Affinage

Showing LIN28A — LIN28 is a alias.

LIN28A

Protein lin-28 homolog A · UniProt Q9H9Z2

Length
209 aa
Mass
22.7 kDa
Annotated
2026-06-10
100 papers in source corpus 28 papers cited in narrative 28 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LIN28A is a bipartite RNA-binding protein that governs cell fate, proliferation, and metabolic programs primarily by blocking biogenesis of the let-7 family of microRNAs (PMID:22118463, PMID:19713957). In the cytoplasm it binds precursor let-7 and recruits the terminal uridylyltransferase TUT4/Zcchc11 to polyuridylate the precursor and block Dicer processing — a conserved mechanism reconstituted from C. elegans LIN-28/PUP-2 to human cells, and mechanistically distinct from the nuclear, uridylation-independent route used by LIN28B (PMID:22118463, PMID:19713957). Selectivity for let-7 among many bound pre-miRNAs is conferred at two levels: the E3 ligase Trim25 binds the pre-let-7 terminal loop to activate TUT4 (PMID:25457611), and the cold-shock domain recognizes a (U)GAU motif that partitions let-7 members into efficiently versus poorly suppressed subclasses (PMID:30029005); meanwhile the large majority of LIN28A binding occurs on non-miRNA transcripts that sequester the protein away from let-7 regulation (PMID:34380031). This let-7 axis is tuned by an extensive set of post-translational modifications: PCAF acetylates the CSD to destabilize LIN28A and is reversed by SIRT1 (PMID:24631505), ERK1/2 phosphorylates Ser-200 to impair let-7 suppression (PMID:28179426), SUMOylation at Lys-15 enhances pre-let-7 binding and TUT4 recruitment (PMID:32333719), and USP28-mediated deubiquitination stabilizes the protein against proteasomal turnover (PMID:30543854). LIN28A also acts independently of let-7 by directly binding specific transcripts to control their translation or stability — enhancing IGF-2 (PMID:17473174) and InR (PMID:26487778) translation, repressing Hmga2 (PMID:27920151) and Lars2 (PMID:36436798), regulating Dnmt3a within an oligomeric RNP containing Ddx3x, Hnrnph1, Hnrnpu and Syncrip (PMID:33504840), inducing decay of Hippo-pathway kinase mRNAs via MSI2 to activate YAP1 (PMID:35102250), and acting through Pck2 and the lncRNA H19 in cardiac growth and repair (PMID:30636447, PMID:36314132). In the nucleus it associates with snoRNAs/rRNA and a Nucleolin/TRIM28 complex to maintain nucleolar integrity and repress the 2C/Dux program (PMID:34331666). A loss-of-function R192G variant causes midbrain dopamine neuron degeneration and Parkinson's-related phenotypes, rescued by wild-type LIN28A (PMID:31750563).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 2007 High

    Established the first molecular activity of Lin-28 — direct binding of a target mRNA to enhance its translation — defining it as a positive translational regulator before the let-7 connection was known.

    Evidence RNA-IP, polysome fractionation, and gain/loss-of-function in myoblasts showing IGF-2 binding and stress-granule localization

    PMID:17473174

    Open questions at the time
    • Did not address let-7 or miRNA biogenesis
    • Mechanism of translational enhancement not resolved at nucleotide level
  2. 2009 High

    Defined the conserved core mechanism of let-7 suppression by showing LIN-28 binds pre-let-7 and directly stimulates its uridylation by a poly(U) polymerase.

    Evidence In vitro uridylation reconstitution, direct binding assays, and C. elegans genetics with PUP-2

    PMID:19713957

    Open questions at the time
    • Human TUTase identity not established here
    • Cofactor requirements for specificity unknown
  3. 2009 Medium

    Placed LIN28 within an oncogenic signaling circuit by showing it is a MAPK/Myc-driven transcriptional output whose suppression unleashes let-7 to block metastasis.

    Evidence LIN28 depletion/rescue epistasis in breast cancer cells and orthotopic murine model with let-7 and HMGA2 readouts

    PMID:19153603

    Open questions at the time
    • Indirect transcriptional regulation, not direct LIN28 activity
    • Did not dissect which let-7 targets drive metastasis
  4. 2011 High

    Resolved the human mechanism and distinguished LIN28A from LIN28B, showing LIN28A recruits TUT4/Zcchc11 to cytoplasmic pre-let-7 whereas LIN28B acts nuclearly and TUTase-independently.

    Evidence Zcchc11 depletion, subcellular fractionation, and functional rescue across cancer cell lines and xenografts

    PMID:22118463

    Open questions at the time
    • Did not explain how only let-7 is selected among bound pre-miRNAs
    • Regulation of TUT4 recruitment unaddressed
  5. 2014 High

    Separated LIN28's let-7-dependent and let-7-independent activities genetically, showing it controls successive developmental cell fates through two distinct mechanisms.

    Evidence C. elegans epistasis with let-7/lin-41 and hbl-1 3'UTR regulation across multiple alleles

    PMID:22457637

    Open questions at the time
    • Molecular mechanism of hbl-1 3'UTR regulation not defined
    • Mammalian equivalence of two-step model not shown
  6. 2014 High

    Explained let-7 selectivity by identifying Trim25 as an RNA-specific cofactor that activates TUT4 on the pre-let-7 terminal loop.

    Evidence RNA pulldown with quantitative mass spectrometry and in vitro TUT4 activity assays

    PMID:25457611

    Open questions at the time
    • Structural basis of Trim25 loop recognition unresolved
    • Whether Trim25 acts on let-7-independent targets unknown
  7. 2014 High

    Opened the post-translational regulation of LIN28A by showing acetylation (PCAF) and phosphorylation (ERK1/2 at Ser-200) modulate its stability and let-7-suppressing activity.

    Evidence In vitro acetylation/kinase assays, domain mapping, SIRT1 reversal, and CRISPR phospho-mutant knock-ins with functional readouts

    PMID:24631505 PMID:28179426

    Open questions at the time
    • Upstream signals integrating these modifications in vivo not mapped
    • Crosstalk between modifications not addressed
  8. 2016 Medium

    Extended the let-7-independent translational mechanism to mammalian stem-cell programs, showing direct binding of Hmga2 and InR transcripts controls differentiation and stem-cell expansion.

    Evidence RNA-IP and genetic rescue in differentiating ESCs (Hmga2) and Drosophila intestinal stem cells (InR)

    PMID:26487778 PMID:27920151

    Open questions at the time
    • Binding-site determinants of let-7-independent targets not generalized
    • How target choice is partitioned from let-7 activity unclear
  9. 2016 Medium

    Demonstrated druggability and validated the LIN28/let-7 interaction as the on-target node using a small-molecule inhibitor.

    Evidence FRET-based inhibition screen, biotinylated-probe pulldown, and let-7 rescue in cancer cells

    PMID:27548809

    Open questions at the time
    • Selectivity over let-7-independent functions not tested
    • In vivo efficacy not established
  10. 2018 High

    Defined the sequence logic of CSD recognition, showing a (U)GAU motif sorts let-7 precursors into high- and low-efficiency suppression subclasses.

    Evidence Single-nucleotide-resolution in vivo CLIP with uridylation and degradation analysis of let-7 subclasses

    PMID:30029005

    Open questions at the time
    • Functional consequence of subclass partitioning across tissues unmapped
    • Interplay with Trim25 loop recognition not integrated
  11. 2018 Medium

    Identified deubiquitination as a stability control point, with USP28 reversing proteasomal turnover to extend LIN28A half-life and promote cancer phenotypes.

    Evidence Co-IP, ubiquitination and protein half-life assays, and cancer cell functional readouts

    PMID:30543854

    Open questions at the time
    • E3 ligase driving ubiquitination not identified
    • Single-lab two-method evidence for the interaction
  12. 2019 High

    Linked LIN28A to a Mendelian-relevant neurodegenerative phenotype, showing an R192G loss-of-function variant drives midbrain dopamine neuron degeneration rescuable by wild-type protein.

    Evidence Conditional KO mice, isogenic patient iPSC model with WT rescue, and transplantation in a rat PD model

    PMID:31750563

    Open questions at the time
    • Molecular target whose dysregulation by R192G causes degeneration not defined
    • Whether let-7 or let-7-independent activity mediates the phenotype unresolved
  13. 2019 High

    Established a let-7-independent metabolic role, showing direct Pck2 mRNA binding mediates cardiac hypertrophic growth and glycolytic reprogramming.

    Evidence RNA-IP, cardiac-specific KO, transverse aortic constriction, epistasis, and metabolomics

    PMID:30636447

    Open questions at the time
    • How LIN28A increases Pck2 transcript level mechanistically unclear
    • Generalizability beyond cardiac tissue untested
  14. 2020 High

    Added SUMOylation at Lys-15 as an activating modification that boosts pre-let-7 binding and TUT4 recruitment, linking stress signals to let-7 suppression.

    Evidence In vivo/in vitro SUMOylation assays, K15R mutagenesis, binding affinity and DICER processing assays, and tumor growth model

    PMID:32333719

    Open questions at the time
    • SUMO E3 ligase and protease enzymes not identified
    • Crosstalk with phosphorylation/acetylation marks unmapped
  15. 2021 Medium

    Revealed a nuclear/nucleolar function distinct from let-7, showing LIN28 binds snoRNAs/rRNA and resides in an NCL/TRIM28 complex maintaining nucleolar integrity and repressing the 2C/Dux program.

    Evidence ChIP, snoRNA/rRNA binding assays, NCL/TRIM28 co-IP, and KO with nucleolar imaging in pluripotent stem cells

    PMID:34331666

    Open questions at the time
    • Direct vs indirect role in phase separation unresolved
    • Single-lab evidence for the NCL/TRIM28 complex
  16. 2021 Medium

    Reframed binding stoichiometry by showing ~99% of LIN28 binding is to non-miRNA transcripts that sequester the protein rather than being directly regulated.

    Evidence Transcriptome-wide single-nucleotide CLIP with quantification of miRNA vs non-miRNA binding and let-7 functional assessment

    PMID:34380031

    Open questions at the time
    • Whether sequestration is dynamically regulated unknown
    • Reconciliation with documented functional mRNA targets not fully addressed
  17. 2021 Medium

    Defined LIN28A as a subunit of oligomeric RNP complexes required for let-7-independent mRNA regulation, with multiple RNA-binding partners needed for target engagement.

    Evidence Complex purification, proteomics, and RNAi epistasis showing Ddx3x/Hnrnph1/Hnrnpu/Syncrip are required for Lin28a binding to Dnmt3a mRNA

    PMID:33504840

    Open questions at the time
    • Architecture and stoichiometry of the RNP not resolved
    • Whether the same complex serves other targets unknown
  18. 2022 Medium

    Identified a let-7-independent oncogenic mechanism in which LIN28A recruits MSI2 to degrade Hippo-pathway kinase mRNAs, activating YAP1 and cancer stem-cell properties.

    Evidence Co-IP with CSD/RRM domain mapping, transcriptome analysis, mRNA stability assays, and YAP1 rescue in xenografts

    PMID:35102250

    Open questions at the time
    • Direct binding to kinase mRNAs vs MSI2-bridged binding not fully separated
    • Single-lab evidence
  19. 2022 Medium

    Extended let-7-independent control to noncoding RNA and additional metabolic targets, placing H19 and Lars2 downstream of LIN28A in cardiac repair and ovarian mitochondrial function.

    Evidence RIP-seq/RNA-IP for direct binding and ablation/overexpression rescue (H19 in cardiomyocytes; Lars2 in granulosa cells)

    PMID:36314132 PMID:36436798

    Open questions at the time
    • Binding-site features distinguishing these targets not defined
    • Single-lab two-method evidence each

Open questions

Synthesis pass · forward-looking unresolved questions
  • How LIN28A integrates its parallel modifications and partitions activity between let-7 suppression, sequestration on abundant non-miRNA RNAs, and diverse let-7-independent mRNA/ncRNA targets within a given cell remains unresolved.
  • No unified model linking modification state to target choice
  • Structural basis of simultaneous CSD/zinc-knuckle target recognition across target classes lacking
  • Which activity drives the R192G neurodegeneration phenotype unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 10 GO:0045182 translation regulator activity 4 GO:0098772 molecular function regulator activity 3 GO:0140098 catalytic activity, acting on RNA 3
Localization
GO:0005829 cytosol 2 GO:0005730 nucleolus 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-1266738 Developmental Biology 5 R-HSA-8953854 Metabolism of RNA 5 R-HSA-392499 Metabolism of proteins 4 R-HSA-1643685 Disease 3
Partners
DDX3XMSI2NCLPCAFSIRT1TRIM25TUT4USP28
Complex memberships
LIN28-Nucleolin-TRIM28 nucleolar complexLIN28A-TUT4/Zcchc11-Trim25 uridylation complexLin28a-Ddx3x/Hnrnph1/Hnrnpu/Syncrip RNP

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 LIN28A recruits the TUTase Zcchc11/TUT4 to precursor let-7 in the cytoplasm, inducing polyuridylation that blocks Dicer processing. This mechanism is distinct from LIN28B, which acts in the nucleus by sequestering primary let-7 transcripts and inhibiting Microprocessor processing in a Zcchc11-independent manner. Zcchc11 depletion, subcellular fractionation, functional assays in cancer cell lines and xenografts Cell High 22118463
2009 C. elegans LIN-28 directly binds precursor let-7 miRNA to prevent Dicer processing, and stimulates uridylation of pre-let-7 by the poly(U) polymerase PUP-2 in vitro. LIN-28 and PUP-2 interact directly, establishing the conserved uridylation-based mechanism for let-7 suppression. In vitro uridylation assay, direct binding assays, C. elegans genetics, in vivo functional experiments Nature structural & molecular biology High 19713957
2007 Lin-28 binds IGF-2 mRNA and associates with polysomes and translation initiation complexes in skeletal myoblasts, increasing translational efficiency of IGF-2. Lin-28 was also found in stress granules (stalled mRNA-protein translation complexes), supporting its role as a translational enhancer. RNA immunoprecipitation, polysome fractionation, loss-of-function and gain-of-function assays in cultured myoblasts, biochemical co-fractionation, stress granule localization Genes & development High 17473174
2013 LIN28A represses miR-9 precursor processing through a uridylation-independent mechanism during neuronal differentiation, reducing mature miR-9 levels and thereby controlling differentiation capacity of P19 cells. P19 cell differentiation assay, inducible LIN28A expression system, miRNA processing assays, loss-of-function experiments Nature communications Medium 24722317
2014 The E3 ligase Trim25 binds the conserved terminal loop of pre-let-7 and acts as an RNA-specific cofactor that activates TUT4, enabling more efficient Lin28A-mediated uridylation of pre-let-7. This cofactor specificity explains why, despite Lin28A binding many pre-miRNAs, only pre-let-7 is efficiently uridylated. RNA pulldown coupled with quantitative mass spectrometry, RNA binding assays, TuT4 activity assays, identification of Trim25 as cofactor Cell reports High 25457611
2018 LIN28 CSD recognizes a (U)GAU motif on pre-let-7, partitioning let-7 family members into CSD+ and CSD- subclasses. CSD+ precursors undergo more efficient in vivo recognition, 3′ uridylation, and degradation, resulting in stronger suppression in LIN28-activated cells. Single-nucleotide-resolution in vivo CLIP mapping of LIN28 binding sites, analysis of uridylation and degradation of let-7 subclasses Molecular cell High 30029005
2014 PCAF directly interacts with and acetylates Lin28 at the cold shock domain (CSD), leading to reduced Lin28 protein levels and increased mature let-7a. SIRT1 reverses this acetylation. The PCAF/SIRT1 balance regulates Lin28 activity in let-7a biogenesis. Co-immunoprecipitation, in vitro acetylation assay, domain mapping, SIRT1 deacetylation assay, let-7a level measurement Biochimica et biophysica acta High 24631505
2014 ERK1/2 kinases directly phosphorylate Lin28a at Ser-200. Phospho-mimetic (S200D) Lin28a shows impaired inhibition of let-7 miRNA and decreased cyclin D1; phospho-deficient (S200A) Lin28a expresses less let-7, proliferates faster, and exhibits a differentiation defect. ERK-mediated phosphorylation thus modulates Lin28a's ability to suppress let-7 and regulate pluripotency. In vitro kinase assay, CRISPR/Cas9 knock-in of S200A and S200D mutants in P19 cells, let-7 miRNA measurement, proliferation and differentiation assays The Journal of biological chemistry High 28179426
2018 USP28, a deubiquitinating enzyme, interacts with LIN28A and reverses its proteasomal ubiquitination-dependent degradation, thereby stabilizing LIN28A protein and extending its half-life. USP28-mediated stabilization of LIN28A enhances cancer cell viability and migration. Co-immunoprecipitation, ubiquitination assay, protein half-life measurement, cancer cell functional assays Biochimica et biophysica acta. Molecular basis of disease Medium 30543854
2020 LIN28A is SUMOylated in vivo and in vitro at Lys-15, a modification that increases its binding affinity for pre-let-7, enhances TUT4 recruitment, and blocks DICER processing, thereby amplifying suppression of mature let-7. SUMOylation is increased by hypoxia and reduced by chemotherapy drugs (Cisplatin, Paclitaxel). A K15R SUMOylation-deficient mutant abolishes these effects. In vivo and in vitro SUMOylation assays, mutagenesis (K15R), pre-let-7 binding affinity assay, TUT4 recruitment assay, DICER processing assay, in vivo tumor growth assay Molecular oncology High 32333719
2019 Lin28a directly binds Pck2 mRNA (mitochondrial phosphoenolpyruvate carboxykinase 2) and increases its transcript level. Cardiac-specific deletion of Lin28a attenuates pressure overload-induced hypertrophy; increasing Pck2 is sufficient to promote hypertrophic growth similar to Lin28a overexpression; epistatic analysis shows Pck2 mediates Lin28a's role in cardiac hypertrophic growth and glycolytic reprogramming. RNA immunoprecipitation, cardiac-specific Lin28a knockout, transverse aortic constriction model, epistasis analysis, metabolomic analysis, Pck2 knockdown/overexpression Circulation High 30636447
2021 LIN28 binds small nucleolar RNAs (snoRNAs) and rRNA to maintain nucleolar integrity. LIN28 resides in a complex with Nucleolin (NCL) and the transcriptional repressor TRIM28 at the Dux and rDNA loci. Loss of LIN28 causes nucleolar phase separation defects, ribosomal stress, P53 activation, and de-repression of the 2C transcription factor Dux. Chromatin immunoprecipitation, RNA binding assays for snoRNAs/rRNA, co-immunoprecipitation of NCL/TRIM28 complex, LIN28 knockout in pluripotent stem cells, nucleolar imaging Protein & cell Medium 34331666
2021 Lin28a directly binds the mRNA of Lars2 (mitochondrial leucyl-tRNA synthetase) and suppresses its translation. Overexpression of LARS2 reversed Lin28a-induced estrogen downregulation and mitochondrial dysfunction in human granulosa cells. RNA immunoprecipitation for direct mRNA binding, LARS2 overexpression rescue, measurement of estrogen, ATP, mitochondrial membrane potential in LIN28A overexpression/knockdown cells Cellular signalling Medium 36436798
2021 LIN28A directly binds the GGAGA motif in the promoter region of CENPE mRNA (as shown by RIP, RNA pulldown, and dual luciferase reporter assays), promoting CENPE expression and thereby sustaining proliferation and chemoresistance in AML cells. RNA immunoprecipitation (RIP), RNA pulldown, dual luciferase reporter assay, CENPE knockdown rescue, AML cell proliferation and apoptosis assays Frontiers in oncology Medium 34868981
2022 LIN28A recruits RNA-binding protein MSI2 via its CSD domain (interacting with MSI2's RRM domain) to directly induce mRNA decay of YAP1 upstream kinases (MST1/2 and LATS1/2), inhibiting the Hippo pathway and activating YAP1 to promote cancer stem cell properties, independently of let-7. Co-immunoprecipitation, domain mapping (CSD of LIN28 and RRM of MSI2), transcriptome analysis, LIN28A/MSI2 knockdown with YAP1 constitutive activation rescue, mRNA stability assays Oncogene Medium 35102250
2014 Lin28 loss-of-function in C. elegans uses two distinct steps: first, a let-7-independent positive regulation of hbl-1 through its 3′ UTR to control L2 stage cell fates; second, a let-7-dependent step controlling subsequent fates via repression of lin-41. This two-step mechanism is separable by genetics. C. elegans genetic epistasis, let-7 pathway double mutants, lin-28/let-7/lin-41 genetic interaction analysis PLoS genetics High 22457637
2022 RNA-IP sequencing in cardiomyocytes identified long noncoding RNA H19 as the most significantly altered LIN28a target after injury. Ablation of H19 blunted LIN28a-induced enhancement of cardiomyocyte metabolism and cell cycle activity, placing H19 downstream of LIN28a in cardiac repair. RNA immunoprecipitation sequencing (RIP-seq) from LIN28a-overexpressing cardiomyocytes after injury, H19 ablation rescue assay, cell cycle and metabolism assays Circulation Medium 36314132
2016 Lin28a overexpression in Drosophila intestinal stem cells boosts insulin signaling by increasing translation of Insulin-like Receptor (InR) mRNA, promoting symmetric division and stem cell expansion. Forced expression of InR completely rescues lin-28 null mutant defects in stem cell number and division pattern. This stem cell activity is independent of let-7. Drosophila lin-28 null mutant analysis, immunoprecipitation of Lin-28-bound mRNAs, InR forced expression rescue, lin-28/let-7 epistasis Development (Cambridge, England) Medium 26487778
2014 LIN28A expression in sickle cell erythrocytes increases fetal hemoglobin (HbF), reduces beta(sickle)-globin expression, and strongly suppresses all members of the let-7 miRNA family, reducing sickling morphology without impairing differentiation or enucleation. Lentiviral LIN28A transgenic expression in CD34+ sickle cells, measurement of HbF, beta-globin, let-7 levels, erythrocyte morphology PloS one Medium 25188417
2021 Lin28a-containing high-molecular-weight complexes in mouse ESCs include helicases Ddx3x and other RNA-binding proteins (Hnrnph1, Hnrnpu, Syncrip). Suppression of Ddx3x, Hnrnph1, Hnrnpu, or Syncrip interferes with Lin28a binding to Dnmt3a mRNA, demonstrating that these proteins form an oligomeric RNP complex required for Lin28a-mediated translational regulation of Dnmt3a, independently of let-7. Purification of Lin28a-containing complexes, proteomic identification of interactors, RNAi-mediated knockdown of candidates, RNA immunoprecipitation of Lin28a-Dnmt3a mRNA interaction Scientific reports Medium 33504840
2016 Lin28 proteins directly bind a conserved element in the 3′ UTR of Hmga2 mRNA, causing down-regulation of its translation in differentiating ESCs, independently of let-7. This let-7-independent mechanism prevents inappropriate accumulation of Hmga2 and aberrant proliferation/apoptosis. RNA immunoprecipitation for Lin28-Hmga2 3′UTR binding, let-7-independent translational regulation assay, Hmga2 protein measurement in Lin28 knockdown/overexpression cells FASEB journal Medium 27920151
2021 LIN28 binding is ~99% to non-miRNA transcripts (protein-coding and ribosomal RNAs), and these non-miRNA binding sites are specific and strong but do not mediate direct post-transcriptional regulation. Instead, they sequester LIN28 protein, reducing its functional availability to regulate let-7 miRNA biogenesis. Transcriptome-wide CLIP-seq mapping of LIN28 binding sites, quantification of miRNA vs. non-miRNA binding proportions, functional assessment of let-7 regulation Cell reports Medium 34380031
2009 RKIP suppresses LIN28 transcription via inhibition of MAPK signaling, which leads to decreased Myc-driven LIN28 transcription. Suppression of LIN28 enables let-7 processing, which in turn inhibits HMGA2. LIN28 depletion and let-7 expression suppress bone metastasis; LIN28 re-expression restores bone metastasis in RKIP-expressing cells. Epistasis via LIN28 depletion/rescue in breast cancer cells and orthotopic murine model, MAPK inhibition, let-7 measurement, HMGA2 quantification The EMBO journal Medium 19153603
2016 The small molecule N-methyl-N-[3-(3-methyl[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl]acetamide blocks LIN28/let-7 interaction (confirmed by FRET assay), rescues let-7 processing and function in Lin28-expressing cancer cells, and a biotinylated derivative captures Lin28 from cell lysates, confirming on-target engagement. Protein/RNA FRET assay screening, biotinylated derivative pulldown from cell lysates, let-7 processing assay in cancer cells, tumor sphere formation assay, ESC differentiation assay ACS chemical biology Medium 27548809
2019 LIN28A loss-of-function variant (R192G) causes developmental defects and Parkinson's disease-related phenotypes in midbrain dopamine neurons derived from patient iPSCs. Conditional Lin28 knockout in mice leads to midbrain dopamine neuron degeneration and PD-related behavioral deficits. Wild-type Lin28A expression rescues R192G phenotypes. Lin28 conditional knockout mice, isogenic hESC/hiPSC-based disease model with R192G variant, neuronal differentiation assays, cell transplantation in PD model rats with behavioral testing The EMBO journal High 31750563
2014 LIN28A knockdown in human trophoblast cells (ACH-3P) results in increased spontaneous syncytialization and upregulation of syncytiotrophoblast markers (hCG, LGALS13, ERVW-1), demonstrating that LIN28A has a functional role in restricting trophoblast differentiation in human but not mouse trophoblast stem cells. shRNA-mediated LIN28A knockdown, mRNA degradation targeting, syncytialization assay, syncytiotrophoblast marker quantification in ACH-3P and mTS cells Biology of reproduction Medium 24006280
2014 LIN28A binds the promoter region GGAGA motif of CENPE and also stabilizes mRNAs such as ATG12 (as shown for LIN28A in the context of DDX11-AS1-mediated chemoresistance). LIN28A stabilizes ATG7 and ATG12 mRNA by increasing their mRNA stability. RNA immunoprecipitation, mRNA stability assay, Western blot for ATG7/ATG12 Pharmacology Low 36382664
2016 MeCP2 binds to methylated CpG islands at the LIN28A promoter and suppresses LIN28A transcription. MeCP2 knockdown transcriptionally activates LIN28A expression. LIN28A expression level is directly associated with CpG methylation status of two promoter-region CpG islands. Bisulfite sequencing, ChIP assay for MeCP2 at LIN28A promoter, MeCP2 knockdown, 5-Aza-CdR treatment, LIN28A mRNA/protein measurement Oncotarget Medium 26910839

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Lin28A and Lin28B inhibit let-7 microRNA biogenesis by distinct mechanisms. Cell 529 22118463
2013 Lin28: primal regulator of growth and metabolism in stem cells. Cell stem cell 401 23561442
2017 The LIN28/let-7 Pathway in Cancer. Frontiers in genetics 382 28400788
2012 How does Lin28 let-7 control development and disease? Trends in cell biology 305 22784697
2009 Raf kinase inhibitory protein suppresses a metastasis signalling cascade involving LIN28 and let-7. The EMBO journal 304 19153603
2016 LIN28 Regulates Stem Cell Metabolism and Conversion to Primed Pluripotency. Cell stem cell 266 27320042
2006 Identification and characterization of lin-28 homolog B (LIN28B) in human hepatocellular carcinoma. Gene 254 16971064
2007 Lin-28 binds IGF-2 mRNA and participates in skeletal myogenesis by increasing translation efficiency. Genes & development 249 17473174
2009 LIN-28 and the poly(U) polymerase PUP-2 regulate let-7 microRNA processing in Caenorhabditis elegans. Nature structural & molecular biology 202 19713957
2013 SOX2-LIN28/let-7 pathway regulates proliferation and neurogenesis in neural precursors. Proceedings of the National Academy of Sciences of the United States of America 181 23884650
2014 Lin28/let-7 axis regulates aerobic glycolysis and cancer progression via PDK1. Nature communications 156 25301052
2015 Aberrant regulation of the LIN28A/LIN28B and let-7 loop in human malignant tumors and its effects on the hallmarks of cancer. Molecular cancer 155 26123544
2015 LIN28: roles and regulation in development and beyond. Development (Cambridge, England) 149 26199409
2013 LIN28/LIN28B: an emerging oncogenic driver in cancer stem cells. The international journal of biochemistry & cell biology 140 23420006
2014 Lin28 sustains early renal progenitors and induces Wilms tumor. Genes & development 138 24732380
2016 A Small-Molecule Inhibitor of Lin28. ACS chemical biology 125 27548809
2018 Lin28 Signaling Supports Mammalian PNS and CNS Axon Regeneration. Cell reports 97 30184489
2018 LIN28 Selectively Modulates a Subclass of Let-7 MicroRNAs. Molecular cell 96 30029005
2013 Mechanisms of Lin28-mediated miRNA and mRNA regulation--a structural and functional perspective. International journal of molecular sciences 96 23939427
2019 LIN28/let-7/PD-L1 Pathway as a Target for Cancer Immunotherapy. Cancer immunology research 85 30651289
2014 Lin28 and let-7: ancient milestones on the road from pluripotency to neurogenesis. Cell and tissue research 77 24825413
2014 Trim25 Is an RNA-Specific Activator of Lin28a/TuT4-Mediated Uridylation. Cell reports 71 25457611
2016 RNA-binding protein Lin28 in cancer and immunity. Cancer letters 68 26945970
2013 LIN28 Expression in malignant germ cell tumors downregulates let-7 and increases oncogene levels. Cancer research 66 23774216
2012 lin-28 controls the succession of cell fate choices via two distinct activities. PLoS genetics 63 22457637
2020 Lin28A promotes IRF6-regulated aerobic glycolysis in glioma cells by stabilizing SNHG14. Cell death & disease 59 32527996
2014 Lin28a regulates neuronal differentiation and controls miR-9 production. Nature communications 57 24722317
2019 The Lin28/let-7 Pathway Regulates the Mammalian Caudal Body Axis Elongation Program. Developmental cell 55 30661985
2016 Lin28 and let-7 in the Metabolic Physiology of Aging. Trends in endocrinology and metabolism: TEM 55 26811207
2021 LIN28 coordinately promotes nucleolar/ribosomal functions and represses the 2C-like transcriptional program in pluripotent stem cells. Protein & cell 52 34331666
2011 RNA-binding protein LIN28 is a marker for testicular germ cell tumors. Human pathology 52 21288558
2020 The Role of LIN28-let-7-ARID3B Pathway in Placental Development. International journal of molecular sciences 51 32455665
2022 RNA-binding protein complex LIN28/MSI2 enhances cancer stem cell-like properties by modulating Hippo-YAP1 signaling and independently of Let-7. Oncogene 49 35102250
2013 Lin28a regulates germ cell pool size and fertility. Stem cells (Dayton, Ohio) 45 23378032
2022 RNA-Binding Protein LIN28a Regulates New Myocyte Formation in the Heart Through Long Noncoding RNA-H19. Circulation 44 36314132
2020 Upregulating Lin28a Promotes Axon Regeneration in Adult Mice with Optic Nerve and Spinal Cord Injury. Molecular therapy : the journal of the American Society of Gene Therapy 44 32353321
2019 Lin28a Regulates Pathological Cardiac Hypertrophic Growth Through Pck2-Mediated Enhancement of Anabolic Synthesis. Circulation 42 30636447
2015 Lin-28 promotes symmetric stem cell division and drives adaptive growth in the adult Drosophila intestine. Development (Cambridge, England) 42 26487778
2017 Role of XIST/miR-29a/LIN28A pathway in denatured dermis and human skin fibroblasts (HSFs) after thermal injury. Journal of cellular biochemistry 41 28771809
2015 Lin28 and let-7 in cell metabolism and cancer. Translational pediatrics 39 26835354
2017 Knockdown of miR-128a induces Lin28a expression and reverts myeloid differentiation blockage in acute myeloid leukemia. Cell death & disease 37 28569789
2016 Lin28 and let-7: roles and regulation in liver diseases. American journal of physiology. Gastrointestinal and liver physiology 36 27012771
2016 Lin28a promotes self-renewal and proliferation of dairy goat spermatogonial stem cells (SSCs) through regulation of mTOR and PI3K/AKT. Scientific reports 36 27941834
2024 Development of miRNA-based PROTACs targeting Lin28 for breast cancer therapy. Science advances 33 39292784
2022 Lin28a induces SOX9 and chondrocyte reprogramming via HMGA2 and blunts cartilage loss in mice. Science advances 32 36026443
2019 LIN28A loss of function is associated with Parkinson's disease pathogenesis. The EMBO journal 30 31750563
2019 NANOG and LIN28 dramatically improve human cell reprogramming by modulating LIN41 and canonical WNT activities. Biology open 30 31806618
2012 Investigation of peripubertal expression of Lin28a and Lin28b in C57BL/6 female mice. Molecular and cellular endocrinology 30 23138112
2016 Lin28 is induced in primed embryonic stem cells and regulates let-7-independent events. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 29 27920151
2013 Lin28 promotes growth of prostate cancer cells and activates the androgen receptor. The American journal of pathology 29 23790802
2021 LINC01451 drives epithelial-mesenchymal transition and progression in bladder cancer cells via LIN28/TGF-β/Smad pathway. Cellular signalling 26 33516780
2021 Lin28a attenuates cerebral ischemia/reperfusion injury through regulating Sirt3-induced autophagy. Brain research bulletin 26 33548334
2020 Yap-lin28a axis targets let7-Wnt pathway to restore progenitors for initiating regeneration. eLife 26 32352377
2018 The stability and oncogenic function of LIN28A are regulated by USP28. Biochimica et biophysica acta. Molecular basis of disease 26 30543854
2014 Lin28/let-7/Bcl-xL pathway: the underlying mechanism of drug resistance in Hep3B cells. Oncology reports 26 24970027
2014 Expression of LIN28 and its regulatory microRNAs in adult adrenocortical cancer. Clinical endocrinology 26 25200669
2016 Lin28: an emerging important oncogene connecting several aspects of cancer. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 25 26762415
2022 LIN28A: A multifunctional versatile molecule with future therapeutic potential. World journal of biological chemistry 24 35432768
2019 CREB1/Lin28/miR-638/VASP Interactive Network Drives the Development of Breast Cancer. International journal of biological sciences 24 31754343
2017 Oncogenic mechanisms of Lin28 in breast cancer: new functions and therapeutic opportunities. Oncotarget 24 28147339
2016 Comparison of the expression and function of Lin28A and Lin28B in colon cancer. Oncotarget 24 27793004
2022 Lin28 Regulates Cancer Cell Stemness for Tumour Progression. Cancers 23 36230562
2020 Lin28a attenuates TGF-β-induced renal fibrosis. BMB reports 23 33050985
2013 Role of LIN28A in mouse and human trophoblast cell differentiation. Biology of reproduction 23 24006280
2022 Discovery of Novel Lin28 Inhibitors to Suppress Cancer Cell Stemness. Cancers 22 36428779
2021 Small molecules with tetrahydroquinoline-containing Povarov scaffolds as inhibitors disrupting the Protein-RNA interaction of LIN28-let-7. European journal of medicinal chemistry 22 34883291
2019 Dppa3 is critical for Lin28a-regulated ES cells naïve-primed state conversion. Journal of molecular cell biology 22 30481289
2016 LIN28: A Stem Cell Factor with a Key Role in Pediatric Tumor Formation. Stem cells and development 22 26692113
2019 LIN28A gene polymorphisms modify neuroblastoma susceptibility: A four-centre case-control study. Journal of cellular and molecular medicine 21 31747721
2016 MeCP2 suppresses LIN28A expression via binding to its methylated-CpG islands in pancreatic cancer cells. Oncotarget 21 26910839
2021 BMP4 activates the Wnt-Lin28A-Blimp1-Wnt pathway to promote primordial germ cell formation via altering H3K4me2. Journal of cell science 20 33443086
2021 LIN28a induced metabolic and redox regulation promotes cardiac cell survival in the heart after ischemic injury. Redox biology 20 34628272
2019 The Long Non-Coding RNA lep-5 Promotes the Juvenile-to-Adult Transition by Destabilizing LIN-28. Developmental cell 20 30956008
2018 Lin28a regulates neurogliogenesis in mammalian retina through the Igf signaling. Developmental biology 20 29758178
2014 Lin28a is dormant, functional, and dispensable during mouse oocyte-to-embryo transition. Biology of reproduction 20 24829024
2020 Lin28 gene and mammalian puberty. Molecular reproduction and development 19 32363678
2018 Role of Lin28A/let-7a/c-Myc Pathway in Growth and Malignant Behavior of Papillary Thyroid Carcinoma. Medical science monitor : international medical journal of experimental and clinical research 19 30531691
2019 LIN28: A cancer stem cell promoter for immunotherapy in head and neck squamous cell carcinoma. Oral oncology 18 31574415
2018 The RNA-binding protein LIN28 controls progenitor and neuronal cell fate during postnatal neurogenesis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 18 30423261
2016 Lin28a protects against postinfarction myocardial remodeling and dysfunction through Sirt1 activation and autophagy enhancement. Biochemical and biophysical research communications 18 27693787
2014 Reversible acetylation of Lin28 mediated by PCAF and SIRT1. Biochimica et biophysica acta 18 24631505
2014 LIN28A expression reduces sickling of cultured human erythrocytes. PloS one 18 25188417
2014 Lin-28 regulates oogenesis and muscle formation in Drosophila melanogaster. PloS one 17 24963666
2023 Mutual connected IL-6, EGFR and LIN28/Let7-related mechanisms modulate PD-L1 and IGF upregulation in HNSCC using immunotherapy. Frontiers in oncology 16 37124491
2021 Identification of RNA-binding proteins that partner with Lin28a to regulate Dnmt3a expression. Scientific reports 16 33504840
2019 FOXH1 Is Regulated by NANOG and LIN28 for Early-stage Reprogramming. Scientific reports 16 31712708
2016 Lin28A and androgen receptor expression in ER-/Her2+ breast cancer. Breast cancer research and treatment 16 26944953
2016 LIN-28 balances longevity and germline stem cell number in Caenorhabditis elegans through let-7/AKT/DAF-16 axis. Aging cell 16 27730721
2022 LIN28 Family in Testis: Control of Cell Renewal, Maturation, Fertility and Aging. International journal of molecular sciences 15 35806250
2020 SUMOylation modulates the LIN28A-let-7 signaling pathway in response to cellular stresses in cancer cells. Molecular oncology 15 32333719
2019 HMGA2 is regulated by LIN28 and BRCA1 in human placental cells. Biology of reproduction 15 30137214
2019 Lin28a expression protects against streptozotocin-induced β-cell destruction and prevents diabetes in mice. Cell biochemistry and function 15 30883865
2019 Lin28a protects against diabetic cardiomyopathy through Mst1 inhibition. Journal of cellular physiology 15 31637712
2023 Lin28a maintains a subset of adult muscle stem cells in an embryonic-like state. Cell research 14 37188880
2021 Lin28A/CENPE Promoting the Proliferation and Chemoresistance of Acute Myeloid Leukemia. Frontiers in oncology 13 34868981
2019 LIN28A gene polymorphisms confer Wilms tumour susceptibility: A four-centre case-control study. Journal of cellular and molecular medicine 13 31338973
2017 Extracellular Signal-regulated Kinases (ERKs) Phosphorylate Lin28a Protein to Modulate P19 Cell Proliferation and Differentiation. The Journal of biological chemistry 13 28179426
2022 LncRNA DDX11-AS1 Promotes Chemoresistance through LIN28A-Mediated ATG12 mRNA Stabilization in Breast Cancer. Pharmacology 12 36382664
2022 Lin28a induced mitochondrial dysfunction in human granulosa cells via suppressing LARS2 expression. Cellular signalling 12 36436798
2021 Non-microRNA binding competitively inhibits LIN28 regulation. Cell reports 12 34380031

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