{"gene":"RPL11","run_date":"2026-06-10T06:43:37","timeline":{"discoveries":[{"year":2015,"finding":"Crystal structure of human MDM2 complexed with RPL11 at 2.4 Å resolution reveals that MDM2 extensively interacts with RPL11 through an acidic domain and two zinc fingers; formation of the complex induces substantial conformational changes in both proteins; MDM2 mimics 28S rRNA binding to RPL11; the C4 zinc finger of MDM2 determines RPL11 binding but not binding to MDMX; MDM2 mutants unable to bind RPL11 fail to induce p53 activation in cells.","method":"X-ray crystallography (2.4 Å), structure-guided mutagenesis, cell-based p53 activation assays","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic-resolution structure with mutagenesis validation in cells, multiple orthogonal methods in a single rigorous study","pmids":["26220995"],"is_preprint":false},{"year":2011,"finding":"PICT1 (GLTSCR2) binds RPL11 in the nucleolus and retains it there; loss of PICT1 releases RPL11 from nucleoli, increasing RPL11-MDM2 binding, blocking MDM2-mediated ubiquitination of p53, and causing p53-dependent G1 arrest and apoptosis even without DNA damage.","method":"Co-immunoprecipitation, Pict1-knockout mice and ES cells, nucleolar fractionation/immunofluorescence, ubiquitination assay","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, genetic knockout model, multiple orthogonal methods, replicated in vivo and in vitro","pmids":["21804542"],"is_preprint":false},{"year":2009,"finding":"Impairment of 40S ribosome biogenesis (via rpS6 depletion) does not disrupt nucleolar integrity yet still induces p53 via RPL11; the mechanism involves selective upregulation of 5'-TOP mRNA translation (including rpL11 mRNA) despite global translational suppression, increasing free RPL11 protein.","method":"siRNA knockdown, mouse liver partial hepatectomy model, p53 reporter assays, polysome fractionation","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (animal model, siRNA, polysome fractionation), replicated in culture and in vivo","pmids":["19287375"],"is_preprint":false},{"year":2011,"finding":"RPL11 is rapidly recruited to promoter sites of p53-regulated genes upon nucleolar stress (actinomycin D); RPL11 is required for recruitment of p300/CBP co-activators and p53 K382 acetylation; NEDDylation of RPL11 and its direct binding to MDM2 are critical for promoter recruitment; binding of RPL11 to MDM2 at the promoter relieves MDM2-mediated transcriptional repression of p53.","method":"Chromatin immunoprecipitation (ChIP), co-immunoprecipitation, siRNA knockdown, promoter reporter assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP and Co-IP with functional mutagenesis, multiple orthogonal methods in one study","pmids":["22081073"],"is_preprint":false},{"year":2011,"finding":"RPL11 interacts with the zinc finger domain of MDM2 via hydrophilic (basic) residues; hydrogen-deuterium exchange mass spectrometry and circular dichroism confirmed direct contact between RPL11 and the MDM2 zinc finger; single mutations of non-cysteine residues in the zinc finger disrupt binding; basic residues in RPL11 are essential for stable MDM2 binding and suppression of MDM2 E3 ligase activity toward p53.","method":"In vitro pull-down, hydrogen-deuterium exchange MS, circular dichroism, computational modeling, mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical reconstitution with mutagenesis and multiple biophysical methods, single lab","pmids":["21903592"],"is_preprint":false},{"year":2007,"finding":"Assembly factors Rpf2 and Rrs1 are required to recruit rpL11 (along with rpL5 and 5S rRNA) into nascent 90S preribosomal particles; in the absence of Rpf2/Rrs1, rpL11 fails to associate with pre-rRNPs, 27SB pre-rRNA processing is blocked, and abortive 66S particles are prematurely released from the nucleolus.","method":"In vitro binding assays, co-immunoprecipitation, pre-rRNA processing analysis, genetic depletion in yeast","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding assays plus genetic depletion with multiple biochemical readouts, replicated across methods","pmids":["17938242"],"is_preprint":false},{"year":2013,"finding":"Loss of RPL5/RPL11 abrogates 60S ribosome biogenesis and translational capacity but, unlike loss of other 60S ribosomal proteins, does NOT trigger a p53-dependent cell cycle checkpoint; instead, depletion reduces ribosome content and suppresses cyclin accumulation at the translational level, impairing cell cycle progression without arrest.","method":"siRNA knockdown in primary human lung fibroblasts, flow cytometry, polysome fractionation, cyclin protein/mRNA measurements","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean KD with multiple cellular and biochemical readouts, rigorous controls comparing RPL5/RPL11 to other RPs","pmids":["24061479"],"is_preprint":false},{"year":2016,"finding":"GRWD1 physically interacts with RPL11; overexpression of GRWD1 competitively inhibits the RPL11-MDM2 interaction via its N-terminal acidic domain, alleviating RPL11-mediated suppression of MDM2 ubiquitin ligase activity toward p53; silencing GRWD1 enhances p53 induction by nucleolar stress.","method":"Co-immunoprecipitation, MDM2 ubiquitin ligase assay, siRNA/overexpression, immunofluorescence","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, in vitro ubiquitination assay, domain mapping, multiple orthogonal methods","pmids":["27856536"],"is_preprint":false},{"year":2018,"finding":"RPL11 is covalently modified by SUMO1 and SUMO2; SUMOylation negatively modulates NEDDylation of RPL11; SUMOylation promotes RPL11 translocation out of the nucleolus; the SUMO-conjugating enzyme Ubc9 is required for RPL11-mediated p53 activation; SUMOylation is triggered by ribosomal stress.","method":"Co-immunoprecipitation, immunofluorescence, siRNA knockdown, SUMO/NEDD8 modification assays","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and localization with functional assays, single lab, multiple methods","pmids":["30024791"],"is_preprint":false},{"year":2014,"finding":"Akt/mTORC1-mediated phosphorylation of PRAS40 at T246 and S221 promotes nuclear-specific association of PRAS40 with RPL11; silencing PRAS40 induces p53 upregulation in an RPL11-dependent manner; PRAS40T246A (RPL11-binding-null mutant) cannot rescue this effect; PRAS40 negatively regulates the RPL11-HDM2-p53 pathway and suppresses p53-mediated cellular senescence.","method":"Co-immunoprecipitation, siRNA knockdown, phospho-site mutagenesis, cellular senescence assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with mutagenesis and functional rescue, single lab","pmids":["24704832"],"is_preprint":false},{"year":2020,"finding":"RPS27a directly binds RPL11 (confirmed by GST pull-down); RPS27a knockdown weakens RPS27a-RPL11 interaction and enhances RPL11-MDM2 binding, thereby inhibiting MDM2-mediated ubiquitination and degradation of p53; p53 stabilization by RPS27a knockdown is RPL11-dependent.","method":"GST pull-down, co-immunoprecipitation, in vitro ubiquitination assay, siRNA knockdown","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vitro binding and ubiquitination assay plus Co-IP, single lab","pmids":["35073964"],"is_preprint":false},{"year":2020,"finding":"MeCP2 represses RPL11 (and RPL5) transcription by binding to their promoter regions; RPL11 overexpression suppresses breast cancer cell proliferation and induces apoptosis; RPL11 suppresses MDM2-mediated ubiquitination of p53 through direct MDM2 binding.","method":"ChIP assay, co-immunoprecipitation, overexpression/knockdown, ubiquitination assay","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for promoter binding, Co-IP for MDM2 interaction, functional rescue, single lab","pmids":["32483207"],"is_preprint":false},{"year":2021,"finding":"RRS1 retains RPL11 in the nucleolus; RRS1 overexpression attenuates ribosomal stress by preventing RPL11 release, potentiating MDM2-mediated ubiquitination and degradation of p53; RRS1 knockdown releases RPL11 from the nucleolus, increases RPL11-MDM2 interaction, and activates p53.","method":"Co-immunoprecipitation, immunofluorescence/nucleolar fractionation, ubiquitination assay, in vitro and in vivo tumor growth assays","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and localization with functional assays in vitro and in vivo, single lab","pmids":["34433556"],"is_preprint":false},{"year":2022,"finding":"miR-101-3p targets USP47, a deubiquitinase for RPL11; USP47-mediated deubiquitination of RPL11 retains it in the nucleolus; inhibition of USP47 by miR-101-3p promotes RPL11 translocation to the nucleoplasm, enhancing RPL11-MDM2 interaction and p53 stabilization; catalytically inactive USP47 cannot rescue these effects.","method":"Co-immunoprecipitation, immunofluorescence, miRNA overexpression, USP47 catalytic mutant","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with localization and catalytic mutant controls, single lab","pmids":["35205710"],"is_preprint":false},{"year":2005,"finding":"RPL11 directly interacts with PPARα within the D-domain (hinge region) of PPARα, confirmed by yeast two-hybrid, mammalian two-hybrid, and in vitro pull-down; RPL11 co-transfection produces ligand-dependent inhibition of PPARα transcriptional activity associated with decreased PPRE DNA binding; RPL11 does not interact with PPARβ or PPARγ.","method":"Yeast two-hybrid, mammalian two-hybrid, GST pull-down, co-transfection reporter assay, siRNA","journal":"Toxicological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple binding assays with functional transcription readout, single lab","pmids":["16280383"],"is_preprint":false},{"year":2015,"finding":"Down-regulation of 5S rRNA (by miR-150/miR-383) intensifies the interaction between rpL11 and c-Myc, attenuating c-Myc oncogenic transcriptional activity and inhibiting esophageal squamous carcinoma cell proliferation.","method":"Co-immunoprecipitation, miRNA overexpression, siRNA knockdown, cell proliferation assays","journal":"FEBS letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP result, single lab, limited mechanistic follow-up","pmids":["26606907"],"is_preprint":false},{"year":2023,"finding":"RBM10 directly binds to c-Myc and promotes its ubiquitin-dependent degradation; RPL11 (uL5) and RPL5 (uL18) directly bind RBM10 and boost this c-Myc suppression; cancer-derived mutant RBM10-I316F fails to bind RPL11/RPL5, abrogating c-Myc inactivation.","method":"Co-immunoprecipitation, ubiquitination assay, domain-mapping mutagenesis, cell growth/proliferation assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, ubiquitination assay, cancer mutant validation, single lab","pmids":["38032932"],"is_preprint":false},{"year":2013,"finding":"v-erbA oncogene expression generates ribosomes devoid of RPL11 in avian erythroid progenitors; immunoprecipitation confirmed ribosome-associated RPL11 is reduced; these specialized RPL11-deficient ribosomes are associated with altered translational efficiency of specific mRNAs (e.g., HSP70).","method":"2D-DIGE proteomics, co-immunoprecipitation of ribosomes, polyribosome fractionation","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal proteomic methods plus polysome fractionation, single lab","pmids":["23563180"],"is_preprint":false},{"year":2015,"finding":"Rpl11 heterozygous deletion in adult mice causes anemia with decreased erythroid progenitors and defective erythroid maturation; fibroblasts and hematopoietic tissue from heterozygous Rpl11 mice show impaired p53 activation upon ribosomal stress or DNA damage and elevated basal c-MYC levels; total/partial RPL11 loss compromises the ribosomal stress-p53 checkpoint.","method":"Conditional knockout mice, bone marrow transplantation, p53 activation assays, flow cytometry","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic mouse model with transplantation experiment, multiple cellular readouts, multiple orthogonal methods","pmids":["26489471"],"is_preprint":false},{"year":2022,"finding":"RPL11 haploinsufficiency in adult mice activates p53 in hematopoietic tissues and impedes erythroid precursor differentiation, causing anemia; reducing p53 dosage (p53 heterozygous deletion) rescues erythropoietic precursor differentiation and restores normal red blood cell levels; introducing an RP-binding mutation in MDM2 (blocking RPL11-MDM2 interaction) prevents p53 activation and rescues the anemia, establishing the RP-MDM2-p53 pathway as the mechanistic basis.","method":"Conditional knockout mice, p53/MDM2 RP-binding mutant knock-in, flow cytometry, genetic epistasis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis in vivo with multiple allele combinations, direct pathway placement confirmed by MDM2 mutant knock-in","pmids":["36435197"],"is_preprint":false},{"year":2021,"finding":"RPL11 deficiency in HEK293T cells causes an almost proportional decrease in 80S ribosomes; transcriptomic analysis shows hundreds of differentially expressed genes at transcriptome and translatome levels; up-regulated genes are associated with rRNA processing, splicing, translation and DNA repair; down-regulated genes are membrane protein genes; genes with altered translational efficiency depend on coding sequence length.","method":"RNA interference, RNA-seq of total and polysome-associated mRNA, ribosome fractionation","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi with parallel transcriptome/translatome sequencing, single lab","pmids":["34948282"],"is_preprint":false},{"year":2014,"finding":"Perturbation of RNA Pol I transcription (via HEATR1 depletion) causes nucleolar disruption and activates p53 in an RPL5/RPL11-dependent manner; p53-dependent cell cycle arrest upon HEATR1 depletion is rescued by co-depletion of RPL5/RPL11.","method":"siRNA knockdown, immunofluorescence, cell cycle analysis, epistasis by double knockdown","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis by double knockdown with cell cycle readout, single lab","pmids":["29143558"],"is_preprint":false},{"year":2016,"finding":"PICT-1 (GLTSCR2) is phosphorylated by ATM at S233/T289 in response to DNA damage; this phosphorylation promotes PICT-1 degradation and releases RPL11 from the nucleolus to the nucleoplasm; released RPL11 increases binding to MDM2 and promotes p53 accumulation and apoptosis in an ATM-dependent manner.","method":"Co-immunoprecipitation, immunofluorescence, phospho-site mutagenesis (S233A/T289A and S233D/T289D), ATM inhibitor treatment","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phospho-site mutagenesis with functional consequence, Co-IP, localization, single lab","pmids":["27829214"],"is_preprint":false},{"year":2020,"finding":"The lncRNA PiHL sequesters RPL11 from MDM2 by enhancing GRWD1-RPL11 complex formation; this promotes MDM2-mediated p53 ubiquitination and degradation, reducing p53 activity in colorectal cancer cells.","method":"Co-immunoprecipitation, RNA immunoprecipitation, ubiquitination assay, siRNA knockdown","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and RNA-IP with ubiquitination assay, single lab","pmids":["31903119"],"is_preprint":false}],"current_model":"RPL11 (uL5) is an integral component of the 60S ribosomal subunit that is recruited into nascent ribosomes by assembly factors Rpf2/Rrs1; under ribosomal or nucleolar stress, free RPL11 translocates from the nucleolus to the nucleoplasm—a process regulated by PICT1/GLTSCR2 retention, SUMO/NEDD8 modification, and USP47-mediated deubiquitination—where it directly binds the acidic domain and C4 zinc finger of MDM2 (as revealed by a 2.4 Å crystal structure), blocking MDM2's E3 ubiquitin ligase activity toward p53 and simultaneously recruiting RPL11 to p53 target gene promoters to relieve MDM2-mediated transcriptional repression; this RPL11-MDM2-p53 checkpoint is the mechanistic basis for anemia in RPL11-haploinsufficient Diamond-Blackfan anemia mouse models, and its dysregulation by oncoproteins (GRWD1, RRS1, PRAS40, MeCP2) or modification crosstalk (Akt/mTOR, ATM, NEDD8) promotes tumor progression; additionally, extra-ribosomal RPL11 inhibits PPARα transcriptional activity and suppresses c-Myc oncogenic function in cooperation with RBM10."},"narrative":{"mechanistic_narrative":"RPL11 (uL5) is a structural component of the 60S ribosomal subunit that doubles as a stress-responsive regulator of the p53 tumor-suppressor pathway [PMID:17938242, PMID:36435197]. During ribosome assembly, RPL11 is recruited together with RPL5 and 5S rRNA into nascent 90S preribosomal particles by the assembly factors Rpf2 and Rrs1, a step required for 27SB pre-rRNA processing and proper 60S maturation [PMID:17938242]; loss of RPL11 collapses 60S biogenesis and overall ribosome content, limiting translational capacity and cyclin accumulation [PMID:24061479, PMID:34948282]. Upon ribosomal or nucleolar stress, free RPL11 escapes the nucleolus and binds MDM2 directly: a 2.4 Å crystal structure shows MDM2 engaging RPL11 through its acidic domain and a C4 zinc finger, mimicking 28S rRNA binding, and MDM2 mutants unable to bind RPL11 fail to activate p53 [PMID:26220995, PMID:21903592]. This interaction blocks MDM2 E3 ubiquitin ligase activity toward p53 and additionally recruits RPL11 to p53 target promoters, where it relieves MDM2-mediated transcriptional repression and licenses p300/CBP-dependent p53 K382 acetylation [PMID:22081073]. Nucleolar release of RPL11 is gated by retention factors PICT1/GLTSCR2 and RRS1 and tuned by post-translational modification—NEDDylation promotes and is antagonized by SUMOylation, while USP47-mediated deubiquitination and ATM-driven PICT1 degradation control the free pool [PMID:21804542, PMID:34433556, PMID:22081073, PMID:30024791, PMID:35205710, PMID:27829214]. This RPL11–MDM2–p53 checkpoint is the mechanistic basis of anemia in RPL11-haploinsufficient Diamond-Blackfan anemia mouse models: erythroid differentiation defects are rescued by lowering p53 dosage or by knocking in an RP-binding-null MDM2 [PMID:26489471, PMID:36435197]. The pathway is dysregulated by oncoproteins and regulators including GRWD1, RPS27a, PRAS40, and MeCP2 that limit RPL11–MDM2 engagement [PMID:27856536, PMID:35073964, PMID:24704832, PMID:32483207]. Beyond p53, extra-ribosomal RPL11 directly inhibits PPARα transcriptional activity [PMID:16280383] and cooperates with RBM10 to promote ubiquitin-dependent degradation of c-Myc, suppressing its oncogenic function [PMID:38032932].","teleology":[{"year":2005,"claim":"Established that RPL11 acts beyond the ribosome as a direct transcriptional modulator, the first extra-ribosomal function defined for it.","evidence":"Yeast/mammalian two-hybrid, GST pull-down and reporter assays mapping RPL11 binding to the PPARα hinge (D-domain)","pmids":["16280383"],"confidence":"Medium","gaps":["Physiological context and target-gene scope of PPARα inhibition undefined","Selectivity over PPARβ/γ explained only by binding, not structurally"]},{"year":2007,"claim":"Defined how RPL11 is incorporated into the ribosome, identifying the assembly factors that load it onto pre-rRNPs.","evidence":"In vitro binding, Co-IP and pre-rRNA processing analysis with Rpf2/Rrs1 depletion in yeast","pmids":["17938242"],"confidence":"High","gaps":["Human ortholog assembly step not directly demonstrated here","Does not address the extra-ribosomal free pool"]},{"year":2009,"claim":"Resolved how impaired 40S biogenesis still signals through RPL11, showing selective 5'-TOP translation raises free RPL11 even without nucleolar disruption.","evidence":"siRNA, partial hepatectomy mouse model, p53 reporters and polysome fractionation","pmids":["19287375"],"confidence":"High","gaps":["Mechanism coupling rpS6 loss to TOP-mRNA selectivity incomplete","Direct measurement of nascent free RPL11 partitioning limited"]},{"year":2011,"claim":"Identified nucleolar retention as the upstream switch controlling RPL11 availability and the modification/promoter steps that translate stress into p53 activation.","evidence":"PICT1-knockout mice/ES cells with Co-IP and ubiquitination assays; ChIP showing RPL11 promoter recruitment and NEDDylation dependence","pmids":["21804542","22081073"],"confidence":"High","gaps":["How nucleolar release is triggered at the molecular level not fully resolved","NEDDylation site/enzyme specificity not mapped"]},{"year":2011,"claim":"Pinpointed the molecular contacts of RPL11 with the MDM2 zinc finger required to suppress its E3 ligase activity.","evidence":"In vitro pull-down, HDX-MS, circular dichroism and mutagenesis","pmids":["21903592"],"confidence":"High","gaps":["Conformational dynamics inferred biophysically, not yet structural","Stoichiometry with 5S rRNA/RPL5 not addressed"]},{"year":2013,"claim":"Distinguished RPL11/RPL5 from other ribosomal proteins by showing their loss limits translation without triggering a p53 arrest, clarifying their dual roles.","evidence":"siRNA in primary fibroblasts with flow cytometry, polysome fractionation and cyclin measurements; v-erbA-induced RPL11-deficient ribosomes by proteomics","pmids":["24061479","23563180"],"confidence":"Medium","gaps":["Why RPL11/RPL5 loss uniquely bypasses arrest mechanistically unclear","Functional consequences of RPL11-deficient specialized ribosomes for specific mRNAs limited"]},{"year":2015,"claim":"Provided the atomic-resolution basis for RPL11–MDM2 recognition, showing MDM2 mimics 28S rRNA and that a specific zinc finger dictates binding and p53 activation.","evidence":"X-ray crystallography at 2.4 Å with structure-guided mutagenesis and cell-based p53 assays","pmids":["26220995"],"confidence":"High","gaps":["Structure of full ternary RPL11/5S/MDM2 assembly not solved","Does not capture in-cell regulation by modification"]},{"year":2015,"claim":"Began linking RPL11 to c-Myc control, indicating a second extra-ribosomal tumor-suppressive axis sensitive to 5S rRNA levels.","evidence":"Co-IP and miRNA/siRNA manipulation with proliferation assays in esophageal carcinoma cells","pmids":["26606907"],"confidence":"Low","gaps":["Single Co-IP without reciprocal/structural validation","Direct vs. indirect RPL11–c-Myc contact unresolved"]},{"year":2015,"claim":"Established RPL11 haploinsufficiency as a cause of anemia via the ribosomal stress–p53 checkpoint, modeling Diamond-Blackfan anemia.","evidence":"Conditional heterozygous Rpl11 mice with bone marrow transplantation, p53 assays and flow cytometry","pmids":["26489471"],"confidence":"High","gaps":["Whether elevated basal c-MYC contributes independently to anemia not isolated","Cell-autonomy across erythroid stages partially defined"]},{"year":2016,"claim":"Identified oncoprotein and DNA-damage inputs that gate RPL11–MDM2 engagement, expanding regulation beyond ribosomal stress.","evidence":"Co-IP, ubiquitination and domain mapping for GRWD1 competition; ATM phospho-site mutagenesis driving PICT-1 degradation","pmids":["27856536","27829214"],"confidence":"Medium","gaps":["Quantitative contribution of each regulator in vivo unknown","Crosstalk hierarchy among GRWD1/PICT1/ATM not integrated"]},{"year":2018,"claim":"Defined modification crosstalk—SUMOylation antagonizing NEDDylation—as a tunable control over RPL11 nucleolar exit and p53 activation.","evidence":"Co-IP, immunofluorescence, siRNA and SUMO/NEDD8 modification assays","pmids":["30024791"],"confidence":"Medium","gaps":["SUMO acceptor sites and ligase specificity not mapped","Single-lab evidence without structural confirmation"]},{"year":2020,"claim":"Broadened the network of factors that sequester RPL11 from MDM2, including a protein partner, a transcriptional repressor, and a lncRNA scaffold.","evidence":"GST pull-down/Co-IP for RPS27a; ChIP for MeCP2 repression; RNA-IP for PiHL-GRWD1-RPL11; ubiquitination assays throughout","pmids":["35073964","32483207","31903119"],"confidence":"Medium","gaps":["Relative importance of these regulators across tissues unknown","Most rest on single-lab Co-IP/RNA-IP without reciprocal structural data"]},{"year":2021,"claim":"Confirmed RRS1 as a nucleolar retention factor for RPL11 with tumor-relevant consequences, and mapped the system-wide translational impact of RPL11 loss.","evidence":"Co-IP, fractionation, ubiquitination and in vivo tumor assays for RRS1; parallel transcriptome/translatome RNA-seq with ribosome fractionation for RPL11 deficiency","pmids":["34433556","34948282"],"confidence":"Medium","gaps":["Direct contribution of altered specific-mRNA translation to phenotype unresolved","Single-lab datasets"]},{"year":2022,"claim":"Placed the RP–MDM2–p53 axis genetically as the cause of RPL11-haploinsufficient anemia and added USP47 deubiquitination as a nucleolar-retention control.","evidence":"p53/MDM2 RP-binding mutant knock-in epistasis in mice; Co-IP, localization and USP47 catalytic-mutant rescue","pmids":["36435197","35205710"],"confidence":"High","gaps":["How USP47 ubiquitination signal is read for nucleolar retention not fully defined","Therapeutic exploitability of the MDM2 RP-binding pocket untested"]},{"year":2023,"claim":"Solidified the c-Myc suppression axis, showing RPL11 with RPL5 binds RBM10 to drive c-Myc ubiquitin-dependent degradation, disrupted by a cancer mutation.","evidence":"Reciprocal Co-IP, ubiquitination assays, domain mapping and the cancer-derived RBM10-I316F mutant in growth assays","pmids":["38032932"],"confidence":"Medium","gaps":["Whether c-Myc and p53 axes are coordinated under the same stress signals unclear","Single-lab evidence without structural detail of the RBM10 complex"]},{"year":null,"claim":"How the various nucleolar retention factors, modifications, and oncoprotein inputs are integrated to set the free RPL11 threshold, and how the ribosomal versus extra-ribosomal pools are physically partitioned, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model of the regulated RPL11/5S/RPL5 module","Quantitative dynamics of nucleolar-to-nucleoplasmic flux not measured in vivo","Coordination of p53 and c-Myc outputs under physiological stress undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[5,6,20]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,5]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,4,7]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[3,14]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[1,8,12,13,22]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[3,8,22]},{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[5,6,17]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[5,6]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[2,3,21]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[3,14]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[6,20]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[18,19]}],"complexes":["60S ribosomal subunit","RPL5-RPL11-5S rRNA module"],"partners":["MDM2","PICT1","RRS1","GRWD1","PRAS40","RPS27A","RBM10","PPARA"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P62913","full_name":"Large ribosomal subunit protein uL5","aliases":["60S ribosomal protein L11","CLL-associated antigen KW-12"],"length_aa":178,"mass_kda":20.3,"function":"Component of the ribosome, a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell (PubMed:19191325, PubMed:32669547). The small ribosomal subunit (SSU) binds messenger RNAs (mRNAs) and translates the encoded message by selecting cognate aminoacyl-transfer RNA (tRNA) molecules (PubMed:19191325, PubMed:32669547). The large subunit (LSU) contains the ribosomal catalytic site termed the peptidyl transferase center (PTC), which catalyzes the formation of peptide bonds, thereby polymerizing the amino acids delivered by tRNAs into a polypeptide chain (PubMed:19191325, PubMed:32669547). The nascent polypeptides leave the ribosome through a tunnel in the LSU and interact with protein factors that function in enzymatic processing, targeting, and the membrane insertion of nascent chains at the exit of the ribosomal tunnel (PubMed:19191325, PubMed:32669547). As part of the 5S RNP/5S ribonucleoprotein particle it is an essential component of the LSU, required for its formation and the maturation of rRNAs (PubMed:12962325, PubMed:19061985, PubMed:24120868). It also couples ribosome biogenesis to p53/TP53 activation. As part of the 5S RNP it accumulates in the nucleoplasm and inhibits MDM2, when ribosome biogenesis is perturbed, mediating the stabilization and the activation of TP53 (PubMed:24120868). Promotes nucleolar location of PML (By similarity)","subcellular_location":"Nucleus, nucleolus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P62913/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/RPL11","classification":"Common 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Dysfunction","date":"2024-09-26","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.25.614959","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47702,"output_tokens":5945,"usd":0.11614,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14595,"output_tokens":5091,"usd":0.100125,"stage2_stop_reason":"end_turn"},"total_usd":0.216265,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"Crystal structure of human MDM2 complexed with RPL11 at 2.4 Å resolution reveals that MDM2 extensively interacts with RPL11 through an acidic domain and two zinc fingers; formation of the complex induces substantial conformational changes in both proteins; MDM2 mimics 28S rRNA binding to RPL11; the C4 zinc finger of MDM2 determines RPL11 binding but not binding to MDMX; MDM2 mutants unable to bind RPL11 fail to induce p53 activation in cells.\",\n      \"method\": \"X-ray crystallography (2.4 Å), structure-guided mutagenesis, cell-based p53 activation assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic-resolution structure with mutagenesis validation in cells, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"26220995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PICT1 (GLTSCR2) binds RPL11 in the nucleolus and retains it there; loss of PICT1 releases RPL11 from nucleoli, increasing RPL11-MDM2 binding, blocking MDM2-mediated ubiquitination of p53, and causing p53-dependent G1 arrest and apoptosis even without DNA damage.\",\n      \"method\": \"Co-immunoprecipitation, Pict1-knockout mice and ES cells, nucleolar fractionation/immunofluorescence, ubiquitination assay\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, genetic knockout model, multiple orthogonal methods, replicated in vivo and in vitro\",\n      \"pmids\": [\"21804542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Impairment of 40S ribosome biogenesis (via rpS6 depletion) does not disrupt nucleolar integrity yet still induces p53 via RPL11; the mechanism involves selective upregulation of 5'-TOP mRNA translation (including rpL11 mRNA) despite global translational suppression, increasing free RPL11 protein.\",\n      \"method\": \"siRNA knockdown, mouse liver partial hepatectomy model, p53 reporter assays, polysome fractionation\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (animal model, siRNA, polysome fractionation), replicated in culture and in vivo\",\n      \"pmids\": [\"19287375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"RPL11 is rapidly recruited to promoter sites of p53-regulated genes upon nucleolar stress (actinomycin D); RPL11 is required for recruitment of p300/CBP co-activators and p53 K382 acetylation; NEDDylation of RPL11 and its direct binding to MDM2 are critical for promoter recruitment; binding of RPL11 to MDM2 at the promoter relieves MDM2-mediated transcriptional repression of p53.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), co-immunoprecipitation, siRNA knockdown, promoter reporter assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP and Co-IP with functional mutagenesis, multiple orthogonal methods in one study\",\n      \"pmids\": [\"22081073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"RPL11 interacts with the zinc finger domain of MDM2 via hydrophilic (basic) residues; hydrogen-deuterium exchange mass spectrometry and circular dichroism confirmed direct contact between RPL11 and the MDM2 zinc finger; single mutations of non-cysteine residues in the zinc finger disrupt binding; basic residues in RPL11 are essential for stable MDM2 binding and suppression of MDM2 E3 ligase activity toward p53.\",\n      \"method\": \"In vitro pull-down, hydrogen-deuterium exchange MS, circular dichroism, computational modeling, mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical reconstitution with mutagenesis and multiple biophysical methods, single lab\",\n      \"pmids\": [\"21903592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Assembly factors Rpf2 and Rrs1 are required to recruit rpL11 (along with rpL5 and 5S rRNA) into nascent 90S preribosomal particles; in the absence of Rpf2/Rrs1, rpL11 fails to associate with pre-rRNPs, 27SB pre-rRNA processing is blocked, and abortive 66S particles are prematurely released from the nucleolus.\",\n      \"method\": \"In vitro binding assays, co-immunoprecipitation, pre-rRNA processing analysis, genetic depletion in yeast\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding assays plus genetic depletion with multiple biochemical readouts, replicated across methods\",\n      \"pmids\": [\"17938242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Loss of RPL5/RPL11 abrogates 60S ribosome biogenesis and translational capacity but, unlike loss of other 60S ribosomal proteins, does NOT trigger a p53-dependent cell cycle checkpoint; instead, depletion reduces ribosome content and suppresses cyclin accumulation at the translational level, impairing cell cycle progression without arrest.\",\n      \"method\": \"siRNA knockdown in primary human lung fibroblasts, flow cytometry, polysome fractionation, cyclin protein/mRNA measurements\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with multiple cellular and biochemical readouts, rigorous controls comparing RPL5/RPL11 to other RPs\",\n      \"pmids\": [\"24061479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"GRWD1 physically interacts with RPL11; overexpression of GRWD1 competitively inhibits the RPL11-MDM2 interaction via its N-terminal acidic domain, alleviating RPL11-mediated suppression of MDM2 ubiquitin ligase activity toward p53; silencing GRWD1 enhances p53 induction by nucleolar stress.\",\n      \"method\": \"Co-immunoprecipitation, MDM2 ubiquitin ligase assay, siRNA/overexpression, immunofluorescence\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, in vitro ubiquitination assay, domain mapping, multiple orthogonal methods\",\n      \"pmids\": [\"27856536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RPL11 is covalently modified by SUMO1 and SUMO2; SUMOylation negatively modulates NEDDylation of RPL11; SUMOylation promotes RPL11 translocation out of the nucleolus; the SUMO-conjugating enzyme Ubc9 is required for RPL11-mediated p53 activation; SUMOylation is triggered by ribosomal stress.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, siRNA knockdown, SUMO/NEDD8 modification assays\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and localization with functional assays, single lab, multiple methods\",\n      \"pmids\": [\"30024791\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Akt/mTORC1-mediated phosphorylation of PRAS40 at T246 and S221 promotes nuclear-specific association of PRAS40 with RPL11; silencing PRAS40 induces p53 upregulation in an RPL11-dependent manner; PRAS40T246A (RPL11-binding-null mutant) cannot rescue this effect; PRAS40 negatively regulates the RPL11-HDM2-p53 pathway and suppresses p53-mediated cellular senescence.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, phospho-site mutagenesis, cellular senescence assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with mutagenesis and functional rescue, single lab\",\n      \"pmids\": [\"24704832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RPS27a directly binds RPL11 (confirmed by GST pull-down); RPS27a knockdown weakens RPS27a-RPL11 interaction and enhances RPL11-MDM2 binding, thereby inhibiting MDM2-mediated ubiquitination and degradation of p53; p53 stabilization by RPS27a knockdown is RPL11-dependent.\",\n      \"method\": \"GST pull-down, co-immunoprecipitation, in vitro ubiquitination assay, siRNA knockdown\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vitro binding and ubiquitination assay plus Co-IP, single lab\",\n      \"pmids\": [\"35073964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MeCP2 represses RPL11 (and RPL5) transcription by binding to their promoter regions; RPL11 overexpression suppresses breast cancer cell proliferation and induces apoptosis; RPL11 suppresses MDM2-mediated ubiquitination of p53 through direct MDM2 binding.\",\n      \"method\": \"ChIP assay, co-immunoprecipitation, overexpression/knockdown, ubiquitination assay\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for promoter binding, Co-IP for MDM2 interaction, functional rescue, single lab\",\n      \"pmids\": [\"32483207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RRS1 retains RPL11 in the nucleolus; RRS1 overexpression attenuates ribosomal stress by preventing RPL11 release, potentiating MDM2-mediated ubiquitination and degradation of p53; RRS1 knockdown releases RPL11 from the nucleolus, increases RPL11-MDM2 interaction, and activates p53.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence/nucleolar fractionation, ubiquitination assay, in vitro and in vivo tumor growth assays\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and localization with functional assays in vitro and in vivo, single lab\",\n      \"pmids\": [\"34433556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"miR-101-3p targets USP47, a deubiquitinase for RPL11; USP47-mediated deubiquitination of RPL11 retains it in the nucleolus; inhibition of USP47 by miR-101-3p promotes RPL11 translocation to the nucleoplasm, enhancing RPL11-MDM2 interaction and p53 stabilization; catalytically inactive USP47 cannot rescue these effects.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, miRNA overexpression, USP47 catalytic mutant\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with localization and catalytic mutant controls, single lab\",\n      \"pmids\": [\"35205710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"RPL11 directly interacts with PPARα within the D-domain (hinge region) of PPARα, confirmed by yeast two-hybrid, mammalian two-hybrid, and in vitro pull-down; RPL11 co-transfection produces ligand-dependent inhibition of PPARα transcriptional activity associated with decreased PPRE DNA binding; RPL11 does not interact with PPARβ or PPARγ.\",\n      \"method\": \"Yeast two-hybrid, mammalian two-hybrid, GST pull-down, co-transfection reporter assay, siRNA\",\n      \"journal\": \"Toxicological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple binding assays with functional transcription readout, single lab\",\n      \"pmids\": [\"16280383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Down-regulation of 5S rRNA (by miR-150/miR-383) intensifies the interaction between rpL11 and c-Myc, attenuating c-Myc oncogenic transcriptional activity and inhibiting esophageal squamous carcinoma cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation, miRNA overexpression, siRNA knockdown, cell proliferation assays\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP result, single lab, limited mechanistic follow-up\",\n      \"pmids\": [\"26606907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RBM10 directly binds to c-Myc and promotes its ubiquitin-dependent degradation; RPL11 (uL5) and RPL5 (uL18) directly bind RBM10 and boost this c-Myc suppression; cancer-derived mutant RBM10-I316F fails to bind RPL11/RPL5, abrogating c-Myc inactivation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, domain-mapping mutagenesis, cell growth/proliferation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, ubiquitination assay, cancer mutant validation, single lab\",\n      \"pmids\": [\"38032932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"v-erbA oncogene expression generates ribosomes devoid of RPL11 in avian erythroid progenitors; immunoprecipitation confirmed ribosome-associated RPL11 is reduced; these specialized RPL11-deficient ribosomes are associated with altered translational efficiency of specific mRNAs (e.g., HSP70).\",\n      \"method\": \"2D-DIGE proteomics, co-immunoprecipitation of ribosomes, polyribosome fractionation\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal proteomic methods plus polysome fractionation, single lab\",\n      \"pmids\": [\"23563180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Rpl11 heterozygous deletion in adult mice causes anemia with decreased erythroid progenitors and defective erythroid maturation; fibroblasts and hematopoietic tissue from heterozygous Rpl11 mice show impaired p53 activation upon ribosomal stress or DNA damage and elevated basal c-MYC levels; total/partial RPL11 loss compromises the ribosomal stress-p53 checkpoint.\",\n      \"method\": \"Conditional knockout mice, bone marrow transplantation, p53 activation assays, flow cytometry\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic mouse model with transplantation experiment, multiple cellular readouts, multiple orthogonal methods\",\n      \"pmids\": [\"26489471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RPL11 haploinsufficiency in adult mice activates p53 in hematopoietic tissues and impedes erythroid precursor differentiation, causing anemia; reducing p53 dosage (p53 heterozygous deletion) rescues erythropoietic precursor differentiation and restores normal red blood cell levels; introducing an RP-binding mutation in MDM2 (blocking RPL11-MDM2 interaction) prevents p53 activation and rescues the anemia, establishing the RP-MDM2-p53 pathway as the mechanistic basis.\",\n      \"method\": \"Conditional knockout mice, p53/MDM2 RP-binding mutant knock-in, flow cytometry, genetic epistasis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis in vivo with multiple allele combinations, direct pathway placement confirmed by MDM2 mutant knock-in\",\n      \"pmids\": [\"36435197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RPL11 deficiency in HEK293T cells causes an almost proportional decrease in 80S ribosomes; transcriptomic analysis shows hundreds of differentially expressed genes at transcriptome and translatome levels; up-regulated genes are associated with rRNA processing, splicing, translation and DNA repair; down-regulated genes are membrane protein genes; genes with altered translational efficiency depend on coding sequence length.\",\n      \"method\": \"RNA interference, RNA-seq of total and polysome-associated mRNA, ribosome fractionation\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi with parallel transcriptome/translatome sequencing, single lab\",\n      \"pmids\": [\"34948282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Perturbation of RNA Pol I transcription (via HEATR1 depletion) causes nucleolar disruption and activates p53 in an RPL5/RPL11-dependent manner; p53-dependent cell cycle arrest upon HEATR1 depletion is rescued by co-depletion of RPL5/RPL11.\",\n      \"method\": \"siRNA knockdown, immunofluorescence, cell cycle analysis, epistasis by double knockdown\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis by double knockdown with cell cycle readout, single lab\",\n      \"pmids\": [\"29143558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PICT-1 (GLTSCR2) is phosphorylated by ATM at S233/T289 in response to DNA damage; this phosphorylation promotes PICT-1 degradation and releases RPL11 from the nucleolus to the nucleoplasm; released RPL11 increases binding to MDM2 and promotes p53 accumulation and apoptosis in an ATM-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, phospho-site mutagenesis (S233A/T289A and S233D/T289D), ATM inhibitor treatment\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phospho-site mutagenesis with functional consequence, Co-IP, localization, single lab\",\n      \"pmids\": [\"27829214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The lncRNA PiHL sequesters RPL11 from MDM2 by enhancing GRWD1-RPL11 complex formation; this promotes MDM2-mediated p53 ubiquitination and degradation, reducing p53 activity in colorectal cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, RNA immunoprecipitation, ubiquitination assay, siRNA knockdown\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and RNA-IP with ubiquitination assay, single lab\",\n      \"pmids\": [\"31903119\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RPL11 (uL5) is an integral component of the 60S ribosomal subunit that is recruited into nascent ribosomes by assembly factors Rpf2/Rrs1; under ribosomal or nucleolar stress, free RPL11 translocates from the nucleolus to the nucleoplasm—a process regulated by PICT1/GLTSCR2 retention, SUMO/NEDD8 modification, and USP47-mediated deubiquitination—where it directly binds the acidic domain and C4 zinc finger of MDM2 (as revealed by a 2.4 Å crystal structure), blocking MDM2's E3 ubiquitin ligase activity toward p53 and simultaneously recruiting RPL11 to p53 target gene promoters to relieve MDM2-mediated transcriptional repression; this RPL11-MDM2-p53 checkpoint is the mechanistic basis for anemia in RPL11-haploinsufficient Diamond-Blackfan anemia mouse models, and its dysregulation by oncoproteins (GRWD1, RRS1, PRAS40, MeCP2) or modification crosstalk (Akt/mTOR, ATM, NEDD8) promotes tumor progression; additionally, extra-ribosomal RPL11 inhibits PPARα transcriptional activity and suppresses c-Myc oncogenic function in cooperation with RBM10.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RPL11 (uL5) is a structural component of the 60S ribosomal subunit that doubles as a stress-responsive regulator of the p53 tumor-suppressor pathway [#5, #19]. During ribosome assembly, RPL11 is recruited together with RPL5 and 5S rRNA into nascent 90S preribosomal particles by the assembly factors Rpf2 and Rrs1, a step required for 27SB pre-rRNA processing and proper 60S maturation [#5]; loss of RPL11 collapses 60S biogenesis and overall ribosome content, limiting translational capacity and cyclin accumulation [#6, #20]. Upon ribosomal or nucleolar stress, free RPL11 escapes the nucleolus and binds MDM2 directly: a 2.4 Å crystal structure shows MDM2 engaging RPL11 through its acidic domain and a C4 zinc finger, mimicking 28S rRNA binding, and MDM2 mutants unable to bind RPL11 fail to activate p53 [#0, #4]. This interaction blocks MDM2 E3 ubiquitin ligase activity toward p53 and additionally recruits RPL11 to p53 target promoters, where it relieves MDM2-mediated transcriptional repression and licenses p300/CBP-dependent p53 K382 acetylation [#3]. Nucleolar release of RPL11 is gated by retention factors PICT1/GLTSCR2 and RRS1 and tuned by post-translational modification—NEDDylation promotes and is antagonized by SUMOylation, while USP47-mediated deubiquitination and ATM-driven PICT1 degradation control the free pool [#1, #12, #3, #8, #13, #22]. This RPL11–MDM2–p53 checkpoint is the mechanistic basis of anemia in RPL11-haploinsufficient Diamond-Blackfan anemia mouse models: erythroid differentiation defects are rescued by lowering p53 dosage or by knocking in an RP-binding-null MDM2 [#18, #19]. The pathway is dysregulated by oncoproteins and regulators including GRWD1, RPS27a, PRAS40, and MeCP2 that limit RPL11–MDM2 engagement [#7, #10, #9, #11]. Beyond p53, extra-ribosomal RPL11 directly inhibits PPARα transcriptional activity [#14] and cooperates with RBM10 to promote ubiquitin-dependent degradation of c-Myc, suppressing its oncogenic function [#16].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established that RPL11 acts beyond the ribosome as a direct transcriptional modulator, the first extra-ribosomal function defined for it.\",\n      \"evidence\": \"Yeast/mammalian two-hybrid, GST pull-down and reporter assays mapping RPL11 binding to the PPARα hinge (D-domain)\",\n      \"pmids\": [\"16280383\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological context and target-gene scope of PPARα inhibition undefined\", \"Selectivity over PPARβ/γ explained only by binding, not structurally\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined how RPL11 is incorporated into the ribosome, identifying the assembly factors that load it onto pre-rRNPs.\",\n      \"evidence\": \"In vitro binding, Co-IP and pre-rRNA processing analysis with Rpf2/Rrs1 depletion in yeast\",\n      \"pmids\": [\"17938242\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Human ortholog assembly step not directly demonstrated here\", \"Does not address the extra-ribosomal free pool\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Resolved how impaired 40S biogenesis still signals through RPL11, showing selective 5'-TOP translation raises free RPL11 even without nucleolar disruption.\",\n      \"evidence\": \"siRNA, partial hepatectomy mouse model, p53 reporters and polysome fractionation\",\n      \"pmids\": [\"19287375\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism coupling rpS6 loss to TOP-mRNA selectivity incomplete\", \"Direct measurement of nascent free RPL11 partitioning limited\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified nucleolar retention as the upstream switch controlling RPL11 availability and the modification/promoter steps that translate stress into p53 activation.\",\n      \"evidence\": \"PICT1-knockout mice/ES cells with Co-IP and ubiquitination assays; ChIP showing RPL11 promoter recruitment and NEDDylation dependence\",\n      \"pmids\": [\"21804542\", \"22081073\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How nucleolar release is triggered at the molecular level not fully resolved\", \"NEDDylation site/enzyme specificity not mapped\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Pinpointed the molecular contacts of RPL11 with the MDM2 zinc finger required to suppress its E3 ligase activity.\",\n      \"evidence\": \"In vitro pull-down, HDX-MS, circular dichroism and mutagenesis\",\n      \"pmids\": [\"21903592\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conformational dynamics inferred biophysically, not yet structural\", \"Stoichiometry with 5S rRNA/RPL5 not addressed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Distinguished RPL11/RPL5 from other ribosomal proteins by showing their loss limits translation without triggering a p53 arrest, clarifying their dual roles.\",\n      \"evidence\": \"siRNA in primary fibroblasts with flow cytometry, polysome fractionation and cyclin measurements; v-erbA-induced RPL11-deficient ribosomes by proteomics\",\n      \"pmids\": [\"24061479\", \"23563180\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Why RPL11/RPL5 loss uniquely bypasses arrest mechanistically unclear\", \"Functional consequences of RPL11-deficient specialized ribosomes for specific mRNAs limited\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Provided the atomic-resolution basis for RPL11–MDM2 recognition, showing MDM2 mimics 28S rRNA and that a specific zinc finger dictates binding and p53 activation.\",\n      \"evidence\": \"X-ray crystallography at 2.4 Å with structure-guided mutagenesis and cell-based p53 assays\",\n      \"pmids\": [\"26220995\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of full ternary RPL11/5S/MDM2 assembly not solved\", \"Does not capture in-cell regulation by modification\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Began linking RPL11 to c-Myc control, indicating a second extra-ribosomal tumor-suppressive axis sensitive to 5S rRNA levels.\",\n      \"evidence\": \"Co-IP and miRNA/siRNA manipulation with proliferation assays in esophageal carcinoma cells\",\n      \"pmids\": [\"26606907\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP without reciprocal/structural validation\", \"Direct vs. indirect RPL11–c-Myc contact unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established RPL11 haploinsufficiency as a cause of anemia via the ribosomal stress–p53 checkpoint, modeling Diamond-Blackfan anemia.\",\n      \"evidence\": \"Conditional heterozygous Rpl11 mice with bone marrow transplantation, p53 assays and flow cytometry\",\n      \"pmids\": [\"26489471\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether elevated basal c-MYC contributes independently to anemia not isolated\", \"Cell-autonomy across erythroid stages partially defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified oncoprotein and DNA-damage inputs that gate RPL11–MDM2 engagement, expanding regulation beyond ribosomal stress.\",\n      \"evidence\": \"Co-IP, ubiquitination and domain mapping for GRWD1 competition; ATM phospho-site mutagenesis driving PICT-1 degradation\",\n      \"pmids\": [\"27856536\", \"27829214\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative contribution of each regulator in vivo unknown\", \"Crosstalk hierarchy among GRWD1/PICT1/ATM not integrated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined modification crosstalk—SUMOylation antagonizing NEDDylation—as a tunable control over RPL11 nucleolar exit and p53 activation.\",\n      \"evidence\": \"Co-IP, immunofluorescence, siRNA and SUMO/NEDD8 modification assays\",\n      \"pmids\": [\"30024791\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SUMO acceptor sites and ligase specificity not mapped\", \"Single-lab evidence without structural confirmation\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Broadened the network of factors that sequester RPL11 from MDM2, including a protein partner, a transcriptional repressor, and a lncRNA scaffold.\",\n      \"evidence\": \"GST pull-down/Co-IP for RPS27a; ChIP for MeCP2 repression; RNA-IP for PiHL-GRWD1-RPL11; ubiquitination assays throughout\",\n      \"pmids\": [\"35073964\", \"32483207\", \"31903119\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative importance of these regulators across tissues unknown\", \"Most rest on single-lab Co-IP/RNA-IP without reciprocal structural data\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Confirmed RRS1 as a nucleolar retention factor for RPL11 with tumor-relevant consequences, and mapped the system-wide translational impact of RPL11 loss.\",\n      \"evidence\": \"Co-IP, fractionation, ubiquitination and in vivo tumor assays for RRS1; parallel transcriptome/translatome RNA-seq with ribosome fractionation for RPL11 deficiency\",\n      \"pmids\": [\"34433556\", \"34948282\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct contribution of altered specific-mRNA translation to phenotype unresolved\", \"Single-lab datasets\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed the RP–MDM2–p53 axis genetically as the cause of RPL11-haploinsufficient anemia and added USP47 deubiquitination as a nucleolar-retention control.\",\n      \"evidence\": \"p53/MDM2 RP-binding mutant knock-in epistasis in mice; Co-IP, localization and USP47 catalytic-mutant rescue\",\n      \"pmids\": [\"36435197\", \"35205710\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How USP47 ubiquitination signal is read for nucleolar retention not fully defined\", \"Therapeutic exploitability of the MDM2 RP-binding pocket untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Solidified the c-Myc suppression axis, showing RPL11 with RPL5 binds RBM10 to drive c-Myc ubiquitin-dependent degradation, disrupted by a cancer mutation.\",\n      \"evidence\": \"Reciprocal Co-IP, ubiquitination assays, domain mapping and the cancer-derived RBM10-I316F mutant in growth assays\",\n      \"pmids\": [\"38032932\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether c-Myc and p53 axes are coordinated under the same stress signals unclear\", \"Single-lab evidence without structural detail of the RBM10 complex\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the various nucleolar retention factors, modifications, and oncoprotein inputs are integrated to set the free RPL11 threshold, and how the ribosomal versus extra-ribosomal pools are physically partitioned, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model of the regulated RPL11/5S/RPL5 module\", \"Quantitative dynamics of nucleolar-to-nucleoplasmic flux not measured in vivo\", \"Coordination of p53 and c-Myc outputs under physiological stress undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [5, 6, 20]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 4, 7]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [3, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [1, 8, 12, 13, 22]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [3, 8, 22]},\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [5, 6, 17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [2, 3, 21]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3, 14]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [6, 20]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [18, 19]}\n    ],\n    \"complexes\": [\"60S ribosomal subunit\", \"RPL5-RPL11-5S rRNA module\"],\n    \"partners\": [\"MDM2\", \"PICT1\", \"RRS1\", \"GRWD1\", \"PRAS40\", \"RPS27a\", \"RBM10\", \"PPARA\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}