{"gene":"PDCD4","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":2024,"finding":"Cryo-EM structures of human PDCD4 bound to the 40S small ribosomal subunit (in Pdcd4-40S, Pdcd4-40S-eIF4A-eIF3-eIF1 complexes) reveal that the C-terminal domain (CTD) interacts with eIF4A at the mRNA entry site, while the N-terminal domain (NTD) inserts into the mRNA channel and decoding site. Quantitative binding and in vitro translation assays confirmed the NTD is critical for ribosomal recruitment and that PDCD4 blocks the eIF4F-independent role of eIF4A during 5' UTR scanning.","method":"Single-particle cryo-EM, quantitative binding assays, in vitro translation assays","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution cryo-EM structure with multiple complex states, validated by orthogonal biochemical assays (binding + in vitro translation) in a single rigorous study","pmids":["39117603"],"is_preprint":false},{"year":2006,"finding":"In response to mitogens, PDCD4 is phosphorylated on Ser67 by S6K1 and subsequently ubiquitylated and degraded via the SCF(βTrCP) E3 ubiquitin ligase. Expression of a stable PDCD4 mutant unable to bind βTrCP inhibited translation of an mRNA with a structured 5' UTR, reduced cell size, and slowed cell cycle progression.","method":"In vivo phosphorylation assay, co-immunoprecipitation, ubiquitylation assay, stable cell line expression of phosphorylation-resistant mutant, translation reporter assay","journal":"Science","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (kinase assay, Co-IP, ubiquitylation, reporter assay, mutant rescue) in a single rigorous study, independently replicated","pmids":["17053147"],"is_preprint":false},{"year":2005,"finding":"Akt phosphorylates PDCD4 at Ser67 and Ser457 in vitro and in vivo. Phosphorylation by Akt causes nuclear translocation of PDCD4 and significantly decreases the ability of PDCD4 to suppress AP-1-responsive promoter transactivation by c-Jun.","method":"In vitro kinase assay, in vivo phosphorylation (cell-based), luciferase reporter assay, subcellular localization imaging","journal":"Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro kinase assay plus in vivo phosphorylation confirmed, functional consequences shown by reporter assay; single lab with multiple orthogonal methods","pmids":["16357133"],"is_preprint":false},{"year":2008,"finding":"Tumor promoter TPA decreases PDCD4 protein levels via proteasomal degradation mediated by PKC-dependent PI3K-Akt-mTOR-p70S6K and MEK-ERK signaling. Both Akt and p70S6K phosphorylate PDCD4, enabling binding of the E3 ubiquitin ligase βTrCP and ubiquitylation; MEK-ERK facilitates subsequent proteasomal degradation. Pdcd4-haploinsufficient mice show increased tumor formation, establishing Pdcd4 as a haploinsufficient tumor suppressor.","method":"In vivo phosphorylation, co-immunoprecipitation, ubiquitylation assay, proteasome inhibitor treatment, Pdcd4-deficient mouse model","journal":"Cancer Research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal biochemical methods plus in vivo mouse genetics, independently corroborating the S6K1/βTrCP axis from PMID 17053147","pmids":["18296647"],"is_preprint":false},{"year":2004,"finding":"PDCD4 interferes with JNK-mediated phosphorylation of c-Jun by interacting with c-Jun directly, blocking JNK access without globally suppressing JNK activity. Additionally, PDCD4 blocks recruitment of the coactivator p300 by c-Jun, thereby suppressing AP-1-dependent transcription.","method":"Co-immunoprecipitation, in vitro kinase assay, reporter gene assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and in vitro kinase assay with functional reporter readout; single lab, multiple orthogonal methods","pmids":["15334056"],"is_preprint":false},{"year":2011,"finding":"PDCD4 suppresses translation of p53 mRNA via its eIF4A-interacting activity and the structured 5' UTR of p53 mRNA. PDCD4 was shown to associate with p53 mRNA, inhibit its translation in a manner dependent on eIF4A interaction and the p53 5' UTR stem-loop, and DNA-damaging agents decrease PDCD4 levels, thereby de-repressing p53 translation.","method":"RNA immunoprecipitation, translation reporter assay (5' UTR-luciferase), eIF4A-binding mutant analysis, western blot","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — RNA-IP, 5' UTR reporter assay, and eIF4A-binding mutant together demonstrate mechanism; single lab with multiple orthogonal methods","pmids":["22033922"],"is_preprint":false},{"year":2012,"finding":"p70S6K1 phosphorylates PDCD4, and this phosphorylation (together with eIF4B phosphorylation) is required to sustain global protein synthesis rates downstream of mTORC1, in addition to the 4E-BP/eIF4E axis.","method":"Genetic/pharmacological inhibition of mTORC1 and p70S6K1, protein synthesis measurement (35S-methionine incorporation), cell-based assays in 4E-BP1/2 double-knockout MEFs and fasted rat liver","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis-type analysis with genetic knockouts and pharmacological inhibitors, multiple readouts; single lab","pmids":["23105104"],"is_preprint":false},{"year":2017,"finding":"PDCD4 inhibits translation of Sin1 (MAPKAP1) mRNA via its eIF4A-binding MA-3 domains in a 5' UTR-dependent manner, thereby suppressing mTORC2 kinase activity and reducing Snail expression and colon cancer cell invasion. The eIF4A-binding mutant Pdcd4(D253A,D418A) failed to inhibit Sin1 translation or invasion.","method":"5' UTR-luciferase reporter assay, eIF4A-binding mutant analysis, polysome profiling, Pdcd4 KO cell lines, invasion assay, eIF4A inhibitor (silvestrol)","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — 5' UTR reporter, eIF4A-binding mutant, eIF4A pharmacological inhibitor, and KO rescue all converge on same mechanism; single lab with multiple orthogonal methods","pmids":["28692058"],"is_preprint":false},{"year":2002,"finding":"PDCD4 interacts with ribosomal protein S13 (RPS13) in in vitro binding assays, co-localizes with polysome fractions, and interacts with eIF4G (by GST pulldown) but not eIF4E, suggesting PDCD4 modulates eIF4G-dependent translation in senescent fibroblasts.","method":"Yeast two-hybrid, in vitro binding assay (GST pulldown), sucrose gradient fractionation (polysome sedimentation)","journal":"Biochemical and Biophysical Research Communications","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — GST pulldown and polysome fractionation confirm interaction and localization; single lab, two orthogonal methods","pmids":["12054647"],"is_preprint":false},{"year":2019,"finding":"SKP2 promotes PDCD4 phosphorylation, ubiquitination, and proteasomal degradation. Reciprocal Co-IP and mass spectrometry confirmed direct interaction between SKP2 and PDCD4. SKP2 promotes breast cancer cell proliferation and radiation resistance through PDCD4 suppression.","method":"Affinity-purification mass spectrometry, reciprocal Co-IP, ubiquitination assay, SKP2 stable overexpression/knockdown, in vitro and in vivo tumor models","journal":"Journal of Experimental & Clinical Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus MS identification and in vitro ubiquitination assay; single lab with multiple orthogonal methods","pmids":["30760284"],"is_preprint":false},{"year":2019,"finding":"DTL (a CUL4-DDB1 associated factor) interacts with PDCD4 and promotes its ubiquitin-dependent proteasomal degradation. Co-IP, immunofluorescence co-localization, and in vitro ubiquitination assays confirmed DTL as a novel E3 ligase substrate adaptor for PDCD4.","method":"Affinity-purification mass spectrometry, Co-IP, immunofluorescence, in vitro ubiquitination assay, functional proliferation/invasion assays","journal":"Journal of Experimental & Clinical Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — AP-MS, Co-IP, in vitro ubiquitination, and rescue experiments; single lab with multiple orthogonal methods","pmids":["31409387"],"is_preprint":false},{"year":2015,"finding":"IBtkα forms a CRL3(IBTK) complex and ubiquitylates PDCD4 for proteasomal degradation. IBtkα was identified as a PDCD4 interactor; serum-induced PDCD4 degradation required both IBtkα and Cul3. IBtkα depletion caused PDCD4 accumulation and decreased translation of Bcl-xL mRNA.","method":"Co-immunoprecipitation, ubiquitylation assay, RNAi knockdown, luciferase translation reporter assay","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitylation assay, and functional translation reporter; single lab, multiple orthogonal methods","pmids":["25882842"],"is_preprint":false},{"year":2008,"finding":"Pdcd4 knockdown in HeLa cells by stable shRNA leads to increased expression of p21(Waf1/Cip1) and other p53-regulated genes. Reporter gene studies show Pdcd4 interferes with p53-mediated transactivation. Knockdown cells show decreased apoptosis and increased survival after UV irradiation.","method":"Stable shRNA knockdown, reporter gene assay (p53-responsive promoters), UV irradiation survival assay, western blot","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — stable KD, reporter assay, and functional survival readout; single lab, multiple orthogonal methods","pmids":["18427550"],"is_preprint":false},{"year":2013,"finding":"PDCD4 inhibits autophagy in multiple cell types in vitro and in vivo by suppressing the expression of ATG5 and the formation of the ATG12-ATG5 complex. The MA-3 domains of PDCD4 are required for this inhibitory activity.","method":"PDCD4 overexpression/knockdown, autophagy flux assays (LC3 conversion, p62), ATG5 expression analysis, domain mutant analysis, in vivo xenograft","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO/KD plus domain mutant analysis with multiple autophagy readouts; single lab","pmids":["23486359"],"is_preprint":false},{"year":2012,"finding":"Pdcd4 knockdown increases MAP4K1 expression and phospho-c-Jun levels via a β-catenin/Tcf4-dependent upregulation of c-Myc, which directly binds the MAP4K1 promoter at -536 bp (confirmed by ChIP), thereby activating JNK/AP-1 signaling and tumor cell invasion.","method":"siRNA knockdown, ChIP assay, promoter mutation analysis, dominant-negative Tcf4 overexpression, AP-1 reporter assay","journal":"Biochimica et Biophysica Acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, promoter mutation, epistasis by DN-Tcf4, and reporter assay; single lab, multiple orthogonal methods","pmids":["22801218"],"is_preprint":false},{"year":2016,"finding":"SRSF3 represses PDCD4 protein expression through two coordinated mechanisms: (1) repressing alternative splicing and nuclear export of minor pdcd4 mRNA isoforms, and (2) repressing translation of the major pdcd4 mRNA isoform. Knockdown of SRSF3 increased PDCD4 protein levels in SW480 colon cancer cells.","method":"SRSF3 knockdown, mRNA isoform analysis (RT-PCR), nuclear/cytoplasmic fractionation, translation assay","journal":"Biochemical and Biophysical Research Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with multiple mechanistic readouts (splicing, export, translation); single lab","pmids":["26773498"],"is_preprint":false},{"year":2020,"finding":"PDCD4 promotes hepatocellular lipid accumulation by negatively regulating PPARα expression and PPARα-dependent peroxisomal β-oxidation genes (Acox1-3). Pdcd4 knockout suppressed FFA-induced lipid accumulation; rescue experiments confirmed the PPARα pathway is required.","method":"Pdcd4 knockout (lentivirus), Pdcd4 overexpression, lipid accumulation assay, gene expression analysis (RT-PCR and western blot), PPARα knockdown rescue experiment","journal":"Molecular and Cellular Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO and rescue with PPARα knockdown, multiple readouts; single lab","pmids":["35051553"],"is_preprint":false},{"year":2020,"finding":"The RNA-binding proteins La and HuR cooperatively bind the 3' UTR of PDCD4 mRNA and counteract miR-21-mediated translation repression. LPS causes nuclear-cytoplasmic translocation of HuR and increases cellular La expression; their cooperative binding enhances PDCD4 expression, reduces proliferation, and promotes apoptosis.","method":"RNA immunoprecipitation, translation reporter assay, nuclear-cytoplasmic fractionation, co-transfection of La and HuR, cell proliferation and apoptosis assays","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-IP and reporter assay with functional readouts; single lab, multiple orthogonal methods","pmids":["33288677"],"is_preprint":false},{"year":2020,"finding":"During mitotic arrest, mTORC1 activity is dramatically reduced (due to raptor phosphorylation), leading to PDCD4 stabilization and consequent inhibition of eIF4A, which promotes cell death. A non-phosphorylatable raptor mutant reactivates mTORC1, degrades PDCD4, and reduces Taxol cytotoxicity; pharmacological eIF4A inhibition rescues Taxol sensitivity in resistant cells.","method":"Non-phosphorylatable raptor mutant expression, mTORC1 activity assay, Taxol cytotoxicity assay, eIF4A inhibitor (silvestrol/rocaglamide), PDCD4 western blot during mitotic arrest","journal":"Cell Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutant rescue and pharmacological intervention with functional readouts; single lab, multiple orthogonal methods","pmids":["33027666"],"is_preprint":false},{"year":2016,"finding":"Pdcd4 deficiency in macrophages enhanced lipoautophagy (autophagy-mediated lipid degradation), prevented foam cell formation in vitro, and reduced atherosclerotic lesions in high-fat-fed ApoE-KO mice. Bone marrow transplantation confirmed that PDCD4-mediated autophagy in hematopoietic cells drives atherosclerosis.","method":"Pdcd4 knockout mouse, bone marrow transplantation, autophagy flux assay, foam cell formation assay, in vivo atherosclerosis model (ApoE-KO + HFD)","journal":"Cell Death & Disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with bone marrow transplantation and in vivo disease model; single lab","pmids":["26775706"],"is_preprint":false},{"year":2016,"finding":"Pdcd4 deficiency accelerated colitis and colitis-associated colorectal cancer in mice via upregulation of IL-6 and enhanced activation of the STAT3 signaling pathway. Blockade of IL-6/STAT3 with sgp130Fc reversed the pro-proliferative effect of Pdcd4 deficiency in vivo.","method":"Pdcd4 knockout mouse (DSS/AOM colitis-CRC model), cytokine ELISA, western blot, BrdU incorporation, sgp130Fc treatment","journal":"Inflammatory Bowel Diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with in vivo rescue by pathway blockade; single lab, multiple readouts","pmids":["26891257"],"is_preprint":false},{"year":2021,"finding":"Microglial Pdcd4 promotes neuroinflammatory responses by inhibiting Daxx-mediated PPARγ nuclear translocation, thereby suppressing anti-inflammatory IL-10 expression. Microglial conditional Pdcd4 knockout protected against LPS-induced microglial hyperactivation and depressive-like behavior; this protection was abolished by intracerebroventricular IL-10Rα neutralizing antibody.","method":"Microglial conditional Pdcd4 knockout mouse, LPS neuroinflammation model, PPARγ nuclear translocation assay, IL-10 ELISA, behavioral assays, neutralizing antibody injection","journal":"Journal of Neuroinflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with in vivo pathway rescue (IL-10 neutralization); single lab, multiple orthogonal readouts","pmids":["38822367"],"is_preprint":false},{"year":2017,"finding":"BCR-ABL1 in CML activates STAT5, which binds the miR-21 promoter and drives miR-21 expression; miR-21 in turn suppresses PDCD4 protein. This phosphoSTAT5-miR-21-PDCD4 axis also operates in AML cells driven by FLT3-ITD. PDCD4 was identified as a STAT5/miR-21 target by proteomics.","method":"miRNA microarray, miR-21 promoter STAT binding site analysis, proteomic identification of PDCD4, BCR-ABL1 and FLT3-ITD inhibitor experiments, CML primary CD34+ cell validation","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway epistasis established with kinase inhibitors, proteomics, and primary cells; single lab","pmids":["29100302"],"is_preprint":false},{"year":2001,"finding":"The chicken Pdcd4 gene is a direct transcriptional target of the v-Myb oncogene, identified by differential display in v-Myb-inducible myelomonocytic cells. This represents the first evidence of direct transcriptional regulation of Pdcd4 by an oncogene.","method":"Differential display, v-Myb inducible cell system, promoter/transcriptional analysis","journal":"Oncogene","confidence":"Low","confidence_rationale":"Tier 3 / Weak — differential display with inducible system, single lab, limited mechanistic follow-up at protein level","pmids":["11313950"],"is_preprint":false},{"year":1999,"finding":"PDCD4 (H731) protein inhibits tumor promoter-induced neoplastic transformation. Antisense-mediated reduction of Pdcd4 in transformation-resistant P- cells converted them to a transformation-sensitive phenotype; this was reversed by re-expression of Pdcd4 sense sequence.","method":"Stable antisense transfection, anchorage-independent colony formation assay, sense rescue experiment","journal":"PNAS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function antisense with gain-of-function rescue in defined genetic variant cell system; single lab","pmids":["10570194"],"is_preprint":false},{"year":2020,"finding":"PDCD4 overexpression in lung cancer cells increased Keap1 expression, which suppressed the p62-Nrf2 pathway. PDCD4-overexpressing cells showed increased apoptosis, inhibited proliferation, and reduced EMT markers. This was confirmed in xenograft models.","method":"Stable PDCD4 overexpression, western blot, apoptosis assay, xenograft tumor model","journal":"American Journal of Cancer Research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — overexpression plus downstream pathway analysis but limited mechanistic detail on direct PDCD4-Keap1 interaction; single lab","pmids":["32195018"],"is_preprint":false},{"year":2020,"finding":"EIF3H interacts with PDCD4 (confirmed by Co-IP and immunofluorescent co-localization). PDCD4 overexpression reduces EIF3H mRNA and protein levels by suppressing c-Jun-induced EIF3H transcription. EIF3H promotes EMT and LUAD cell metastasis, which is abrogated by PDCD4.","method":"Co-immunoprecipitation combined with mass spectrometry, immunofluorescent co-localization, PDCD4 overexpression, western blot, migration/invasion assays, xenograft model","journal":"American Journal of Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP/MS and co-localization plus functional rescue; single lab, multiple orthogonal methods","pmids":["32064160"],"is_preprint":false}],"current_model":"PDCD4 is a tumor suppressor that directly inhibits eIF4A helicase activity by binding at the mRNA entry channel of the 40S ribosomal subunit (via its NTD in the mRNA channel and CTD contacting eIF4A), thereby blocking translation of mRNAs with structured 5' UTRs (including p53, Sin1/MAPKAP1); its levels are regulated by S6K1/Akt-mediated phosphorylation at Ser67 (and Ser457), which triggers polyubiquitylation via SCF(βTrCP), CRL3(IBTK), DTL, or SKP2 E3 ligase complexes and proteasomal degradation; PDCD4 additionally suppresses AP-1 transcription by blocking JNK-mediated c-Jun phosphorylation and p300 recruitment, modulates autophagy by suppressing ATG5 expression, and regulates inflammatory signaling through the IL-6/STAT3 and MAPK/NF-κB pathways."},"narrative":{"mechanistic_narrative":"PDCD4 is a tumor suppressor that restrains cap-dependent translation initiation and inflammatory and oncogenic signaling, with loss-of-function promoting neoplastic transformation [PMID:10570194, PMID:18296647]. Mechanistically, PDCD4 binds the 40S small ribosomal subunit through its C-terminal domain contacting eIF4A at the mRNA entry site while its N-terminal domain inserts into the mRNA channel and decoding site, blocking the eIF4F-independent role of eIF4A during 5' UTR scanning [PMID:39117603]. Through eIF4A engagement it selectively suppresses translation of mRNAs bearing structured 5' UTRs, including p53 and Sin1/MAPKAP1, the latter linking PDCD4 to mTORC2 activity, Snail expression, and cancer cell invasion [PMID:22033922, PMID:28692058]. PDCD4 abundance is controlled by mitogenic signaling: S6K1 and Akt phosphorylate it at Ser67 (and Ser457), creating a phosphodegron that recruits SCF(βTrCP) for polyubiquitylation and proteasomal degradation, a step potentiated by MEK-ERK signaling [PMID:17053147, PMID:16357133, PMID:18296647]; additional E3 ligase adaptors SKP2, DTL (CUL4-DDB1), and CRL3(IBTK) likewise target PDCD4 for turnover [PMID:30760284, PMID:31409387, PMID:25882842]. Independent of translation, PDCD4 suppresses AP-1 transcription by binding c-Jun directly to block JNK-mediated phosphorylation and p300 coactivator recruitment [PMID:15334056], and it inhibits autophagy through its MA-3 domains by suppressing ATG5 expression and ATG12-ATG5 complex formation [PMID:23486359]. In vivo, PDCD4 modulates inflammatory and metabolic disease via IL-6/STAT3 signaling in colitis-associated cancer and Daxx/PPARγ/IL-10 signaling in microglia [PMID:26891257, PMID:38822367].","teleology":[{"year":1999,"claim":"Established PDCD4 as a functional suppressor of neoplastic transformation, defining the gene's tumor-suppressor identity before its molecular mechanism was known.","evidence":"Antisense knockdown converting transformation-resistant cells to sensitive, reversed by sense rescue, in a defined cell system","pmids":["10570194"],"confidence":"Medium","gaps":["No molecular mechanism of suppression identified","Effect shown in one engineered cell variant system"]},{"year":2001,"claim":"Identified PDCD4 as a direct transcriptional target of an oncogene, placing it downstream of oncogenic transcription programs.","evidence":"Differential display in v-Myb-inducible avian myelomonocytic cells","pmids":["11313950"],"confidence":"Low","gaps":["Limited mechanistic follow-up at the protein level","Avian system; human relevance not established here"]},{"year":2002,"claim":"First connected PDCD4 to the translation apparatus, showing physical association with ribosomal and initiation components.","evidence":"Yeast two-hybrid and GST pulldown with RPS13 and eIF4G, polysome sedimentation in senescent fibroblasts","pmids":["12054647"],"confidence":"Medium","gaps":["Functional consequence of eIF4G binding not resolved","Did not establish eIF4A as the key target"]},{"year":2005,"claim":"Defined Akt as an upstream kinase regulating PDCD4 localization and AP-1 suppression, linking PI3K-Akt signaling to PDCD4 inactivation.","evidence":"In vitro and in vivo kinase assays at Ser67/Ser457, subcellular imaging, AP-1 luciferase reporter","pmids":["16357133"],"confidence":"Medium","gaps":["Did not identify the degradation machinery downstream of phosphorylation","Single lab"]},{"year":2006,"claim":"Resolved the degradation mechanism: S6K1-mediated Ser67 phosphorylation triggers SCF(βTrCP)-dependent ubiquitylation and turnover, coupling mitogen signaling to relief of translational repression.","evidence":"In vivo phosphorylation, Co-IP, ubiquitylation assay, phospho-resistant mutant with translation reporter and cell-size/cycle readouts","pmids":["17053147"],"confidence":"High","gaps":["Identity of the structured-UTR mRNA targets not fully enumerated","Did not address additional E3 ligases"]},{"year":2008,"claim":"Confirmed PDCD4 as a haploinsufficient tumor suppressor in vivo and integrated MEK-ERK with the Akt/S6K1-βTrCP degradation axis under tumor-promoter stimulation.","evidence":"Pdcd4-haploinsufficient mice, Co-IP, ubiquitylation, proteasome inhibition under TPA treatment","pmids":["18296647"],"confidence":"High","gaps":["Precise division of labor between Akt and p70S6K phosphosites not fully dissected"]},{"year":2008,"claim":"Showed PDCD4 interferes with p53-mediated transactivation, expanding its role to p53 pathway and DNA-damage survival responses.","evidence":"Stable shRNA knockdown, p53-responsive reporter assays, UV survival/apoptosis readouts","pmids":["18427550"],"confidence":"Medium","gaps":["Mechanistic basis of interference (transcriptional vs translational) not separated here","Single cell line"]},{"year":2011,"claim":"Demonstrated that PDCD4 represses p53 mRNA translation via eIF4A and the p53 5' UTR stem-loop, providing a specific mRNA target of its translational control.","evidence":"RNA-IP, 5' UTR-luciferase reporter, eIF4A-binding mutant, DNA-damage de-repression","pmids":["22033922"],"confidence":"High","gaps":["Genome-wide scope of structured-UTR targets not defined","Single lab"]},{"year":2012,"claim":"Placed PDCD4 phosphorylation within mTORC1 control of global protein synthesis, parallel to the 4E-BP/eIF4E axis.","evidence":"Genetic/pharmacological mTORC1 and p70S6K1 manipulation, 35S-methionine incorporation in 4E-BP1/2 DKO MEFs and rat liver","pmids":["23105104"],"confidence":"Medium","gaps":["Relative contribution of PDCD4 vs eIF4B to the effect not isolated"]},{"year":2012,"claim":"Mapped a transcriptional arm of PDCD4 tumor suppression, showing its loss activates JNK/AP-1 via β-catenin/c-Myc-driven MAP4K1 induction.","evidence":"siRNA knockdown, ChIP at the MAP4K1 promoter, promoter mutation, DN-Tcf4 epistasis, AP-1 reporter","pmids":["22801218"],"confidence":"Medium","gaps":["Connection to PDCD4's translational activity not established"]},{"year":2013,"claim":"Identified autophagy regulation as a distinct PDCD4 function, suppressing ATG5 and ATG12-ATG5 complex formation via its MA-3 domains.","evidence":"Overexpression/knockdown, LC3/p62 flux assays, ATG5 expression, domain mutants, xenograft","pmids":["23486359"],"confidence":"Medium","gaps":["Whether ATG5 suppression is translational or transcriptional not resolved","Single lab"]},{"year":2015,"claim":"Added CRL3(IBTK) as an E3 ligase controlling PDCD4 turnover, broadening the degradation network beyond SCF(βTrCP).","evidence":"Co-IP, ubiquitylation assay, RNAi, Bcl-xL 5' UTR translation reporter","pmids":["25882842"],"confidence":"Medium","gaps":["Phosphodependence of IBTK recognition not defined","Single lab"]},{"year":2016,"claim":"Revealed in vivo inflammatory and metabolic roles for PDCD4 through IL-6/STAT3 in colitis-associated cancer and macrophage lipoautophagy in atherosclerosis.","evidence":"Pdcd4 KO mice in DSS/AOM colitis-CRC and ApoE-KO/HFD atherosclerosis models, bone marrow transplant, pathway blockade (sgp130Fc)","pmids":["26891257","26775706"],"confidence":"Medium","gaps":["Direct molecular target of PDCD4 in these pathways not pinpointed","Tissue/cell-type-specific mechanisms partly inferred"]},{"year":2016,"claim":"Showed PDCD4 protein levels are set post-transcriptionally by trans-acting RNA factors, with SRSF3 repressing PDCD4 splicing, export, and translation.","evidence":"SRSF3 knockdown, isoform RT-PCR, nuclear/cytoplasmic fractionation, translation assay in colon cancer cells","pmids":["26773498"],"confidence":"Medium","gaps":["Direct SRSF3 binding sites on pdcd4 mRNA not mapped"]},{"year":2017,"claim":"Connected PDCD4's eIF4A-dependent translational repression to mTORC2 by identifying Sin1/MAPKAP1 mRNA as a structured-UTR target controlling invasion.","evidence":"5' UTR reporter, eIF4A-binding mutant (D253A,D418A), polysome profiling, KO rescue, silvestrol","pmids":["28692058"],"confidence":"High","gaps":["Generality across tumor types not established"]},{"year":2017,"claim":"Established oncogenic kinase control of PDCD4 via the STAT5-miR-21 axis in leukemia, explaining PDCD4 loss downstream of BCR-ABL1 and FLT3-ITD.","evidence":"miRNA microarray, STAT binding site analysis on miR-21 promoter, proteomics, kinase inhibitor experiments, primary CD34+ cells","pmids":["29100302"],"confidence":"Medium","gaps":["Direct miR-21 binding on PDCD4 mRNA not shown in this study"]},{"year":2019,"claim":"Expanded the E3 ligase repertoire degrading PDCD4 to SKP2 and DTL, linking PDCD4 turnover to proliferation and radiation resistance.","evidence":"AP-MS, reciprocal Co-IP, ubiquitination assays, overexpression/knockdown, in vitro and in vivo tumor models","pmids":["30760284","31409387"],"confidence":"Medium","gaps":["Hierarchy and redundancy among βTrCP, SKP2, DTL, IBTK ligases not resolved"]},{"year":2020,"claim":"Showed PDCD4 stability is a node controlling chemotherapy response, with mTORC1 inactivation during mitotic arrest stabilizing PDCD4 to inhibit eIF4A and promote death.","evidence":"Non-phosphorylatable raptor mutant, mTORC1 activity assays, Taxol cytotoxicity, eIF4A inhibitors during mitotic arrest","pmids":["33027666"],"confidence":"Medium","gaps":["Specific PDCD4-controlled mRNAs driving death not identified"]},{"year":2020,"claim":"Identified RNA-binding proteins La and HuR as positive regulators of PDCD4 by counteracting miR-21 repression at the 3' UTR.","evidence":"RNA-IP, translation reporter, fractionation, La/HuR co-transfection, proliferation/apoptosis assays under LPS","pmids":["33288677"],"confidence":"Medium","gaps":["Interplay with the STAT5-miR-21 leukemia axis not integrated"]},{"year":2020,"claim":"Extended PDCD4 function to metabolism and additional signaling outputs, including PPARα-dependent β-oxidation and Keap1/Nrf2 and EIF3H/c-Jun control.","evidence":"Pdcd4 KO/overexpression with PPARα rescue (hepatocytes), overexpression with Co-IP/MS for EIF3H and Keap1 readouts, xenografts","pmids":["35051553","32064160","32195018"],"confidence":"Medium","gaps":["Direct molecular link between PDCD4 and PPARα/Keap1 not demonstrated","Keap1 finding is overexpression-based and low confidence"]},{"year":2021,"claim":"Defined a microglia-specific neuroinflammatory mechanism in which PDCD4 suppresses Daxx-mediated PPARγ nuclear translocation and IL-10, linking it to depressive-like behavior.","evidence":"Microglial conditional Pdcd4 KO, LPS model, PPARγ translocation and IL-10 readouts, IL-10Rα neutralization rescue","pmids":["38822367"],"confidence":"Medium","gaps":["Direct PDCD4-Daxx interaction not biochemically resolved"]},{"year":2024,"claim":"Provided the structural basis for translational repression, showing PDCD4 bridges eIF4A and the 40S mRNA channel to block eIF4F-independent eIF4A scanning function.","evidence":"Cryo-EM of multiple PDCD4-40S-initiation factor complexes, quantitative binding, in vitro translation","pmids":["39117603"],"confidence":"High","gaps":["How phosphorylation alters ribosome binding not structurally captured","Selectivity for specific structured 5' UTRs not structurally explained"]},{"year":null,"claim":"How the diverse degradation, RNA-regulatory, and signaling inputs are integrated to set PDCD4 levels and select among its translational versus transcriptional and metabolic outputs in a given cell context remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified hierarchy of the βTrCP/SKP2/DTL/IBTK ligases established","Genome-wide map of PDCD4-repressed structured-UTR mRNAs lacking","Context determinants of translational vs transcriptional roles unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[5,7,11]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[0,5,7]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,4]},{"term_id":"GO:0140110","term_label":"transcription regulator 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Model.","date":"2022","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/36552834","citation_count":13,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50121,"output_tokens":6852,"usd":0.126572,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16049,"output_tokens":6156,"usd":0.117072,"stage2_stop_reason":"end_turn"},"total_usd":0.243644,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2024,\n      \"finding\": \"Cryo-EM structures of human PDCD4 bound to the 40S small ribosomal subunit (in Pdcd4-40S, Pdcd4-40S-eIF4A-eIF3-eIF1 complexes) reveal that the C-terminal domain (CTD) interacts with eIF4A at the mRNA entry site, while the N-terminal domain (NTD) inserts into the mRNA channel and decoding site. Quantitative binding and in vitro translation assays confirmed the NTD is critical for ribosomal recruitment and that PDCD4 blocks the eIF4F-independent role of eIF4A during 5' UTR scanning.\",\n      \"method\": \"Single-particle cryo-EM, quantitative binding assays, in vitro translation assays\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution cryo-EM structure with multiple complex states, validated by orthogonal biochemical assays (binding + in vitro translation) in a single rigorous study\",\n      \"pmids\": [\"39117603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"In response to mitogens, PDCD4 is phosphorylated on Ser67 by S6K1 and subsequently ubiquitylated and degraded via the SCF(βTrCP) E3 ubiquitin ligase. Expression of a stable PDCD4 mutant unable to bind βTrCP inhibited translation of an mRNA with a structured 5' UTR, reduced cell size, and slowed cell cycle progression.\",\n      \"method\": \"In vivo phosphorylation assay, co-immunoprecipitation, ubiquitylation assay, stable cell line expression of phosphorylation-resistant mutant, translation reporter assay\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (kinase assay, Co-IP, ubiquitylation, reporter assay, mutant rescue) in a single rigorous study, independently replicated\",\n      \"pmids\": [\"17053147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Akt phosphorylates PDCD4 at Ser67 and Ser457 in vitro and in vivo. Phosphorylation by Akt causes nuclear translocation of PDCD4 and significantly decreases the ability of PDCD4 to suppress AP-1-responsive promoter transactivation by c-Jun.\",\n      \"method\": \"In vitro kinase assay, in vivo phosphorylation (cell-based), luciferase reporter assay, subcellular localization imaging\",\n      \"journal\": \"Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro kinase assay plus in vivo phosphorylation confirmed, functional consequences shown by reporter assay; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"16357133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Tumor promoter TPA decreases PDCD4 protein levels via proteasomal degradation mediated by PKC-dependent PI3K-Akt-mTOR-p70S6K and MEK-ERK signaling. Both Akt and p70S6K phosphorylate PDCD4, enabling binding of the E3 ubiquitin ligase βTrCP and ubiquitylation; MEK-ERK facilitates subsequent proteasomal degradation. Pdcd4-haploinsufficient mice show increased tumor formation, establishing Pdcd4 as a haploinsufficient tumor suppressor.\",\n      \"method\": \"In vivo phosphorylation, co-immunoprecipitation, ubiquitylation assay, proteasome inhibitor treatment, Pdcd4-deficient mouse model\",\n      \"journal\": \"Cancer Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal biochemical methods plus in vivo mouse genetics, independently corroborating the S6K1/βTrCP axis from PMID 17053147\",\n      \"pmids\": [\"18296647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"PDCD4 interferes with JNK-mediated phosphorylation of c-Jun by interacting with c-Jun directly, blocking JNK access without globally suppressing JNK activity. Additionally, PDCD4 blocks recruitment of the coactivator p300 by c-Jun, thereby suppressing AP-1-dependent transcription.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, reporter gene assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and in vitro kinase assay with functional reporter readout; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"15334056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PDCD4 suppresses translation of p53 mRNA via its eIF4A-interacting activity and the structured 5' UTR of p53 mRNA. PDCD4 was shown to associate with p53 mRNA, inhibit its translation in a manner dependent on eIF4A interaction and the p53 5' UTR stem-loop, and DNA-damaging agents decrease PDCD4 levels, thereby de-repressing p53 translation.\",\n      \"method\": \"RNA immunoprecipitation, translation reporter assay (5' UTR-luciferase), eIF4A-binding mutant analysis, western blot\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — RNA-IP, 5' UTR reporter assay, and eIF4A-binding mutant together demonstrate mechanism; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"22033922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"p70S6K1 phosphorylates PDCD4, and this phosphorylation (together with eIF4B phosphorylation) is required to sustain global protein synthesis rates downstream of mTORC1, in addition to the 4E-BP/eIF4E axis.\",\n      \"method\": \"Genetic/pharmacological inhibition of mTORC1 and p70S6K1, protein synthesis measurement (35S-methionine incorporation), cell-based assays in 4E-BP1/2 double-knockout MEFs and fasted rat liver\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis-type analysis with genetic knockouts and pharmacological inhibitors, multiple readouts; single lab\",\n      \"pmids\": [\"23105104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PDCD4 inhibits translation of Sin1 (MAPKAP1) mRNA via its eIF4A-binding MA-3 domains in a 5' UTR-dependent manner, thereby suppressing mTORC2 kinase activity and reducing Snail expression and colon cancer cell invasion. The eIF4A-binding mutant Pdcd4(D253A,D418A) failed to inhibit Sin1 translation or invasion.\",\n      \"method\": \"5' UTR-luciferase reporter assay, eIF4A-binding mutant analysis, polysome profiling, Pdcd4 KO cell lines, invasion assay, eIF4A inhibitor (silvestrol)\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — 5' UTR reporter, eIF4A-binding mutant, eIF4A pharmacological inhibitor, and KO rescue all converge on same mechanism; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"28692058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"PDCD4 interacts with ribosomal protein S13 (RPS13) in in vitro binding assays, co-localizes with polysome fractions, and interacts with eIF4G (by GST pulldown) but not eIF4E, suggesting PDCD4 modulates eIF4G-dependent translation in senescent fibroblasts.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding assay (GST pulldown), sucrose gradient fractionation (polysome sedimentation)\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — GST pulldown and polysome fractionation confirm interaction and localization; single lab, two orthogonal methods\",\n      \"pmids\": [\"12054647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SKP2 promotes PDCD4 phosphorylation, ubiquitination, and proteasomal degradation. Reciprocal Co-IP and mass spectrometry confirmed direct interaction between SKP2 and PDCD4. SKP2 promotes breast cancer cell proliferation and radiation resistance through PDCD4 suppression.\",\n      \"method\": \"Affinity-purification mass spectrometry, reciprocal Co-IP, ubiquitination assay, SKP2 stable overexpression/knockdown, in vitro and in vivo tumor models\",\n      \"journal\": \"Journal of Experimental & Clinical Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus MS identification and in vitro ubiquitination assay; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"30760284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DTL (a CUL4-DDB1 associated factor) interacts with PDCD4 and promotes its ubiquitin-dependent proteasomal degradation. Co-IP, immunofluorescence co-localization, and in vitro ubiquitination assays confirmed DTL as a novel E3 ligase substrate adaptor for PDCD4.\",\n      \"method\": \"Affinity-purification mass spectrometry, Co-IP, immunofluorescence, in vitro ubiquitination assay, functional proliferation/invasion assays\",\n      \"journal\": \"Journal of Experimental & Clinical Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — AP-MS, Co-IP, in vitro ubiquitination, and rescue experiments; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"31409387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IBtkα forms a CRL3(IBTK) complex and ubiquitylates PDCD4 for proteasomal degradation. IBtkα was identified as a PDCD4 interactor; serum-induced PDCD4 degradation required both IBtkα and Cul3. IBtkα depletion caused PDCD4 accumulation and decreased translation of Bcl-xL mRNA.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitylation assay, RNAi knockdown, luciferase translation reporter assay\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitylation assay, and functional translation reporter; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"25882842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Pdcd4 knockdown in HeLa cells by stable shRNA leads to increased expression of p21(Waf1/Cip1) and other p53-regulated genes. Reporter gene studies show Pdcd4 interferes with p53-mediated transactivation. Knockdown cells show decreased apoptosis and increased survival after UV irradiation.\",\n      \"method\": \"Stable shRNA knockdown, reporter gene assay (p53-responsive promoters), UV irradiation survival assay, western blot\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — stable KD, reporter assay, and functional survival readout; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"18427550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PDCD4 inhibits autophagy in multiple cell types in vitro and in vivo by suppressing the expression of ATG5 and the formation of the ATG12-ATG5 complex. The MA-3 domains of PDCD4 are required for this inhibitory activity.\",\n      \"method\": \"PDCD4 overexpression/knockdown, autophagy flux assays (LC3 conversion, p62), ATG5 expression analysis, domain mutant analysis, in vivo xenograft\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO/KD plus domain mutant analysis with multiple autophagy readouts; single lab\",\n      \"pmids\": [\"23486359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Pdcd4 knockdown increases MAP4K1 expression and phospho-c-Jun levels via a β-catenin/Tcf4-dependent upregulation of c-Myc, which directly binds the MAP4K1 promoter at -536 bp (confirmed by ChIP), thereby activating JNK/AP-1 signaling and tumor cell invasion.\",\n      \"method\": \"siRNA knockdown, ChIP assay, promoter mutation analysis, dominant-negative Tcf4 overexpression, AP-1 reporter assay\",\n      \"journal\": \"Biochimica et Biophysica Acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, promoter mutation, epistasis by DN-Tcf4, and reporter assay; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"22801218\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SRSF3 represses PDCD4 protein expression through two coordinated mechanisms: (1) repressing alternative splicing and nuclear export of minor pdcd4 mRNA isoforms, and (2) repressing translation of the major pdcd4 mRNA isoform. Knockdown of SRSF3 increased PDCD4 protein levels in SW480 colon cancer cells.\",\n      \"method\": \"SRSF3 knockdown, mRNA isoform analysis (RT-PCR), nuclear/cytoplasmic fractionation, translation assay\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with multiple mechanistic readouts (splicing, export, translation); single lab\",\n      \"pmids\": [\"26773498\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PDCD4 promotes hepatocellular lipid accumulation by negatively regulating PPARα expression and PPARα-dependent peroxisomal β-oxidation genes (Acox1-3). Pdcd4 knockout suppressed FFA-induced lipid accumulation; rescue experiments confirmed the PPARα pathway is required.\",\n      \"method\": \"Pdcd4 knockout (lentivirus), Pdcd4 overexpression, lipid accumulation assay, gene expression analysis (RT-PCR and western blot), PPARα knockdown rescue experiment\",\n      \"journal\": \"Molecular and Cellular Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO and rescue with PPARα knockdown, multiple readouts; single lab\",\n      \"pmids\": [\"35051553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The RNA-binding proteins La and HuR cooperatively bind the 3' UTR of PDCD4 mRNA and counteract miR-21-mediated translation repression. LPS causes nuclear-cytoplasmic translocation of HuR and increases cellular La expression; their cooperative binding enhances PDCD4 expression, reduces proliferation, and promotes apoptosis.\",\n      \"method\": \"RNA immunoprecipitation, translation reporter assay, nuclear-cytoplasmic fractionation, co-transfection of La and HuR, cell proliferation and apoptosis assays\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-IP and reporter assay with functional readouts; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"33288677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"During mitotic arrest, mTORC1 activity is dramatically reduced (due to raptor phosphorylation), leading to PDCD4 stabilization and consequent inhibition of eIF4A, which promotes cell death. A non-phosphorylatable raptor mutant reactivates mTORC1, degrades PDCD4, and reduces Taxol cytotoxicity; pharmacological eIF4A inhibition rescues Taxol sensitivity in resistant cells.\",\n      \"method\": \"Non-phosphorylatable raptor mutant expression, mTORC1 activity assay, Taxol cytotoxicity assay, eIF4A inhibitor (silvestrol/rocaglamide), PDCD4 western blot during mitotic arrest\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutant rescue and pharmacological intervention with functional readouts; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"33027666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Pdcd4 deficiency in macrophages enhanced lipoautophagy (autophagy-mediated lipid degradation), prevented foam cell formation in vitro, and reduced atherosclerotic lesions in high-fat-fed ApoE-KO mice. Bone marrow transplantation confirmed that PDCD4-mediated autophagy in hematopoietic cells drives atherosclerosis.\",\n      \"method\": \"Pdcd4 knockout mouse, bone marrow transplantation, autophagy flux assay, foam cell formation assay, in vivo atherosclerosis model (ApoE-KO + HFD)\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with bone marrow transplantation and in vivo disease model; single lab\",\n      \"pmids\": [\"26775706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Pdcd4 deficiency accelerated colitis and colitis-associated colorectal cancer in mice via upregulation of IL-6 and enhanced activation of the STAT3 signaling pathway. Blockade of IL-6/STAT3 with sgp130Fc reversed the pro-proliferative effect of Pdcd4 deficiency in vivo.\",\n      \"method\": \"Pdcd4 knockout mouse (DSS/AOM colitis-CRC model), cytokine ELISA, western blot, BrdU incorporation, sgp130Fc treatment\",\n      \"journal\": \"Inflammatory Bowel Diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with in vivo rescue by pathway blockade; single lab, multiple readouts\",\n      \"pmids\": [\"26891257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Microglial Pdcd4 promotes neuroinflammatory responses by inhibiting Daxx-mediated PPARγ nuclear translocation, thereby suppressing anti-inflammatory IL-10 expression. Microglial conditional Pdcd4 knockout protected against LPS-induced microglial hyperactivation and depressive-like behavior; this protection was abolished by intracerebroventricular IL-10Rα neutralizing antibody.\",\n      \"method\": \"Microglial conditional Pdcd4 knockout mouse, LPS neuroinflammation model, PPARγ nuclear translocation assay, IL-10 ELISA, behavioral assays, neutralizing antibody injection\",\n      \"journal\": \"Journal of Neuroinflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with in vivo pathway rescue (IL-10 neutralization); single lab, multiple orthogonal readouts\",\n      \"pmids\": [\"38822367\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"BCR-ABL1 in CML activates STAT5, which binds the miR-21 promoter and drives miR-21 expression; miR-21 in turn suppresses PDCD4 protein. This phosphoSTAT5-miR-21-PDCD4 axis also operates in AML cells driven by FLT3-ITD. PDCD4 was identified as a STAT5/miR-21 target by proteomics.\",\n      \"method\": \"miRNA microarray, miR-21 promoter STAT binding site analysis, proteomic identification of PDCD4, BCR-ABL1 and FLT3-ITD inhibitor experiments, CML primary CD34+ cell validation\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway epistasis established with kinase inhibitors, proteomics, and primary cells; single lab\",\n      \"pmids\": [\"29100302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The chicken Pdcd4 gene is a direct transcriptional target of the v-Myb oncogene, identified by differential display in v-Myb-inducible myelomonocytic cells. This represents the first evidence of direct transcriptional regulation of Pdcd4 by an oncogene.\",\n      \"method\": \"Differential display, v-Myb inducible cell system, promoter/transcriptional analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — differential display with inducible system, single lab, limited mechanistic follow-up at protein level\",\n      \"pmids\": [\"11313950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"PDCD4 (H731) protein inhibits tumor promoter-induced neoplastic transformation. Antisense-mediated reduction of Pdcd4 in transformation-resistant P- cells converted them to a transformation-sensitive phenotype; this was reversed by re-expression of Pdcd4 sense sequence.\",\n      \"method\": \"Stable antisense transfection, anchorage-independent colony formation assay, sense rescue experiment\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function antisense with gain-of-function rescue in defined genetic variant cell system; single lab\",\n      \"pmids\": [\"10570194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PDCD4 overexpression in lung cancer cells increased Keap1 expression, which suppressed the p62-Nrf2 pathway. PDCD4-overexpressing cells showed increased apoptosis, inhibited proliferation, and reduced EMT markers. This was confirmed in xenograft models.\",\n      \"method\": \"Stable PDCD4 overexpression, western blot, apoptosis assay, xenograft tumor model\",\n      \"journal\": \"American Journal of Cancer Research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — overexpression plus downstream pathway analysis but limited mechanistic detail on direct PDCD4-Keap1 interaction; single lab\",\n      \"pmids\": [\"32195018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"EIF3H interacts with PDCD4 (confirmed by Co-IP and immunofluorescent co-localization). PDCD4 overexpression reduces EIF3H mRNA and protein levels by suppressing c-Jun-induced EIF3H transcription. EIF3H promotes EMT and LUAD cell metastasis, which is abrogated by PDCD4.\",\n      \"method\": \"Co-immunoprecipitation combined with mass spectrometry, immunofluorescent co-localization, PDCD4 overexpression, western blot, migration/invasion assays, xenograft model\",\n      \"journal\": \"American Journal of Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP/MS and co-localization plus functional rescue; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"32064160\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PDCD4 is a tumor suppressor that directly inhibits eIF4A helicase activity by binding at the mRNA entry channel of the 40S ribosomal subunit (via its NTD in the mRNA channel and CTD contacting eIF4A), thereby blocking translation of mRNAs with structured 5' UTRs (including p53, Sin1/MAPKAP1); its levels are regulated by S6K1/Akt-mediated phosphorylation at Ser67 (and Ser457), which triggers polyubiquitylation via SCF(βTrCP), CRL3(IBTK), DTL, or SKP2 E3 ligase complexes and proteasomal degradation; PDCD4 additionally suppresses AP-1 transcription by blocking JNK-mediated c-Jun phosphorylation and p300 recruitment, modulates autophagy by suppressing ATG5 expression, and regulates inflammatory signaling through the IL-6/STAT3 and MAPK/NF-κB pathways.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PDCD4 is a tumor suppressor that restrains cap-dependent translation initiation and inflammatory and oncogenic signaling, with loss-of-function promoting neoplastic transformation [#24, #3]. Mechanistically, PDCD4 binds the 40S small ribosomal subunit through its C-terminal domain contacting eIF4A at the mRNA entry site while its N-terminal domain inserts into the mRNA channel and decoding site, blocking the eIF4F-independent role of eIF4A during 5' UTR scanning [#0]. Through eIF4A engagement it selectively suppresses translation of mRNAs bearing structured 5' UTRs, including p53 and Sin1/MAPKAP1, the latter linking PDCD4 to mTORC2 activity, Snail expression, and cancer cell invasion [#5, #7]. PDCD4 abundance is controlled by mitogenic signaling: S6K1 and Akt phosphorylate it at Ser67 (and Ser457), creating a phosphodegron that recruits SCF(βTrCP) for polyubiquitylation and proteasomal degradation, a step potentiated by MEK-ERK signaling [#1, #2, #3]; additional E3 ligase adaptors SKP2, DTL (CUL4-DDB1), and CRL3(IBTK) likewise target PDCD4 for turnover [#9, #10, #11]. Independent of translation, PDCD4 suppresses AP-1 transcription by binding c-Jun directly to block JNK-mediated phosphorylation and p300 coactivator recruitment [#4], and it inhibits autophagy through its MA-3 domains by suppressing ATG5 expression and ATG12-ATG5 complex formation [#13]. In vivo, PDCD4 modulates inflammatory and metabolic disease via IL-6/STAT3 signaling in colitis-associated cancer and Daxx/PPARγ/IL-10 signaling in microglia [#20, #21].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established PDCD4 as a functional suppressor of neoplastic transformation, defining the gene's tumor-suppressor identity before its molecular mechanism was known.\",\n      \"evidence\": \"Antisense knockdown converting transformation-resistant cells to sensitive, reversed by sense rescue, in a defined cell system\",\n      \"pmids\": [\"10570194\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular mechanism of suppression identified\", \"Effect shown in one engineered cell variant system\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identified PDCD4 as a direct transcriptional target of an oncogene, placing it downstream of oncogenic transcription programs.\",\n      \"evidence\": \"Differential display in v-Myb-inducible avian myelomonocytic cells\",\n      \"pmids\": [\"11313950\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Limited mechanistic follow-up at the protein level\", \"Avian system; human relevance not established here\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"First connected PDCD4 to the translation apparatus, showing physical association with ribosomal and initiation components.\",\n      \"evidence\": \"Yeast two-hybrid and GST pulldown with RPS13 and eIF4G, polysome sedimentation in senescent fibroblasts\",\n      \"pmids\": [\"12054647\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of eIF4G binding not resolved\", \"Did not establish eIF4A as the key target\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined Akt as an upstream kinase regulating PDCD4 localization and AP-1 suppression, linking PI3K-Akt signaling to PDCD4 inactivation.\",\n      \"evidence\": \"In vitro and in vivo kinase assays at Ser67/Ser457, subcellular imaging, AP-1 luciferase reporter\",\n      \"pmids\": [\"16357133\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not identify the degradation machinery downstream of phosphorylation\", \"Single lab\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Resolved the degradation mechanism: S6K1-mediated Ser67 phosphorylation triggers SCF(βTrCP)-dependent ubiquitylation and turnover, coupling mitogen signaling to relief of translational repression.\",\n      \"evidence\": \"In vivo phosphorylation, Co-IP, ubiquitylation assay, phospho-resistant mutant with translation reporter and cell-size/cycle readouts\",\n      \"pmids\": [\"17053147\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the structured-UTR mRNA targets not fully enumerated\", \"Did not address additional E3 ligases\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Confirmed PDCD4 as a haploinsufficient tumor suppressor in vivo and integrated MEK-ERK with the Akt/S6K1-βTrCP degradation axis under tumor-promoter stimulation.\",\n      \"evidence\": \"Pdcd4-haploinsufficient mice, Co-IP, ubiquitylation, proteasome inhibition under TPA treatment\",\n      \"pmids\": [\"18296647\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise division of labor between Akt and p70S6K phosphosites not fully dissected\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed PDCD4 interferes with p53-mediated transactivation, expanding its role to p53 pathway and DNA-damage survival responses.\",\n      \"evidence\": \"Stable shRNA knockdown, p53-responsive reporter assays, UV survival/apoptosis readouts\",\n      \"pmids\": [\"18427550\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic basis of interference (transcriptional vs translational) not separated here\", \"Single cell line\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrated that PDCD4 represses p53 mRNA translation via eIF4A and the p53 5' UTR stem-loop, providing a specific mRNA target of its translational control.\",\n      \"evidence\": \"RNA-IP, 5' UTR-luciferase reporter, eIF4A-binding mutant, DNA-damage de-repression\",\n      \"pmids\": [\"22033922\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide scope of structured-UTR targets not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Placed PDCD4 phosphorylation within mTORC1 control of global protein synthesis, parallel to the 4E-BP/eIF4E axis.\",\n      \"evidence\": \"Genetic/pharmacological mTORC1 and p70S6K1 manipulation, 35S-methionine incorporation in 4E-BP1/2 DKO MEFs and rat liver\",\n      \"pmids\": [\"23105104\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of PDCD4 vs eIF4B to the effect not isolated\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Mapped a transcriptional arm of PDCD4 tumor suppression, showing its loss activates JNK/AP-1 via β-catenin/c-Myc-driven MAP4K1 induction.\",\n      \"evidence\": \"siRNA knockdown, ChIP at the MAP4K1 promoter, promoter mutation, DN-Tcf4 epistasis, AP-1 reporter\",\n      \"pmids\": [\"22801218\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Connection to PDCD4's translational activity not established\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified autophagy regulation as a distinct PDCD4 function, suppressing ATG5 and ATG12-ATG5 complex formation via its MA-3 domains.\",\n      \"evidence\": \"Overexpression/knockdown, LC3/p62 flux assays, ATG5 expression, domain mutants, xenograft\",\n      \"pmids\": [\"23486359\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ATG5 suppression is translational or transcriptional not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Added CRL3(IBTK) as an E3 ligase controlling PDCD4 turnover, broadening the degradation network beyond SCF(βTrCP).\",\n      \"evidence\": \"Co-IP, ubiquitylation assay, RNAi, Bcl-xL 5' UTR translation reporter\",\n      \"pmids\": [\"25882842\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phosphodependence of IBTK recognition not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed in vivo inflammatory and metabolic roles for PDCD4 through IL-6/STAT3 in colitis-associated cancer and macrophage lipoautophagy in atherosclerosis.\",\n      \"evidence\": \"Pdcd4 KO mice in DSS/AOM colitis-CRC and ApoE-KO/HFD atherosclerosis models, bone marrow transplant, pathway blockade (sgp130Fc)\",\n      \"pmids\": [\"26891257\", \"26775706\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular target of PDCD4 in these pathways not pinpointed\", \"Tissue/cell-type-specific mechanisms partly inferred\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed PDCD4 protein levels are set post-transcriptionally by trans-acting RNA factors, with SRSF3 repressing PDCD4 splicing, export, and translation.\",\n      \"evidence\": \"SRSF3 knockdown, isoform RT-PCR, nuclear/cytoplasmic fractionation, translation assay in colon cancer cells\",\n      \"pmids\": [\"26773498\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct SRSF3 binding sites on pdcd4 mRNA not mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected PDCD4's eIF4A-dependent translational repression to mTORC2 by identifying Sin1/MAPKAP1 mRNA as a structured-UTR target controlling invasion.\",\n      \"evidence\": \"5' UTR reporter, eIF4A-binding mutant (D253A,D418A), polysome profiling, KO rescue, silvestrol\",\n      \"pmids\": [\"28692058\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality across tumor types not established\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established oncogenic kinase control of PDCD4 via the STAT5-miR-21 axis in leukemia, explaining PDCD4 loss downstream of BCR-ABL1 and FLT3-ITD.\",\n      \"evidence\": \"miRNA microarray, STAT binding site analysis on miR-21 promoter, proteomics, kinase inhibitor experiments, primary CD34+ cells\",\n      \"pmids\": [\"29100302\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct miR-21 binding on PDCD4 mRNA not shown in this study\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Expanded the E3 ligase repertoire degrading PDCD4 to SKP2 and DTL, linking PDCD4 turnover to proliferation and radiation resistance.\",\n      \"evidence\": \"AP-MS, reciprocal Co-IP, ubiquitination assays, overexpression/knockdown, in vitro and in vivo tumor models\",\n      \"pmids\": [\"30760284\", \"31409387\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Hierarchy and redundancy among βTrCP, SKP2, DTL, IBTK ligases not resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed PDCD4 stability is a node controlling chemotherapy response, with mTORC1 inactivation during mitotic arrest stabilizing PDCD4 to inhibit eIF4A and promote death.\",\n      \"evidence\": \"Non-phosphorylatable raptor mutant, mTORC1 activity assays, Taxol cytotoxicity, eIF4A inhibitors during mitotic arrest\",\n      \"pmids\": [\"33027666\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific PDCD4-controlled mRNAs driving death not identified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified RNA-binding proteins La and HuR as positive regulators of PDCD4 by counteracting miR-21 repression at the 3' UTR.\",\n      \"evidence\": \"RNA-IP, translation reporter, fractionation, La/HuR co-transfection, proliferation/apoptosis assays under LPS\",\n      \"pmids\": [\"33288677\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interplay with the STAT5-miR-21 leukemia axis not integrated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended PDCD4 function to metabolism and additional signaling outputs, including PPARα-dependent β-oxidation and Keap1/Nrf2 and EIF3H/c-Jun control.\",\n      \"evidence\": \"Pdcd4 KO/overexpression with PPARα rescue (hepatocytes), overexpression with Co-IP/MS for EIF3H and Keap1 readouts, xenografts\",\n      \"pmids\": [\"35051553\", \"32064160\", \"32195018\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between PDCD4 and PPARα/Keap1 not demonstrated\", \"Keap1 finding is overexpression-based and low confidence\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined a microglia-specific neuroinflammatory mechanism in which PDCD4 suppresses Daxx-mediated PPARγ nuclear translocation and IL-10, linking it to depressive-like behavior.\",\n      \"evidence\": \"Microglial conditional Pdcd4 KO, LPS model, PPARγ translocation and IL-10 readouts, IL-10Rα neutralization rescue\",\n      \"pmids\": [\"38822367\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct PDCD4-Daxx interaction not biochemically resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Provided the structural basis for translational repression, showing PDCD4 bridges eIF4A and the 40S mRNA channel to block eIF4F-independent eIF4A scanning function.\",\n      \"evidence\": \"Cryo-EM of multiple PDCD4-40S-initiation factor complexes, quantitative binding, in vitro translation\",\n      \"pmids\": [\"39117603\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How phosphorylation alters ribosome binding not structurally captured\", \"Selectivity for specific structured 5' UTRs not structurally explained\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the diverse degradation, RNA-regulatory, and signaling inputs are integrated to set PDCD4 levels and select among its translational versus transcriptional and metabolic outputs in a given cell context remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified hierarchy of the βTrCP/SKP2/DTL/IBTK ligases established\", \"Genome-wide map of PDCD4-repressed structured-UTR mRNAs lacking\", \"Context determinants of translational vs transcriptional roles unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [5, 7, 11]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [0, 5, 7]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [4, 12, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [0, 8]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-72613\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 5, 7]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [4, 12, 14]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [13, 19]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2, 3, 18]}\n    ],\n    \"complexes\": [\n      \"PDCD4-40S ribosomal subunit complex\"\n    ],\n    \"partners\": [\n      \"EIF4A\",\n      \"EIF4G1\",\n      \"RPS13\",\n      \"JUN\",\n      \"BTRC\",\n      \"SKP2\",\n      \"DTL\",\n      \"IBTK\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}