,20]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[15]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,3,5]}],"complexes":[],"partners":["OAZ1","AZIN1","MYC","MAX","ZNF9","NQO1"],"other_free_text":[]},"mechanistic_narrative":"ODC1 encodes ornithine decarboxylase, the rate-limiting pyridoxal-5'-phosphate (PLP)-dependent enzyme that decarboxylates L-ornithine to putrescine, thereby governing polyamine biosynthesis and influencing cell proliferation, DNA methylation homeostasis, and inflammation resolution. ODC1 is subject to multilayered regulation: its transcription is activated by c-Myc/Max binding to tandem intronic E-boxes and by NF-κB [PMID:9162900, PMID:15240510], its mRNA is translated via both cap-dependent (eIF-4E-requiring) and IRES-mediated cap-independent mechanisms [PMID:9367873, PMID:20174632], and transcriptional elongation is modulated by two intrinsic attenuator sites [PMID:7537363]. The protein is rapidly turned over through ubiquitin-independent proteasomal degradation requiring a C-terminal degron and the polyamine-induced cofactor antizyme, which binds ODC monomers, exposes an N-terminal unstructured degron, and targets the enzyme for destruction by the 26S proteasome; loss of antizyme or truncation of the C-terminal degron stabilizes ODC and elevates putrescine, driving tumorigenesis or, in humans, a syndromic neurodevelopmental disorder (Bachmann–Bupp syndrome) [PMID:2928784, PMID:8486633, PMID:21295581, PMID:30239107]. Downstream, ODC-derived putrescine sustains MerTK-dependent anti-inflammatory signaling in macrophages, maintains LINE-1 DNA methylation in uroepithelial cells, and in astrocytes feeds the putrescine-to-GABA conversion pathway relevant to amyloid clearance [PMID:33406854, PMID:32123240, PMID:38216963]."},"prefetch_data":{"uniprot":{"accession":"P11926","full_name":"Ornithine decarboxylase","aliases":[],"length_aa":461,"mass_kda":51.1,"function":"Catalyzes the first and rate-limiting step of polyamine biosynthesis that converts ornithine into putrescine, which is the precursor for the polyamines, spermidine and spermine. Polyamines are essential for cell proliferation and are implicated in cellular processes, ranging from DNA replication to apoptosis","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/P11926/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ODC1","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/ODC1","total_profiled":1310},"omim":[{"mim_id":"619075","title":"BACHMANN-BUPP SYNDROME; BABS","url":"https://www.omim.org/entry/619075"},{"mim_id":"618703","title":"ZINC FINGER PROTEIN 281; ZNF281","url":"https://www.omim.org/entry/618703"},{"mim_id":"617887","title":"AGMATINASE; AGMAT","url":"https://www.omim.org/entry/617887"},{"mim_id":"616061","title":"MAX DIMERIZATION PROTEIN MGA; MGA","url":"https://www.omim.org/entry/616061"},{"mim_id":"615854","title":"SPERMINE OXIDASE; SMOX","url":"https://www.omim.org/entry/615854"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ODC1"},"hgnc":{"alias_symbol":["ODC"],"prev_symbol":[]},"alphafold":{"accession":"P11926","domains":[{"cath_id":"2.40.37.10","chopping":"12-44_284-300_311-410","consensus_level":"high","plddt":93.5927,"start":12,"end":410},{"cath_id":"3.20.20.10","chopping":"47-279","consensus_level":"high","plddt":96.4344,"start":47,"end":279}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P11926","model_url":"https://alphafold.ebi.ac.uk/files/AF-P11926-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P11926-F1-predicted_aligned_error_v6.png","plddt_mean":88.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ODC1","jax_strain_url":"https://www.jax.org/strain/search?query=ODC1"},"sequence":{"accession":"P11926","fasta_url":"https://rest.uniprot.org/uniprotkb/P11926.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P11926/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P11926"}},"corpus_meta":[{"pmid":"2928784","id":"PMC_2928784","title":"Prevention of rapid intracellular degradation of ODC by a carboxyl-terminal truncation.","date":"1989","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/2928784","citation_count":229,"is_preprint":false},{"pmid":"19047152","id":"PMC_19047152","title":"ODC1 is a critical determinant of MYCN oncogenesis and a therapeutic target in neuroblastoma.","date":"2008","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/19047152","citation_count":218,"is_preprint":false},{"pmid":"11314000","id":"PMC_11314000","title":"A novel transformation suppressor, Pdcd4, inhibits AP-1 transactivation but not NF-kappaB or ODC transactivation.","date":"2001","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/11314000","citation_count":169,"is_preprint":false},{"pmid":"15538383","id":"PMC_15538383","title":"Polyamines regulate their synthesis by inducing expression and blocking degradation of ODC antizyme.","date":"2004","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/15538383","citation_count":110,"is_preprint":false},{"pmid":"15240510","id":"PMC_15240510","title":"Hepatocyte growth factor-activated NF-kappaB regulates HIF-1 activity and ODC expression, implicated in survival, differently in different carcinoma cell lines.","date":"2004","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/15240510","citation_count":99,"is_preprint":false},{"pmid":"1711188","id":"PMC_1711188","title":"Effects of overexpression of ornithine decarboxylase (ODC) on growth control and oncogene-induced cell transformation.","date":"1991","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/1711188","citation_count":93,"is_preprint":false},{"pmid":"6437251","id":"PMC_6437251","title":"Polyamines and intestinal growth: absolute requirement for ODC activity in adaptation during lactation.","date":"1984","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/6437251","citation_count":82,"is_preprint":false},{"pmid":"7485512","id":"PMC_7485512","title":"L-glutamine and L-asparagine stimulate ODC activity and proliferation in a porcine jejunal enterocyte line.","date":"1995","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/7485512","citation_count":72,"is_preprint":false},{"pmid":"9926931","id":"PMC_9926931","title":"Anti-tumor activity of antizyme which targets the ornithine decarboxylase (ODC) required for cell growth and transformation.","date":"1999","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/9926931","citation_count":71,"is_preprint":false},{"pmid":"9162900","id":"PMC_9162900","title":"c-Myc/Max heterodimers bind cooperatively to the E-box sequences located in the first intron of the rat ornithine decarboxylase (ODC) gene.","date":"1997","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/9162900","citation_count":69,"is_preprint":false},{"pmid":"8550442","id":"PMC_8550442","title":"The ornithine decarboxylase gene odc is required for alcaligin siderophore biosynthesis in Bordetella spp.: putrescine is a precursor of alcaligin.","date":"1996","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/8550442","citation_count":67,"is_preprint":false},{"pmid":"2719109","id":"PMC_2719109","title":"Cholecystokinin and gastrin peptides stimulate ODC activity in a rat pancreatic cell line.","date":"1989","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/2719109","citation_count":65,"is_preprint":false},{"pmid":"3277634","id":"PMC_3277634","title":"Dissociation of c-fos from ODC expression and neuronal differentiation in a PC12 subline stably transfected with an inducible N-ras oncogene.","date":"1988","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/3277634","citation_count":65,"is_preprint":false},{"pmid":"11059762","id":"PMC_11059762","title":"Inhibition of ornithine decarboxylase (ODC) decreases tumor vascularization and reverses spontaneous tumors in ODC/Ras transgenic mice.","date":"2000","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/11059762","citation_count":60,"is_preprint":false},{"pmid":"165059","id":"PMC_165059","title":"Regulation of thyroid ornithine ornithine decarboxylase (ODC) by thyrotropin. I. The rat.","date":"1975","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/165059","citation_count":60,"is_preprint":false},{"pmid":"10906419","id":"PMC_10906419","title":"K6/ODC transgenic mice as a sensitive model for carcinogen identification.","date":"2000","source":"Toxicology letters","url":"https://pubmed.ncbi.nlm.nih.gov/10906419","citation_count":50,"is_preprint":false},{"pmid":"30239107","id":"PMC_30239107","title":"Novel de novo pathogenic variant in the ODC1 gene in a girl with developmental delay, alopecia, and dysmorphic features.","date":"2018","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/30239107","citation_count":49,"is_preprint":false},{"pmid":"22850629","id":"PMC_22850629","title":"Glutamatergic GRIN2B and polyaminergic ODC1 genes in suicide attempts: associations and gene-environment interactions with childhood/adolescent physical assault.","date":"2012","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/22850629","citation_count":48,"is_preprint":false},{"pmid":"16205122","id":"PMC_16205122","title":"Mechanisms of protein degradation: an odyssey with ODC.","date":"2005","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/16205122","citation_count":46,"is_preprint":false},{"pmid":"6229581","id":"PMC_6229581","title":"The role of mitogens and lymphokines in the induction of ornithine decarboxylase (ODC) in T lymphocytes.","date":"1984","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/6229581","citation_count":46,"is_preprint":false},{"pmid":"24386364","id":"PMC_24386364","title":"Quantitative analysis of BTF3, HINT1, NDRG1 and ODC1 protein over-expression in human prostate cancer tissue.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24386364","citation_count":44,"is_preprint":false},{"pmid":"33406854","id":"PMC_33406854","title":"ODC (Ornithine Decarboxylase)-Dependent Putrescine Synthesis Maintains MerTK (MER Tyrosine-Protein Kinase) Expression to Drive Resolution.","date":"2021","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/33406854","citation_count":43,"is_preprint":false},{"pmid":"1573975","id":"PMC_1573975","title":"Polyamine levels, ornithine decarboxylase (ODC) activity, and ODC-mRNA expression in normal and cancerous human colonocytes.","date":"1992","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/1573975","citation_count":42,"is_preprint":false},{"pmid":"9367873","id":"PMC_9367873","title":"Translation of ODC mRNA and polyamine transport are suppressed in ras-transformed CREF cells by depleting translation initiation factor 4E.","date":"1997","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/9367873","citation_count":39,"is_preprint":false},{"pmid":"12672797","id":"PMC_12672797","title":"X-ray structure determination of Trypanosoma brucei ornithine decarboxylase bound to D-ornithine and to G418: insights into substrate binding and ODC conformational flexibility.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12672797","citation_count":38,"is_preprint":false},{"pmid":"7591239","id":"PMC_7591239","title":"Life-long over-expression of ornithine decarboxylase (ODC) gene in transgenic mice does not lead to generally enhanced tumorigenesis or neuronal degeneration.","date":"1995","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/7591239","citation_count":37,"is_preprint":false},{"pmid":"30475435","id":"PMC_30475435","title":"Gain-of-function variants in the ODC1 gene cause a syndromic neurodevelopmental disorder associated with macrocephaly, alopecia, dysmorphic features, and neuroimaging abnormalities.","date":"2018","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/30475435","citation_count":36,"is_preprint":false},{"pmid":"15734996","id":"PMC_15734996","title":"Haploinsufficiency for odc modifies mouse skin tumor susceptibility.","date":"2005","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/15734996","citation_count":36,"is_preprint":false},{"pmid":"21295581","id":"PMC_21295581","title":"The N-terminal unstructured domain of yeast ODC functions as a transplantable and replaceable ubiquitin-independent degron.","date":"2011","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/21295581","citation_count":35,"is_preprint":false},{"pmid":"23300995","id":"PMC_23300995","title":"Critical roles of Myc-ODC axis in the cellular transformation induced by myeloproliferative neoplasm-associated JAK2 V617F mutant.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23300995","citation_count":34,"is_preprint":false},{"pmid":"27592554","id":"PMC_27592554","title":"Targeting ODC1 inhibits tumor growth through reduction of lipid metabolism in human hepatocellular carcinoma.","date":"2016","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/27592554","citation_count":34,"is_preprint":false},{"pmid":"15820114","id":"PMC_15820114","title":"Factors associated with variation in bulk-tank-milk Salmonella Dublin ELISA ODC% in dairy herds.","date":"2005","source":"Preventive veterinary medicine","url":"https://pubmed.ncbi.nlm.nih.gov/15820114","citation_count":33,"is_preprint":false},{"pmid":"28157137","id":"PMC_28157137","title":"Extracellular polyamines-induced proliferation and migration of cancer cells by ODC, SSAT, and Akt1-mediated pathway.","date":"2017","source":"Anti-cancer drugs","url":"https://pubmed.ncbi.nlm.nih.gov/28157137","citation_count":33,"is_preprint":false},{"pmid":"9464483","id":"PMC_9464483","title":"Effects of 50 Hz magnetic fields on UV-induced skin tumourigenesis in ODC-transgenic and non-transgenic mice.","date":"1998","source":"International journal of radiation biology","url":"https://pubmed.ncbi.nlm.nih.gov/9464483","citation_count":32,"is_preprint":false},{"pmid":"10721738","id":"PMC_10721738","title":"Sequence, expression and functional analysis of the Coccidioides immitis ODC (ornithine decarboxylase) gene.","date":"2000","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/10721738","citation_count":32,"is_preprint":false},{"pmid":"30217446","id":"PMC_30217446","title":"ODC1 inhibits the inflammatory response and ROS-induced apoptosis in macrophages.","date":"2018","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/30217446","citation_count":31,"is_preprint":false},{"pmid":"31239700","id":"PMC_31239700","title":"ODC1 promotes proliferation and mobility via the AKT/GSK3β/β-catenin pathway and modulation of acidotic microenvironment in human hepatocellular carcinoma.","date":"2019","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/31239700","citation_count":31,"is_preprint":false},{"pmid":"16400186","id":"PMC_16400186","title":"Tumor suppressor activity of ODC antizyme in MEK-driven skin tumorigenesis.","date":"2006","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/16400186","citation_count":31,"is_preprint":false},{"pmid":"20840600","id":"PMC_20840600","title":"Life without putrescine: disruption of the gene-encoding polyamine oxidase in Ustilago maydis odc mutants.","date":"2010","source":"FEMS yeast research","url":"https://pubmed.ncbi.nlm.nih.gov/20840600","citation_count":29,"is_preprint":false},{"pmid":"29029040","id":"PMC_29029040","title":"Herbacetin suppresses cutaneous squamous cell carcinoma and melanoma cell growth by targeting AKT and ODC.","date":"2017","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/29029040","citation_count":29,"is_preprint":false},{"pmid":"10757046","id":"PMC_10757046","title":"DNA damage, cell kinetics and ODC activities studied in CBA mice exposed to electromagnetic fields generated by transmission lines.","date":"1999","source":"In vivo (Athens, Greece)","url":"https://pubmed.ncbi.nlm.nih.gov/10757046","citation_count":29,"is_preprint":false},{"pmid":"8486633","id":"PMC_8486633","title":"Spermidine-induced destabilization of ornithine decarboxylase (ODC) is mediated by accumulation of antizyme in ODC-overproducing variant cells.","date":"1993","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8486633","citation_count":28,"is_preprint":false},{"pmid":"9562432","id":"PMC_9562432","title":"Trypanosoma brucei brucei: characterization of an ODC null bloodstream form mutant and the action of alpha-difluoromethylornithine.","date":"1998","source":"Experimental parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/9562432","citation_count":27,"is_preprint":false},{"pmid":"11433525","id":"PMC_11433525","title":"Amplification of Mycn, Ddx1, Rrm2, and Odc1 in rat uterine endometrial carcinomas.","date":"2001","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/11433525","citation_count":26,"is_preprint":false},{"pmid":"20174632","id":"PMC_20174632","title":"ZNF9 activation of IRES-mediated translation of the human ODC mRNA is decreased in myotonic dystrophy type 2.","date":"2010","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/20174632","citation_count":26,"is_preprint":false},{"pmid":"33806076","id":"PMC_33806076","title":"Emerging Role of ODC1 in Neurodevelopmental Disorders and Brain Development.","date":"2021","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/33806076","citation_count":25,"is_preprint":false},{"pmid":"9688139","id":"PMC_9688139","title":"Analysis of ras gene mutational spectra in epidermal papillomas from K6/ODC transgenic mice.","date":"1998","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/9688139","citation_count":25,"is_preprint":false},{"pmid":"9365242","id":"PMC_9365242","title":"Cells transformed by ODC, c-Ha-ras and v-src exhibit MAP kinase/Erk-independent constitutive phosphorylation of Sos, Raf and c-Jun activation domain, and reduced PDGF receptor expression.","date":"1997","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/9365242","citation_count":25,"is_preprint":false},{"pmid":"29872701","id":"PMC_29872701","title":"Targeting ornithine decarboxylase (ODC) inhibits esophageal squamous cell carcinoma progression.","date":"2017","source":"NPJ precision oncology","url":"https://pubmed.ncbi.nlm.nih.gov/29872701","citation_count":24,"is_preprint":false},{"pmid":"16520895","id":"PMC_16520895","title":"Increasing ornithine decarboxylase activity is another way of prolactin preventing methotrexate-induced apoptosis: crosstalk between ODC and BCL-2.","date":"2006","source":"Apoptosis : an international journal on programmed cell death","url":"https://pubmed.ncbi.nlm.nih.gov/16520895","citation_count":23,"is_preprint":false},{"pmid":"11104505","id":"PMC_11104505","title":"Expression of ODC and its regulatory protein antizyme in the adult rat brain.","date":"2000","source":"Journal of neuroscience research","url":"https://pubmed.ncbi.nlm.nih.gov/11104505","citation_count":23,"is_preprint":false},{"pmid":"9073141","id":"PMC_9073141","title":"Polyamine levels and ODC activity in intestinal-type and diffuse-type gastric carcinoma.","date":"1997","source":"Digestive diseases and sciences","url":"https://pubmed.ncbi.nlm.nih.gov/9073141","citation_count":22,"is_preprint":false},{"pmid":"9692545","id":"PMC_9692545","title":"Reduction of ornithine decarboxylase antizyme (ODC-Az) level in the 7,12-dimethylbenz(a)anthracene-induced hamster buccal pouch carcinogenesis model.","date":"1998","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/9692545","citation_count":22,"is_preprint":false},{"pmid":"2834102","id":"PMC_2834102","title":"Cloning of the orotidine 5'-phosphate decarboxylase (ODC) gene of Schwanniomyces occidentalis by complementation of the ura3 mutation in S. cerevisiae.","date":"1988","source":"Current genetics","url":"https://pubmed.ncbi.nlm.nih.gov/2834102","citation_count":22,"is_preprint":false},{"pmid":"8329117","id":"PMC_8329117","title":"Isolation and characterization of the Drosophila ornithine decarboxylase locus: evidence for the presence of two transcribed ODC genes in the Drosophila genome.","date":"1993","source":"DNA and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/8329117","citation_count":22,"is_preprint":false},{"pmid":"2384152","id":"PMC_2384152","title":"Superinduction of ornithine decarboxylase (ODC) by actinomycin D is due to stimulation of ODC mRNA translation.","date":"1990","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/2384152","citation_count":20,"is_preprint":false},{"pmid":"2593487","id":"PMC_2593487","title":"GFR increases before renal mass or ODC activity increase in rats fed high protein diets.","date":"1989","source":"Kidney international","url":"https://pubmed.ncbi.nlm.nih.gov/2593487","citation_count":20,"is_preprint":false},{"pmid":"21730362","id":"PMC_21730362","title":"A prolonged and exaggerated wound response with elevated ODC activity mimics early tumor development.","date":"2011","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/21730362","citation_count":20,"is_preprint":false},{"pmid":"15375010","id":"PMC_15375010","title":"Elevated polyamines lead to selective induction of apoptosis and inhibition of tumorigenesis by (-)-epigallocatechin-3-gallate (EGCG) in ODC/Ras transgenic mice.","date":"2004","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/15375010","citation_count":20,"is_preprint":false},{"pmid":"31297892","id":"PMC_31297892","title":"SKP2, positively regulated by circ_ODC1/miR-422a axis, promotes the proliferation of retinoblastoma.","date":"2019","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31297892","citation_count":19,"is_preprint":false},{"pmid":"31249027","id":"PMC_31249027","title":"Biochemical features of primary cells from a pediatric patient with a gain-of-function ODC1 genetic mutation.","date":"2019","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/31249027","citation_count":19,"is_preprint":false},{"pmid":"2472417","id":"PMC_2472417","title":"Effect of Na + flux inhibitors on induction of c-fos, c-myc, and ODC genes during cell cycle.","date":"1989","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/2472417","citation_count":19,"is_preprint":false},{"pmid":"26963840","id":"PMC_26963840","title":"Expression of ODC Antizyme Inhibitor 2 (AZIN2) in Human Secretory Cells and Tissues.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26963840","citation_count":18,"is_preprint":false},{"pmid":"11149424","id":"PMC_11149424","title":"Retinoic acid (RA) receptor transcriptional activation correlates with inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced ornithine decarboxylase (ODC) activity by retinoids: a potential role for trans-RA-induced ZBP-89 in ODC inhibition.","date":"2001","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/11149424","citation_count":18,"is_preprint":false},{"pmid":"16234506","id":"PMC_16234506","title":"Ornithine decarboxylase (ODC) expression pattern in human prostate tissues and ODC transgenic mice.","date":"2005","source":"The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society","url":"https://pubmed.ncbi.nlm.nih.gov/16234506","citation_count":18,"is_preprint":false},{"pmid":"26178413","id":"PMC_26178413","title":"Bag-1 promotes cell survival through c-Myc-mediated ODC upregulation that is not preferred under apoptotic stimuli in MCF-7 cells.","date":"2015","source":"Cell biochemistry and function","url":"https://pubmed.ncbi.nlm.nih.gov/26178413","citation_count":17,"is_preprint":false},{"pmid":"35541910","id":"PMC_35541910","title":"Downregulation of MTAP promotes Tumor Growth and Metastasis by regulating ODC Activity in Breast Cancer.","date":"2022","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35541910","citation_count":17,"is_preprint":false},{"pmid":"2575591","id":"PMC_2575591","title":"Linkage genetics of mouse ornithine decarboxylase (Odc).","date":"1989","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/2575591","citation_count":17,"is_preprint":false},{"pmid":"34175802","id":"PMC_34175802","title":"Effects of ODC on polyamine metabolism, hormone levels, cell proliferation and apoptosis in goose ovarian granulosa cells.","date":"2021","source":"Poultry science","url":"https://pubmed.ncbi.nlm.nih.gov/34175802","citation_count":16,"is_preprint":false},{"pmid":"27293987","id":"PMC_27293987","title":"Simultaneous targeting of 5-LOX-COX and ODC block NNK-induced lung adenoma progression to adenocarcinoma in A/J mice.","date":"2016","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/27293987","citation_count":16,"is_preprint":false},{"pmid":"28315656","id":"PMC_28315656","title":"Expression of ODC1, SPD, SPM and AZIN1 in the hypothalamus, ovary and uterus during rat estrous cycle.","date":"2017","source":"General and comparative endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/28315656","citation_count":16,"is_preprint":false},{"pmid":"16850337","id":"PMC_16850337","title":"Modest increase in temperature affects ODC activity in L929 cells: Low-level radiofrequency radiation does not.","date":"2006","source":"Radiation and environmental biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/16850337","citation_count":16,"is_preprint":false},{"pmid":"27387533","id":"PMC_27387533","title":"Plasmodium AdoMetDC/ODC bifunctional enzyme is essential for male sexual stage development and mosquito transmission.","date":"2016","source":"Biology open","url":"https://pubmed.ncbi.nlm.nih.gov/27387533","citation_count":15,"is_preprint":false},{"pmid":"1752793","id":"PMC_1752793","title":"Postnatal developmental changes in inner ear ornithine decarboxylase (ODC).","date":"1991","source":"Hearing research","url":"https://pubmed.ncbi.nlm.nih.gov/1752793","citation_count":15,"is_preprint":false},{"pmid":"38216963","id":"PMC_38216963","title":"Long-term inhibition of ODC1 in APP/PS1 mice rescues amyloid pathology and switches astrocytes from a reactive to active state.","date":"2024","source":"Molecular brain","url":"https://pubmed.ncbi.nlm.nih.gov/38216963","citation_count":14,"is_preprint":false},{"pmid":"2556329","id":"PMC_2556329","title":"Human ornithine decarboxylase(ODC)-encoding gene: cloning and expression in ODC-deficient CHO cells.","date":"1989","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/2556329","citation_count":14,"is_preprint":false},{"pmid":"3347509","id":"PMC_3347509","title":"Identification of an X-linked member of the Odc gene family in the mouse.","date":"1988","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/3347509","citation_count":14,"is_preprint":false},{"pmid":"32123240","id":"PMC_32123240","title":"Basic Hallmarks of Urothelial Cancer Unleashed in Primary Uroepithelium by Interference with the Epigenetic Master Regulator ODC1.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/32123240","citation_count":13,"is_preprint":false},{"pmid":"1576258","id":"PMC_1576258","title":"Developmental regulation of ornithine decarboxylase (ODC) in rat testis: comparison of changes in ODC activity with changes in ODC mRNA levels during testicular maturation.","date":"1992","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/1576258","citation_count":13,"is_preprint":false},{"pmid":"28851936","id":"PMC_28851936","title":"Putrescine independent wound response phenotype is produced by ODC-like RNAi in planarians.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28851936","citation_count":13,"is_preprint":false},{"pmid":"16290266","id":"PMC_16290266","title":"Regional and temporal alterations of ODC/polyamine system during ALS-like neurodegenerative motor syndrome in G93A transgenic mice.","date":"2005","source":"Neurochemistry international","url":"https://pubmed.ncbi.nlm.nih.gov/16290266","citation_count":13,"is_preprint":false},{"pmid":"3197454","id":"PMC_3197454","title":"A functional mouse ornithine decarboxylase gene (Odc) maps to chromosome 12: further evidence of homoeology between mouse chromosome 12 and the short arm of human chromosome 2.","date":"1988","source":"Cytogenetics and cell genetics","url":"https://pubmed.ncbi.nlm.nih.gov/3197454","citation_count":13,"is_preprint":false},{"pmid":"32615186","id":"PMC_32615186","title":"Increased putrescine levels due to ODC1 overexpression prevents mitochondrial dysfunction-related apoptosis induced by methylmercury.","date":"2020","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32615186","citation_count":12,"is_preprint":false},{"pmid":"28188263","id":"PMC_28188263","title":"Overexpression of mitochondrial oxodicarboxylate carrier (ODC1) preserves oxidative phosphorylation in a yeast model of Barth syndrome.","date":"2017","source":"Disease models & mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/28188263","citation_count":12,"is_preprint":false},{"pmid":"9194572","id":"PMC_9194572","title":"Catecholamines are required for androgen-induced ODC expression but not for hypertrophy of mouse kidney.","date":"1997","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/9194572","citation_count":12,"is_preprint":false},{"pmid":"23177980","id":"PMC_23177980","title":"RNAi-mediated down-regulation of ornithine decarboxylase (ODC) impedes wound-stress stimulation of anabasine synthesis in Nicotiana glauca.","date":"2012","source":"Phytochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23177980","citation_count":12,"is_preprint":false},{"pmid":"38395945","id":"PMC_38395945","title":"Elevated expression of HIGD1A drives hepatocellular carcinoma progression by regulating polyamine metabolism through c-Myc-ODC1 nexus.","date":"2024","source":"Cancer & metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/38395945","citation_count":11,"is_preprint":false},{"pmid":"17928125","id":"PMC_17928125","title":"Folate deficiency enhances arsenic effects on expression of genes involved in epidermal differentiation in transgenic K6/ODC mouse skin.","date":"2007","source":"Toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/17928125","citation_count":11,"is_preprint":false},{"pmid":"16998202","id":"PMC_16998202","title":"Polyamine analogs with xylene rings induce antizyme frameshifting, reduce ODC activity, and deplete cellular polyamines.","date":"2006","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16998202","citation_count":10,"is_preprint":false},{"pmid":"7537363","id":"PMC_7537363","title":"Transcription elongation of the murine ornithine decarboxylase (ODC) gene is regulated in vitro at two downstream elements by different attenuation mechanisms.","date":"1995","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/7537363","citation_count":10,"is_preprint":false},{"pmid":"2243540","id":"PMC_2243540","title":"Differential effects of sex steroids on uterine and renal ODC activity in ovariectomized rats.","date":"1990","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/2243540","citation_count":10,"is_preprint":false},{"pmid":"26693057","id":"PMC_26693057","title":"TP53 modulating agent, CP-31398 enhances antitumor effects of ODC inhibitor in mouse model of urinary bladder transitional cell carcinoma.","date":"2015","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/26693057","citation_count":10,"is_preprint":false},{"pmid":"8366761","id":"PMC_8366761","title":"ODC activity and polyamine levels in isolated human colonocytes.","date":"1993","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/8366761","citation_count":10,"is_preprint":false},{"pmid":"33037185","id":"PMC_33037185","title":"FATS regulates polyamine biosynthesis by promoting ODC degradation in an ERβ-dependent manner in non-small-cell lung cancer.","date":"2020","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/33037185","citation_count":9,"is_preprint":false},{"pmid":"21236653","id":"PMC_21236653","title":"Isolation, characterization and expression analysis of the ornithine decarboxylase gene (ODC1) of the entomopathogenic fungus, Metarhizium anisopliae.","date":"2011","source":"Microbiological research","url":"https://pubmed.ncbi.nlm.nih.gov/21236653","citation_count":9,"is_preprint":false},{"pmid":"19876766","id":"PMC_19876766","title":"Targeted antitumor effect induced by hTERT promoter mediated ODC antisense adenovirus.","date":"2009","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/19876766","citation_count":9,"is_preprint":false},{"pmid":"1584960","id":"PMC_1584960","title":"Activity of ornithine decarboxylase (ODC) and polyamine levels as biochemical markers of malignancy in human brain tumors.","date":"1992","source":"Acta histochemica. Supplementband","url":"https://pubmed.ncbi.nlm.nih.gov/1584960","citation_count":9,"is_preprint":false},{"pmid":"16490173","id":"PMC_16490173","title":"Adenovirus-mediated expression of both antisense ODC and AdoMetDC inhibited colorectal cancer cell growth in vitro.","date":"2006","source":"Acta pharmacologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/16490173","citation_count":9,"is_preprint":false},{"pmid":"2428603","id":"PMC_2428603","title":"Aging in the AXC/SSh rat: diminished prostate L-ornithine decarboxylase (ODC) activity reflects diminished prostate ODC protein and transcript content.","date":"1986","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/2428603","citation_count":9,"is_preprint":false},{"pmid":"29472377","id":"PMC_29472377","title":"TAAR1 induces a disturbed GSK3β phosphorylation in recurrent miscarriages through the ODC.","date":"2018","source":"Endocrine connections","url":"https://pubmed.ncbi.nlm.nih.gov/29472377","citation_count":8,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47613,"output_tokens":5435,"usd":0.112182},"stage2":{"model":"claude-opus-4-6","input_tokens":9047,"output_tokens":4003,"usd":0.217965},"total_usd":0.330147,"stage1_batch_id":"msgbatch_012ZiiCUBfB62NCTQd4Bk1Jo","stage2_batch_id":"msgbatch_01Xuqq9aUHoQouS7UVGZNStZ","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1989,\n      \"finding\": \"A carboxyl-terminal domain of ODC (last 37 residues) is required for rapid intracellular degradation; truncation of these residues converts ODC from a short-lived protein (t½ ~1 h) to a stable protein retaining full activity for at least 4 hours.\",\n      \"method\": \"C-terminal truncation mutants expressed in mammalian cells; pulse-chase immunoprecipitation and gel electrophoresis\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct mutagenesis with functional readout, foundational paper with 229 citations\",\n      \"pmids\": [\"2928784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Antizyme (Az), induced by spermidine, binds to ODC and is essential for accelerated ODC degradation by the proteasome; this degradation is ubiquitin-independent and the rate correlates with antizyme levels in cell extracts. ODC is phosphorylated (likely at serine 303 in a PEST region), but antizyme promotes degradation of both phosphorylated and dephosphorylated ODC.\",\n      \"method\": \"In vitro ODC degradation system using cell extracts; immunodepletion of antizyme with anti-antizyme antibody; cycloheximide/actinomycin D experiments; pulse-chase\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with antibody depletion controls and multiple orthogonal methods\",\n      \"pmids\": [\"8486633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"In yeast, ODC antizyme (Oaz1) is itself subject to ubiquitin-mediated proteasomal degradation, and this degradation is inhibited by polyamines. Polyamines thus inhibit ODC biosynthesis by two mechanisms: inducing Oaz1 synthesis (via frameshifting) and inhibiting Oaz1 degradation. Degradation of yeast ODC by the proteasome is Oaz1-dependent.\",\n      \"method\": \"Genetic identification and characterization of yeast Oaz1; frameshifting assays; proteasome-dependent degradation assays in S. cerevisiae\",\n      \"journal\": \"The EMBO Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — reconstitution in yeast model with genetic and biochemical validation, ortholog of mammalian AZ system\",\n      \"pmids\": [\"15538383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"ODC undergoes ubiquitin-independent degradation by the 20S proteasome regulated by NAD(P)H quinone oxidoreductase 1 (NQO1), in addition to the antizyme-mediated ubiquitin-independent 26S proteasome pathway. The regulator antizyme (Az) is itself degraded in a ubiquitin-dependent manner, as is antizyme inhibitor (AzI).\",\n      \"method\": \"Review synthesizing biochemical and genetic studies on ODC degradation pathways\",\n      \"journal\": \"Cell Cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — review paper synthesizing prior experiments; underlying mechanistic findings replicated across labs\",\n      \"pmids\": [\"16205122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Crystal structure of Trypanosoma brucei ODC bound to D-ornithine and G418 (2.5-Å resolution) shows D-ornithine forms a Schiff base with the PLP cofactor; the carboxylate binds on the si face of PLP. G418 binds at the boundary between two domains and disorders a 10-residue active-site loop (residues 392–401), providing a mechanism for allosteric inhibition.\",\n      \"method\": \"X-ray crystallography at 2.5-Å resolution with substrate analog and inhibitor\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with functional validation; trypanosomal ODC is a validated structural model for the enzyme mechanism\",\n      \"pmids\": [\"12672797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In yeast ODC, an N-terminal unstructured domain (~45 residues, ODS) functions as a transplantable, ubiquitin-independent degron. The unstructured nature (not a specific sequence) is required; ODS can be functionally replaced by an unrelated unstructured domain. Oaz1 binding to ODC monomers is required to activate/expose ODS, and increasing the distance of ODS from the rest of ODC reduces Oaz1-dependence.\",\n      \"method\": \"Extensive mutagenesis; domain-swap experiments; proteasome degradation assays in S. cerevisiae; fusion protein stability assays\",\n      \"journal\": \"Journal of Molecular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution with extensive mutagenesis and multiple orthogonal experiments\",\n      \"pmids\": [\"21295581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ZNF9 associates with actively translating ribosomes and activates cap-independent (IRES-mediated) translation of human ODC mRNA by directly binding the IRES in the 5′UTR of ODC mRNA. This activity is reduced in primary myoblasts from a DM2 patient.\",\n      \"method\": \"Polyribosome fractionation; direct RNA binding assay; IRES-reporter translation assay in primary human myoblasts including DM2 patient cells\",\n      \"journal\": \"PLoS ONE\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct binding demonstrated with functional IRES assay, confirmed in disease-relevant primary cells\",\n      \"pmids\": [\"20174632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"c-Myc/Max heterodimers bind cooperatively to two adjacent E-box sequences (CACGTG) in the first intron of the rat ODC gene, with higher affinity than to a single E-box; cooperative binding of c-Myc/Max to these tandem E-boxes likely contributes to target gene specificity.\",\n      \"method\": \"In vitro DNA binding assay with vaccinia-virus-expressed c-Myc and Max proteins; electrophoretic mobility shift assay with the ODC gene fragment\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro reconstituted binding with purified proteins, directly on natural ODC target sequence\",\n      \"pmids\": [\"9162900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"ODC-transformed cells display constitutive phosphorylation of Sos-1 and Raf-1 (detected as electrophoretic mobility shifts) and constitutive phosphorylation of c-Jun at serines 63 and 73, driven by a kinase distinct from Erk1/2. ODC-transformed cells also show loss of both PDGF α- and β-receptors.\",\n      \"method\": \"Immunoblotting/gel electrophoresis for mobility shifts in NIH3T3 and Rat-1 ODC-transformed cells; comparison with ras- and v-src-transformed cells\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single-lab biochemical characterization of signaling alterations in transformed cells\",\n      \"pmids\": [\"9365242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Translation initiation factor eIF-4E is required for ODC mRNA translation in ras-transformed cells; antisense suppression of eIF-4E decreases ODC activity and also suppresses polyamine transporter activity, linking ras-induced malignancy to polyamine metabolism through eIF-4E.\",\n      \"method\": \"Antisense eIF-4E expression in CREFT24 ras-transformed rat embryo fibroblasts; measurement of ODC activity and polyamine uptake\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with defined molecular and biochemical readouts\",\n      \"pmids\": [\"9367873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"Superinduction of ODC activity by actinomycin D is due to stimulation of ODC mRNA translation (increased rate of ODC protein synthesis), not to mRNA stabilization; steady-state ODC mRNA levels are unchanged while ODC synthesis rate increases, indicating translational regulation.\",\n      \"method\": \"[35S]methionine incorporation into immunoprecipitated ODC protein; ODC activity assays; RNA quantification in Ehrlich ascites tumor cells\",\n      \"journal\": \"FEBS Letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct measurement of translation rate with metabolic labeling\",\n      \"pmids\": [\"2384152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A de novo heterozygous gain-of-function nonsense mutation in ODC1 (c.1342 A>T) leads to a C-terminal truncation removing 14 amino acids; the truncated protein is resistant to normal proteasomal degradation, accumulates to high levels, and produces elevated putrescine in patient cells (RBCs and fibroblasts), causing a syndromic neurodevelopmental disorder.\",\n      \"method\": \"Whole-exome sequencing; Sanger sequencing confirmation; red blood cell ODC protein and polyamine level measurement; patient cell biochemistry\",\n      \"journal\": \"American Journal of Medical Genetics Part A\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — human genetic variant with direct biochemical validation in patient-derived primary cells, consistent with known C-terminal degron mechanism\",\n      \"pmids\": [\"30239107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Primary dermal fibroblasts from a patient with the ODC1 gain-of-function mutation (c.1342 A>T) show 12–17-fold elevated ODC enzyme activity and large accumulation of ODC protein and putrescine; the accumulated truncated ODC protein variant remains enzymatically active. DFMO treatment normalizes ODC activity and putrescine levels without cell toxicity.\",\n      \"method\": \"14C radioactive ODC enzyme activity assay; ODC protein quantification; putrescine measurement in primary patient-derived fibroblasts and RBCs; DFMO inhibitor treatment\",\n      \"journal\": \"The Biochemical Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct enzymatic assay in patient-derived cells with inhibitor rescue, multiple orthogonal readouts\",\n      \"pmids\": [\"31249027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Ectopic expression of antizyme induces rapid decline in intracellular polyamines and cell death in both normal and transformed cell lines; antizyme blocks tumor formation in vivo in nude mice, demonstrating that antizyme exerts its anti-tumor activity through ODC inactivation and polyamine depletion.\",\n      \"method\": \"Inducible antizyme expression vector in transformed NIH3T3 cells; nude mouse tumor formation assay; polyamine measurement\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo and in vitro functional experiments with defined molecular mechanism\",\n      \"pmids\": [\"9926931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"In oral carcinogenesis, reduced/lost expression of ODC antizyme (ODC-Az) leads to elevated ODC mRNA, prolonged ODC protein half-life, and elevated ODC enzymatic activity, demonstrating that loss of antizyme function is a mechanism for ODC deregulation in tumor development.\",\n      \"method\": \"Subtractive hybridization; Northern blot; Southern blot (RFLP); direct ODC enzymatic activity measurement in hamster oral keratinocytes vs. malignant cells\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods comparing normal and malignant cells with direct enzymatic readout\",\n      \"pmids\": [\"9692545\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ODC-dependent putrescine synthesis in macrophages maintains basal expression of MerTK (MER tyrosine-protein kinase) via a histone methylation-dependent transcriptional mechanism; lower basal MerTK in ODC-deficient macrophages impairs MerTK-Erk1/2-dependent IL-10 production upon apoptotic cell exposure, reducing inflammation resolution.\",\n      \"method\": \"RNA-seq of ODC-deficient macrophages; myeloid-specific ODC deletion; zymosan peritonitis model; nanoparticle-mediated ODC silencing; putrescine rescue experiments; Western blotting for MerTK and Erk1/2 signaling\",\n      \"journal\": \"Arteriosclerosis, Thrombosis, and Vascular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal in vivo and in vitro methods with defined downstream pathway\",\n      \"pmids\": [\"33406854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Antizyme overexpression in K14-MEK transgenic skin dramatically delays tumor incidence and reduces tumor multiplicity, primarily by inhibiting putrescine accumulation (putrescine decreased in MEK/AZ tumors while spermidine/spermine unaffected); the mechanism involves slowing cell growth by increasing G2/M transit time rather than inducing apoptosis.\",\n      \"method\": \"Cross-breeding of MEK and antizyme transgenic mice; polyamine measurement; S-phase and mitotic index analysis; TUNEL assay\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic epistasis with biochemical and cell-cycle mechanistic readouts\",\n      \"pmids\": [\"16400186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FATS (fragile-site associated tumour suppressor) binds to ERβ and translocates to the cytosol, leading to ODC protein degradation; FATS suppresses ODC at both protein and mRNA levels in an ERβ-dependent manner, thereby inhibiting polyamine biosynthesis in NSCLC cells.\",\n      \"method\": \"Co-immunoprecipitation (FATS-ERβ binding); subcellular fractionation; Western blot; ODC mRNA quantification; functional apoptosis assays in NSCLC cells\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, Co-IP with functional follow-up but limited mechanistic detail on degradation\",\n      \"pmids\": [\"33037185\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Long-term knockdown of astrocytic Odc1 in APP/PS1 Alzheimer's disease mice completely clears Aβ plaques in the hippocampus and switches astrocytes from a reactive to a regenerative active state (characterized by proBDNF expression); ODC1 acts as a bridge between the astrocytic urea cycle and the putrescine-to-GABA conversion pathway.\",\n      \"method\": \"Viral-mediated Odc1 knockdown in astrocytes of APP/PS1 mice; Aβ plaque immunostaining; transcriptomic analysis; proBDNF western blot\",\n      \"journal\": \"Molecular Brain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo loss-of-function with defined cellular and molecular phenotype, single lab\",\n      \"pmids\": [\"38216963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Two sites of transcription arrest in the murine ODC gene downstream of the transcription start site are identified: Attenuator 1 (Att.1) at +220 near two USF/Myc-Max binding E-boxes (acts as transient pause) and Attenuator 2 (Att.2) at +1590 near a T-stretch (more prolonged arrest); both are modulated by elongation factor TFIIS. Att.2 recognition is an intrinsic property of RNA Pol II, while Att.1 requires an auxiliary factor.\",\n      \"method\": \"In vitro transcription in HeLa nuclear extract; isolated transcription complex elongation assays; promoter-independent transcription with purified RNA Pol II\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstituted transcription assays with mechanistic dissection\",\n      \"pmids\": [\"7537363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"NF-κB directly transactivates the ODC gene in HGF-treated tumor cells, as demonstrated by transient transfection of two ODC gene reporter constructs.\",\n      \"method\": \"Transient transfection of ODC promoter-reporter constructs; NF-κB manipulation in HGF-treated carcinoma cell lines\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reporter assay with direct promoter readout, replicated across two reporter constructs\",\n      \"pmids\": [\"15240510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Prolactin induces ODC activity through a protein kinase C delta (PKCδ) pathway without changing ODC mRNA or protein levels; ODC activity in turn upregulates Bcl-2 expression (blocked by DFMO, rescued by putrescine), contributing to anti-apoptotic effects. Bcl-2 does not affect ODC activity or protein levels.\",\n      \"method\": \"PKCδ inhibitor (rottlerin) treatment; ODC activity assay; Western blot for ODC and Bcl-2; DFMO and putrescine rescue experiments in HL-60 cells\",\n      \"journal\": \"Apoptosis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — inhibitor dissection with rescue experiment, multiple readouts, single lab\",\n      \"pmids\": [\"16520895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"siRNA-mediated knockdown of ODC1 in primary cultured uroepithelial cells causes genome-wide LINE-1 demethylation, induction of LINE-1 transcripts, double-strand DNA breaks, and decreased cell viability, indicating that ODC1 activity is required to maintain DNA methylation homeostasis.\",\n      \"method\": \"siRNA knockdown; LINE-1 methylation assay; LINE-1 RT-qPCR; γH2AX (DSB marker) immunostaining; cell viability assay in primary uroepithelial cells\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with multiple orthogonal epigenetic and DNA damage readouts\",\n      \"pmids\": [\"32123240\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ODC1 (ornithine decarboxylase 1) is the rate-limiting pyridoxal-5'-phosphate-dependent enzyme that catalyzes the decarboxylation of L-ornithine to putrescine, thereby controlling polyamine biosynthesis; its activity is tightly regulated by rapid ubiquitin-independent proteasomal degradation mediated through a C-terminal degron and through interaction with antizyme (which is itself induced by polyamines via ribosomal frameshifting and stabilized by polyamines), while its translation is regulated cap-independently via an IRES, its transcription is activated by c-Myc/Max binding to tandem E-boxes and by NF-κB, and downstream putrescine production drives cell proliferation, modulates inflammation resolution via MerTK/Erk1/2/IL-10, and maintains DNA methylation homeostasis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ODC1 encodes ornithine decarboxylase, the rate-limiting pyridoxal-5'-phosphate (PLP)-dependent enzyme that decarboxylates L-ornithine to putrescine, thereby governing polyamine biosynthesis and influencing cell proliferation, DNA methylation homeostasis, and inflammation resolution. ODC1 is subject to multilayered regulation: its transcription is activated by c-Myc/Max binding to tandem intronic E-boxes and by NF-κB [PMID:9162900, PMID:15240510], its mRNA is translated via both cap-dependent (eIF-4E-requiring) and IRES-mediated cap-independent mechanisms [PMID:9367873, PMID:20174632], and transcriptional elongation is modulated by two intrinsic attenuator sites [PMID:7537363]. The protein is rapidly turned over through ubiquitin-independent proteasomal degradation requiring a C-terminal degron and the polyamine-induced cofactor antizyme, which binds ODC monomers, exposes an N-terminal unstructured degron, and targets the enzyme for destruction by the 26S proteasome; loss of antizyme or truncation of the C-terminal degron stabilizes ODC and elevates putrescine, driving tumorigenesis or, in humans, a syndromic neurodevelopmental disorder (Bachmann–Bupp syndrome) [PMID:2928784, PMID:8486633, PMID:21295581, PMID:30239107]. Downstream, ODC-derived putrescine sustains MerTK-dependent anti-inflammatory signaling in macrophages, maintains LINE-1 DNA methylation in uroepithelial cells, and in astrocytes feeds the putrescine-to-GABA conversion pathway relevant to amyloid clearance [PMID:33406854, PMID:32123240, PMID:38216963].\",\n  \"teleology\": [\n    {\n      \"year\": 1989,\n      \"claim\": \"Identification of the C-terminal degron established that ODC's notoriously short half-life is encoded in its last 37 residues, separating catalytic function from protein stability control.\",\n      \"evidence\": \"C-terminal truncation mutants in mammalian cells with pulse-chase immunoprecipitation\",\n      \"pmids\": [\"2928784\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The trans-acting factor(s) recognizing the C-terminal degron were not identified\",\n        \"Whether additional degron elements exist elsewhere in ODC was unknown\"\n      ]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Demonstration that antizyme is required for accelerated ODC degradation and that this process is ubiquitin-independent resolved the mechanism by which polyamines feed back to eliminate ODC protein.\",\n      \"evidence\": \"In vitro degradation reconstitution with antizyme immunodepletion; cycloheximide chase in mammalian cell extracts\",\n      \"pmids\": [\"8486633\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How antizyme physically presents ODC to the proteasome was not defined\",\n        \"Role of ODC phosphorylation at Ser303 in degradation kinetics remained unclear\"\n      ]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Discovery of two transcriptional attenuator sites in the ODC gene revealed an elongation-level regulatory checkpoint, showing that ODC output is controlled not only at initiation but also by RNA Pol II pausing.\",\n      \"evidence\": \"In vitro transcription in HeLa nuclear extract with purified RNA Pol II and elongation factor TFIIS\",\n      \"pmids\": [\"7537363\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"In vivo relevance of both attenuators was not demonstrated\",\n        \"Identity of the auxiliary factor required for Att.1 recognition was unknown\"\n      ]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Showing that c-Myc/Max binds cooperatively to tandem E-boxes in ODC intron 1 established ODC as a direct Myc target and explained how Myc-driven proliferation channels through polyamine synthesis.\",\n      \"evidence\": \"Electrophoretic mobility shift assay with purified vaccinia-expressed c-Myc and Max on the native ODC genomic fragment\",\n      \"pmids\": [\"9162900\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Functional consequence of tandem versus single E-box occupancy on ODC transcription in vivo was not measured\",\n        \"Whether Myc/Max binding is sufficient or requires co-activators was unresolved\"\n      ]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Connecting ODC-mediated transformation to Sos-1/Raf-1 phosphorylation and eIF-4E-dependent ODC mRNA translation placed ODC downstream of Ras signaling and upstream of growth factor receptor remodeling.\",\n      \"evidence\": \"Immunoblotting in ODC- and ras-transformed NIH3T3 cells; antisense eIF-4E in ras-transformed fibroblasts\",\n      \"pmids\": [\"9365242\", \"9367873\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct versus indirect effects of ODC overexpression on Sos-1/Raf-1 were not delineated\",\n        \"The kinase responsible for c-Jun phosphorylation in ODC-transformed cells was not identified\"\n      ]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Antizyme overexpression was shown to be sufficient to kill transformed cells and block tumor formation in vivo, validating the ODC–antizyme axis as a druggable node in cancer.\",\n      \"evidence\": \"Inducible antizyme expression in NIH3T3 cells; nude mouse tumorigenicity assay with polyamine measurements\",\n      \"pmids\": [\"9926931\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether antizyme exerts ODC-independent anti-proliferative effects was not excluded\",\n        \"Therapeutic delivery of antizyme was not explored\"\n      ]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"The crystal structure of trypanosomal ODC with D-ornithine and the inhibitor G418 revealed the Schiff-base catalytic mechanism and an allosteric inhibition site involving active-site loop disordering.\",\n      \"evidence\": \"X-ray crystallography at 2.5 Å resolution of T. brucei ODC with substrate analog and inhibitor\",\n      \"pmids\": [\"12672797\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structure of mammalian ODC in complex with antizyme was not determined\",\n        \"The allosteric site's druggability for human ODC was not assessed\"\n      ]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Establishing that antizyme itself is degraded by ubiquitin-dependent proteolysis inhibited by polyamines completed the feedback circuit: polyamines both induce antizyme synthesis and stabilize antizyme protein.\",\n      \"evidence\": \"Genetic identification of yeast Oaz1; frameshifting and proteasome-dependent degradation assays in S. cerevisiae\",\n      \"pmids\": [\"15538383\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The E3 ligase ubiquitinating antizyme was not identified\",\n        \"Quantitative contribution of antizyme stabilization versus synthesis to polyamine homeostasis was unmeasured\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"In vivo genetic epistasis showed that antizyme delays Ras/MEK-driven skin tumorigenesis primarily by depleting putrescine and prolonging G2/M rather than inducing apoptosis, dissecting the cell-cycle mechanism downstream of ODC.\",\n      \"evidence\": \"MEK × antizyme double-transgenic mice; polyamine quantification; S-phase/mitotic index; TUNEL assay\",\n      \"pmids\": [\"16400186\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular target linking putrescine to G2/M transit was not identified\",\n        \"Whether spermidine/spermine contribute independently was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstration that ZNF9 binds the ODC 5′UTR IRES and activates cap-independent translation provided the first trans-acting factor for IRES-mediated ODC regulation, with relevance to myotonic dystrophy type 2.\",\n      \"evidence\": \"Polyribosome fractionation; direct RNA binding; IRES-reporter assay in human myoblasts including DM2 patient cells\",\n      \"pmids\": [\"20174632\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether ZNF9 is the sole IRES trans-acting factor for ODC mRNA was unknown\",\n        \"Structural basis of ZNF9–IRES interaction was not determined\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identifying an N-terminal unstructured degron (ODS) in yeast ODC that is activated by antizyme binding unified the C-terminal and N-terminal degron models: antizyme monomerizes ODC to expose the N-terminal unstructured initiation site for proteasomal threading.\",\n      \"evidence\": \"Domain-swap and extensive mutagenesis; fusion protein stability assays in S. cerevisiae\",\n      \"pmids\": [\"21295581\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether mammalian ODC uses the same N-terminal unstructured degron was not tested\",\n        \"Structural details of antizyme-induced conformational change were lacking\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Discovery that a heterozygous C-terminal truncating ODC1 mutation causes a human neurodevelopmental syndrome (Bachmann–Bupp syndrome) via protein stabilization and putrescine accumulation provided the first Mendelian disease link and validated the degron mechanism in human disease.\",\n      \"evidence\": \"Whole-exome sequencing; Sanger validation; RBC and fibroblast ODC protein and polyamine quantification\",\n      \"pmids\": [\"30239107\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Genotype–phenotype correlation across different truncation mutations was not established\",\n        \"CNS-specific consequences of putrescine excess were not mechanistically defined\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Quantifying 12–17-fold elevated ODC activity in patient fibroblasts and demonstrating normalization by DFMO established proof-of-concept for therapeutic inhibition in Bachmann–Bupp syndrome.\",\n      \"evidence\": \"14C radioactive ODC activity assay; putrescine measurement; DFMO rescue in patient-derived fibroblasts\",\n      \"pmids\": [\"31249027\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"In vivo efficacy and safety of DFMO in patients was not demonstrated\",\n        \"Whether DFMO fully rescues neurodevelopmental phenotypes was unknown\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linking ODC1 knockdown to genome-wide LINE-1 demethylation and DNA double-strand breaks revealed a previously unrecognized role for polyamine metabolism in maintaining epigenomic integrity.\",\n      \"evidence\": \"siRNA knockdown in primary uroepithelial cells; LINE-1 methylation assay; γH2AX immunostaining\",\n      \"pmids\": [\"32123240\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Which polyamine species (putrescine, spermidine, or spermine) mediates the methylation effect was not determined\",\n        \"Whether ODC1 loss affects methylation at loci beyond LINE-1 was not systematically assessed\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showing that macrophage ODC-derived putrescine sustains MerTK expression via histone methylation and thereby enables Erk1/2-dependent IL-10 production during efferocytosis connected polyamine biosynthesis to innate immune resolution of inflammation.\",\n      \"evidence\": \"Myeloid-specific ODC deletion; zymosan peritonitis; RNA-seq; nanoparticle-mediated silencing; putrescine rescue; Western blot for MerTK/Erk1/2\",\n      \"pmids\": [\"33406854\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The specific histone methyltransferase downstream of putrescine was not identified\",\n        \"Relevance to chronic inflammatory diseases beyond peritonitis models was not tested\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Astrocytic ODC1 knockdown cleared amyloid plaques and switched astrocytes to a regenerative state in an Alzheimer's model, positioning ODC1 as a bridge between the urea cycle and GABA production in neurodegeneration.\",\n      \"evidence\": \"Viral-mediated Odc1 knockdown in astrocytes of APP/PS1 mice; Aβ plaque immunostaining; transcriptomics; proBDNF Western blot\",\n      \"pmids\": [\"38216963\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether plaque clearance is due to reduced putrescine, reduced GABA, or another metabolite was not resolved\",\n        \"Behavioral and cognitive rescue was not reported\",\n        \"Single mouse model without independent replication\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A high-resolution structure of mammalian ODC in complex with antizyme, the identity of the E3 ligase that ubiquitinates antizyme, the specific histone methyltransferases mediating putrescine's epigenomic effects, and in vivo clinical outcomes of DFMO in Bachmann–Bupp syndrome remain to be established.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No mammalian ODC–antizyme co-crystal structure exists\",\n        \"The E3 ligase for antizyme ubiquitination is unidentified\",\n        \"Clinical trial data for DFMO in Bachmann–Bupp syndrome are unavailable in the primary mechanism literature\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016831\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0016829\", \"supporting_discovery_ids\": [4, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 1, 4, 12, 15]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [16]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [7, 19, 20]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [15]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 3, 5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"OAZ1\",\n      \"AZIN1\",\n      \"MYC\",\n      \"MAX\",\n      \"ZNF9\",\n      \"NQO1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}