Affinage

LIN28A

Protein lin-28 homolog A · UniProt Q9H9Z2

Length
209 aa
Mass
22.7 kDa
Annotated
2026-04-28
100 papers in source corpus 32 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LIN28A is a conserved RNA-binding protein that functions as a central post-transcriptional regulator of stem cell maintenance, metabolic programming, tissue regeneration, and oncogenesis by operating through both let-7-dependent and let-7-independent mechanisms. LIN28A blocks let-7 miRNA maturation by binding GGAGA motifs in the terminal loops of pre-let-7 via its cold shock domain (CSD) and zinc knuckle domain (ZKD), with the ZKD recruiting TUT4/TUT7 (aided by the cofactor TRIM25) to oligouridylate pre-let-7 for degradation; in the nucleus, SET7/9-methylated LIN28A sequesters pri-let-7 in nucleoli independently of TUTases (PMID:22898984, PMID:28297670, PMID:25457611, PMID:25479749). Beyond let-7, LIN28A directly binds hundreds of mRNAs—including those encoding IGF-2, OCT4, oxidative phosphorylation factors, and splicing regulators—enhancing their translation through recruitment of RNA helicase A to polysomes, and also maintains nucleolar integrity through a complex with nucleolin and TRIM28 (PMID:17473174, PMID:22959275, PMID:27920042, PMID:34331666). LIN28A activity is tuned by multiple post-translational modifications: SUMOylation at K15 enhances pre-let-7 binding, acetylation by PCAF (reversed by SIRT1) modulates protein levels, USP28-mediated deubiquitination extends its half-life, and MAPK-dependent phosphorylation of TRBP stabilizes LIN28A downstream of BDNF signaling (PMID:32333719, PMID:24631505, PMID:30543854, PMID:28132840).

Mechanistic history

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

    Before LIN28A's RNA targets were known, demonstration that it binds IGF-2 mRNA on polysomes and enhances translation in differentiating myoblasts established LIN28A as a translational regulator of specific mRNAs, not merely a developmental timing gene.

    Evidence Polysome fractionation, pulldown, and gain/loss-of-function in myoblasts

    PMID:17473174

    Open questions at the time
    • Mechanism of translational enhancement (cofactor identity) not yet known
    • Scope of mRNA targets unclear
  2. 2009 High

    Showing that LIN28A blocks processing of let-7 precursors and derepresses let-7 targets (HMGA2, K-Ras, c-Myc) to facilitate transformation established LIN28A as a master negative regulator of let-7 biogenesis with direct oncogenic consequences.

    Evidence Overexpression and loss-of-function in cancer cell lines with miRNA and target quantification

    PMID:19483683

    Open questions at the time
    • Enzymatic mechanism of let-7 destruction not identified
    • Whether LIN28A acts on pri- versus pre-let-7 not resolved
  3. 2009 Medium

    Identification that LIN28A binds Oct4 mRNA and stimulates its translation through interaction with RNA helicase A (RHA) revealed the cofactor mechanism underlying LIN28A's translational enhancement activity.

    Evidence RNA immunoprecipitation, reporter assays, and RHA knockdown in hESCs

    PMID:19966271

    Open questions at the time
    • RHA interaction domain not yet mapped
    • Generality beyond Oct4 unknown
  4. 2010 High

    A let-7-insensitive LIN28A mutant that still blocked gliogenesis demonstrated a biologically significant let-7-independent function, establishing that LIN28A operates through dual mechanisms.

    Evidence Constitutive expression of WT and mutant LIN28A in neural progenitor cultures with cell fate analysis

    PMID:20179095

    Open questions at the time
    • Molecular target(s) mediating let-7-independent gliogenesis block not identified
  5. 2011 Medium

    Domain mapping showed the LIN28A C-terminus recruits RHA to polysomes, and a C-terminal deletion acts as a dominant negative, clarifying the structural basis of LIN28A's translational enhancer function.

    Evidence Co-IP, polysome fractionation, and dominant-negative mutant analysis

    PMID:21247876

    Open questions at the time
    • Crystal structure of LIN28A–RHA complex not available
    • Mechanism by which RHA stimulates translation on specific mRNAs unknown
  6. 2012 High

    Biochemical reconstitution showing LIN28A recruits TUT4 (and redundantly TUT7) to uridylate pre-let-7 identified the enzymatic effector mechanism through which LIN28A destroys let-7 precursors.

    Evidence In vitro uridylation assays, domain dissection, ES cell knockdown

    PMID:22898984

    Open questions at the time
    • Structural basis of ZKD–TUT4 interaction not resolved
    • Cofactors enhancing TUT4 processivity not yet identified
  7. 2012 High

    Genome-wide CLIP-seq revealing LIN28A binds GGAGA motifs in hundreds of mRNAs (including splicing regulators) and autoregulates its own mRNA expanded LIN28A from a let-7 regulator to a broad post-transcriptional coordinator.

    Evidence CLIP-seq in hESCs and somatic cells with splicing-sensitive microarrays

    PMID:22959275

    Open questions at the time
    • Functional consequence validated for only a subset of targets
    • Mechanism of splicing regulation by LIN28A not characterized
  8. 2013 High

    Demonstration that SOX2 directly binds the LIN28 promoter and regulates its transcription established the upstream transcriptional control of LIN28A in neural precursor cells, positioning it within a SOX2→LIN28→let-7 axis.

    Evidence ChIP, promoter reporters, LIN28 rescue of SOX2-KD, let-7 misexpression

    PMID:23884650

    Open questions at the time
    • Other transcription factors controlling LIN28A in non-neural contexts not mapped
  9. 2014 High

    Multiple discoveries in 2014 resolved key regulatory layers: TRIM25 was identified as an RNA-specific cofactor activating TUT4 processivity; SET7/9 methylation was shown to retain LIN28A in nucleoli to sequester pri-let-7 independently of TUTases; PCAF acetylation (reversed by SIRT1) was found to reduce LIN28A protein; and uridylation-independent degradation of pre-miR-9 broadened LIN28A's miRNA substrate range.

    Evidence RNA pulldown/mass spectrometry and in vitro uridylation (TRIM25); methylation assays, subcellular fractionation, and pri-let-7 processing (SET7/9); in vitro acetylation/deacetylation assays (PCAF/SIRT1); inducible expression and miR-9 processing assays

    PMID:24631505 PMID:24722317 PMID:25457611 PMID:25479749

    Open questions at the time
    • Methylation site on LIN28A not identified at residue level
    • How uridylation-independent miR-9 degradation is mechanistically executed is unknown
    • Interplay between acetylation and methylation modifications not addressed
  10. 2014 High

    Conditional knockout showing Lin28a is required for clonal expansion of transit-amplifying spermatogonial progenitors—but not stem cell self-renewal—defined a cell-type-specific proliferative role distinct from pluripotency maintenance.

    Evidence Conditional KO mice; BrdU incorporation; spermatogonial transplantation

    PMID:24715688

    Open questions at the time
    • Direct mRNA targets mediating the proliferative effect in spermatogonia not identified
  11. 2015 High

    Systematic analysis of all 12 let-7 isoforms revealed that let-7a-3/let-7c-2 escapes LIN28A regulation due to loop geometry constraints, demonstrating that productive CSD–ZKD binding requires specific RNA secondary structure.

    Evidence In vitro binding and regulation assays across all let-7 family members

    PMID:26440890

    Open questions at the time
    • Structural basis of the incompatible loop geometry not solved at atomic resolution
  12. 2016 High

    Proteomic and metabolomic profiling showed LIN28A binds mRNAs encoding oxidative phosphorylation components and regulates one-carbon/nucleotide metabolism, linking LIN28A directly to metabolic reprogramming in stem cells.

    Evidence Proteomics, metabolomics, and mRNA binding assays in pluripotent cells

    PMID:27320042

    Open questions at the time
    • Whether metabolic regulation is entirely let-7-dependent or involves direct mRNA regulation not fully separated
  13. 2017 High

    Crystal structure of ZKD bound to pre-let-7f-1 at 2.0 Å showed the ZKD–RNA interface occupies a small druggable cavity, and reconstitution of a ZKD:NTUT4:pre-let-7 ternary complex demonstrated how TUT4 acquires processivity, providing the structural blueprint for the let-7 destruction machinery.

    Evidence X-ray crystallography; in vitro uridylation; domain mutagenesis; ternary complex reconstitution

    PMID:28297670

    Open questions at the time
    • Full-length LIN28A–TUT4–pre-let-7 complex structure not available
    • No small-molecule inhibitor validated against the druggable cavity
  14. 2017 High

    MAPK-dependent phosphorylation of TRBP was shown to stabilize LIN28A (but not LIN28B) downstream of BDNF signaling, coupling extracellular growth factor signaling to LIN28A activity and dendritic spine growth.

    Evidence Phospho-mimic TRBP; BDNF stimulation; Lin28a KD; dendritic spine imaging

    PMID:28132840

    Open questions at the time
    • Mechanism by which phospho-TRBP stabilizes LIN28A protein not resolved
    • Whether other kinase pathways converge on TRBP-LIN28A unknown
  15. 2018 Medium

    Identification of USP28 as a deubiquitinase that stabilizes LIN28A by reversing proteasomal ubiquitination revealed a key degradation-control mechanism and linked it to cancer cell viability.

    Evidence Co-IP; ubiquitination assays; protein half-life measurement; cancer cell functional assays

    PMID:30543854

    Open questions at the time
    • Identity of the E3 ubiquitin ligase targeting LIN28A not determined
    • Single-lab finding without independent replication
  16. 2018 High

    Demonstration that LIN28A overexpression drives robust optic nerve regeneration in retinal ganglion cells—additive with PTEN loss—established LIN28A as a sufficient pro-regenerative factor in the adult CNS via let-7 suppression.

    Evidence Gain/loss-of-function in primary neurons; optic nerve crush; let-7 epistasis

    PMID:30184489

    Open questions at the time
    • Direct regeneration-relevant mRNA targets of LIN28A in RGCs not catalogued
    • Whether let-7-independent mechanisms contribute to axon regeneration not fully excluded
  17. 2020 High

    SUMOylation at K15 was found to enhance LIN28A binding to pre-let-7 and TUT4 recruitment while blocking Dicer processing, integrating a stress-responsive modification (hypoxia-induced) into the let-7 regulatory circuit.

    Evidence In vivo/in vitro SUMOylation; K15R mutant; pre-let-7 binding; TUT4 co-IP; Dicer assays

    PMID:32333719

    Open questions at the time
    • SUMO E3 ligase responsible not identified
    • Whether SUMOylation alters LIN28A's mRNA-binding activity unknown
  18. 2021 High

    Discovery that LIN28A binds snoRNAs and rRNA, resides in a nucleolar complex with nucleolin and TRIM28, and that its loss triggers nucleolar stress and a 2C-like transcriptional program revealed a previously unappreciated role in nucleolar integrity and totipotency suppression.

    Evidence RIP, ChIP, Co-IP, loss-of-function in pluripotent stem cells, transcriptome analysis

    PMID:34331666

    Open questions at the time
    • Direct RNA targets within rDNA/snoRNA that mediate nucleolar integrity not mapped at single-nucleotide resolution
    • Whether nucleolar and cytoplasmic LIN28A pools are independently regulated unknown
  19. 2021 Medium

    Proteomic identification of high-molecular-weight LIN28A RNP complexes containing Ddx3x, Hnrnph1, Hnrnpu, and Syncrip—required for LIN28A binding to Dnmt3a mRNA—established that LIN28A functions as part of an oligomeric translational regulatory complex rather than as a monomeric RNA-binding protein.

    Evidence Affinity purification, quantitative mass spectrometry, RIP, functional knockdown in mESCs

    PMID:33504840

    Open questions at the time
    • Stoichiometry and assembly order of the complex not determined
    • Whether complex composition varies across cell types or target mRNAs unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Open question: how the multiple post-translational modifications (SUMOylation, methylation, acetylation, ubiquitination) are coordinately regulated and how they partition LIN28A between its nuclear/nucleolar and cytoplasmic functions remains unresolved.
  • No integrated model of PTM crosstalk on LIN28A
  • Full-length structure of LIN28A in complex with TUT4 and pre-let-7 not solved
  • Relative contributions of let-7-dependent versus let-7-independent mechanisms in vivo not quantified in most tissue contexts

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 9 GO:0098772 molecular function regulator activity 5 GO:0045182 translation regulator activity 4 GO:0140098 catalytic activity, acting on RNA 4
Localization
GO:0005829 cytosol 3 GO:0005730 nucleolus 2 GO:0005634 nucleus 1
Pathway
R-HSA-8953854 Metabolism of RNA 7 R-HSA-1266738 Developmental Biology 3 R-HSA-1430728 Metabolism 3 R-HSA-1643685 Disease 3 R-HSA-162582 Signal Transduction 2
Partners
DHX9NCLTRBPTRIM25TRIM28TUT4TUT7USP28
Complex memberships
LIN28A–NCL–TRIM28 nucleolar complexLIN28A–RHA translational RNPLIN28A–TUT4/TUT7–pre-let-7 uridylation complex

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 LIN28A blocks let-7 precursors from being processed to mature miRNAs, and overexpression coordinately represses let-7 family miRNAs while derepressing let-7 targets such as HMGA2, K-Ras and c-Myc, thereby facilitating cellular transformation in vitro. Overexpression and loss-of-function assays in cancer cell lines; let-7 and target mRNA/protein quantification Nature genetics High 19483683
2007 Lin-28 binds IGF-2 mRNA and increases translation efficiency in differentiating myoblasts by associating with polysomes and translation initiation complexes; Lin-28 localizes to stress granules and acts as a translational enhancer for IGF-2 to promote skeletal muscle differentiation. Loss-of-function and gain-of-function assays in myoblasts; polysome fractionation; biochemical pulldown; localization to stress granules by immunofluorescence Genes & development High 17473174
2012 LIN28A binds GGAGA sequence motifs enriched within loop structures of mRNAs (in addition to pre-let-7), directly regulates the protein abundance of splicing regulators in stem and somatic cells, and causes widespread alternative splicing changes; LIN28A also autoregulates its own mRNA. CLIP-seq in human embryonic stem cells and somatic cells; splicing-sensitive microarrays Molecular cell High 22959275
2012 LIN28A recruits the terminal uridylyl transferase Zcchc11 (TUT4) to selectively uridylate pre-let-7, blocking let-7 biogenesis; a second TUTase, Zcchc6 (TUT7), functions redundantly with LIN28A in embryonic stem cells to control let-7 expression. Biochemical reconstitution assays; domain dissection; in vitro uridylation assays; ES cell knockdown RNA (New York, N.Y.) High 22898984
2009 Lin28 binds Oct4 mRNA directly through high-affinity sites within its coding region and facilitates Oct4 expression at the post-transcriptional level in human embryonic stem cells; this involves an interaction between Lin28 and RNA helicase A (RHA), and reducing RHA levels impairs Lin28-dependent translational stimulation. RNA immunoprecipitation; reporter assays; RHA knockdown Nucleic acids research Medium 19966271
2011 Lin28a stimulates translation by recruiting RNA helicase A (RHA) to polysomes; the carboxyl terminus of Lin28 is required for interaction with both amino and carboxyl termini of RHA, and a C-terminal deletion mutant retaining RNA-binding activity fails to interact with RHA and acts as a dominant-negative inhibitor of Lin28-dependent translation. Polysome fractionation; Co-IP/pulldown; dominant-negative mutant analysis Nucleic acids research Medium 21247876
2009 Lin28a specifically associates with histone H2a mRNA in mouse embryonic stem cells; the coding region of H2a mRNA harbors high-affinity Lin28 binding sequences that stimulate reporter expression in a Lin28-dependent manner. RNA immunoprecipitation; reporter assays with Lin28-binding sequences Nucleic acids research Medium 19443445
2014 TRIM25 acts as an RNA-specific cofactor that binds the conserved terminal loop of pre-let-7 and activates TUT4, enabling more efficient Lin28a-mediated uridylation of pre-let-7 but not other pre-miRNAs; TRIM25 was identified via RNA pulldown coupled with quantitative mass spectrometry. RNA pulldown coupled with quantitative mass spectrometry; in vitro uridylation assays; domain mapping Cell reports High 25457611
2014 SET7/9 monomethylates LIN28A in a putative nucleolar localization region, increasing its nuclear retention and protein stability; methylated LIN28A sequesters pri-let-7 in the nucleoli of human ESCs and blocks its processing independently of TUT4/7, and also regulates MYC-pathway transcriptional targets to maintain stemness. Methylation assays; subcellular fractionation; immunofluorescence; pri-let-7 processing assays; gene expression analysis Cell stem cell High 25479749
2017 The zinc knuckle domain (ZKD) of LIN28A is necessary and sufficient to recruit TUT4 and initiate oligouridylation of pre-let-7; crystal structure of human LIN28 ZKD in complex with pre-let-7f-1 at 2.0 Å shows the ZKD-RNA interaction is constrained to a small druggable cavity; a stable ZKD:NTUT4:pre-let-7 ternary complex is crucial for acquired TUT4 processivity. Crystal structure (2.0 Å); in vitro uridylation assays; domain mutagenesis; ternary complex reconstitution Cell reports High 28297670
2014 Lin28a regulates miR-9 by inducing degradation of its precursor through a uridylation-independent mechanism during neuronal differentiation of P19 cells; Lin28a also blocks differentiation capacity of P19 cells in a manner coinciding with reduced miR-9 levels. Inducible expression system; miRNA processing assays; neuronal differentiation assays Nature communications Medium 24722317
2014 Lin28a/let-7 axis regulates aerobic glycolysis (Warburg effect) in cancer cells by targeting pyruvate dehydrogenase kinase 1 (PDK1) in a HIF-1-independent manner; PDK1 is critical for Lin28A-mediated cancer cell proliferation both in vitro and in vivo. Gain- and loss-of-function in cancer cells; in vivo tumor models; PDK1 target validation Nature communications High 25301052
2014 Lin28a binds the terminal loops of pre-let-7 miRNAs via its CSD and ZKD (GGAG/GGAGA motif recognition), with ZKD providing sequence specificity; the CSD and ZKD together form bipartite recognition of let-7 precursors. Biochemical binding assays; structural data reviewed; mutagenesis International journal of molecular sciences High 23939427
2014 PCAF directly interacts with and acetylates Lin28A, primarily at the cold shock domain, reducing Lin28 protein levels and increasing mature let-7a; SIRT1 specifically reverses this acetylation, and the PCAF/SIRT1 balance regulates Lin28 activity during let-7a biogenesis. Co-IP; in vitro acetylation assays; deacetylation assays with SIRT1; let-7a quantification Biochimica et biophysica acta Medium 24631505
2018 USP28 (a deubiquitinating enzyme) interacts with and stabilizes LIN28A protein by reversing its proteasomal ubiquitination-dependent degradation, thereby extending LIN28A half-life and augmenting LIN28A-mediated cancer cell viability and migration. Co-IP; ubiquitination assays; protein half-life measurement; functional cancer cell assays Biochimica et biophysica acta. Molecular basis of disease Medium 30543854
2020 LIN28A is SUMOylated at K15; SUMOylation increases LIN28A's binding affinity to pre-let-7, enhances LIN28A-mediated recruitment of TUT4, and simultaneously blocks Dicer processing of pre-let-7, thereby reducing mature let-7 production; SUMOylation is increased by hypoxia and reduced by chemotherapy drugs. In vivo and in vitro SUMOylation assays; K15R mutant analysis; pre-let-7 binding assays; TUT4 co-IP; Dicer processing assays Molecular oncology High 32333719
2017 MAPK-dependent phosphorylation of TRBP promotes binding and stabilization of Lin28a (but not Lin28b) downstream of BDNF signaling; phospho-TRBP reduces Lin28-regulated miRNAs and phospho-TRBP recapitulates BDNF-induced dendritic spine growth in a Lin28a-dependent manner. In vitro binding assays with phospho-mimic TRBP; BDNF stimulation; Lin28a KD; dendritic spine imaging Molecular cell High 28132840
2010 LIN28A expression blocks gliogenesis and promotes neurogenesis in vitro; a mutant LIN28A that permits let-7 accumulation still completely blocks gliogenesis, demonstrating that LIN28A has a let-7-independent biological activity in controlling cell fate succession. Constitutive expression and let-7-insensitive mutant in primary neural progenitor cultures; cell fate analysis Development (Cambridge, England) High 20179095
2016 LIN28A binds mRNAs encoding proteins important for oxidative phosphorylation and modulates their protein abundance; LIN28A and LIN28B regulate one-carbon metabolism, nucleotide metabolism, and histone methylation in stem cells, and maintain low mitochondrial function associated with primed pluripotency. Proteomics; metabolomics; mRNA binding assays; pluripotency conversion assays Cell stem cell High 27320042
2021 LIN28A binds small nucleolar RNAs and rRNA to maintain nucleolar integrity; LIN28A resides in a complex with nucleolin (NCL) and TRIM28, and LIN28A loss reduces NCL/TRIM28 occupancy at Dux and rDNA loci, de-repressing Dux and reducing rRNA expression, thereby triggering nucleolar stress and a 2C-like transcriptional program. RIP; ChIP; Co-IP; loss-of-function in pluripotent stem cells; transcriptome analysis Protein & cell High 34331666
2021 Lin28a forms high molecular weight ribonucleoprotein complexes in mouse ESCs containing multiple RNA-binding proteins and helicases (including Ddx3x, Hnrnph1, Hnrnpu, and Syncrip); suppression of these partner proteins interferes with Lin28a binding to Dnmt3a mRNA, indicating they are required components of an oligomeric RNP complex necessary for Lin28a's translational regulatory activity. Affinity purification of Lin28a complexes; quantitative mass spectrometry proteomics; RIP; functional knockdown assays Scientific reports Medium 33504840
2014 Lin28a is required for cyclic clonal expansion of transit-amplifying A(undiff) spermatogonial progenitors in the adult male germline; conditional deletion of Lin28a reduces in vivo BrdU incorporation in A(undiff) cells without affecting stem cell self-renewal capacity or causing precocious differentiation. Conditional knockout mice; BrdU incorporation; spermatogonial transplantation assays Stem cells (Dayton, Ohio) High 24715688
2018 Lin28a/b are necessary and sufficient for axon regeneration in mature sensory neurons through their regulatory partner let-7 miRNAs; overexpression of Lin28a in retinal ganglion cells produces robust optic nerve regeneration; combined overexpression of Lin28a and downregulation of Pten act additively to promote CNS axon regeneration. Loss-of-function and gain-of-function in primary neurons; optic nerve crush model; let-7 epistasis Cell reports High 30184489
2013 SOX2 binds the LIN28 promoter and regulates LIN28 promoter acetylation through interactions with a histone acetyltransferase complex, establishing a SOX2→LIN28→let-7 axis that governs neural precursor cell proliferation and neurogenic potential. ChIP; promoter reporter assays; LIN28 rescue of SOX2-KD phenotype; let-7 misexpression Proceedings of the National Academy of Sciences of the United States of America High 23884650
2015 A single human let-7 family member, let-7a-3 (murine let-7c-2), escapes LIN28A-mediated regulation because the pre-let-7c-2 terminal loop structure precludes LIN28A binding; this demonstrates that the cold shock domain and CCHC zinc fingers require specific loop geometry for productive interaction. Systematic in vitro binding assays; LIN28A regulation assays for all 12 let-7 isoforms Cell reports High 26440890
2016 Lin28a binds and stabilizes FBXL19-AS1 lncRNA (demonstrated by RIP assay); stabilized FBXL19-AS1 promotes breast cancer migration, invasion, and EMT by upregulating WDR66 expression. RIP assay; gain- and loss-of-function; Western blot; migration/invasion assays In vitro cellular & developmental biology. Animal Low 31140103
2017 Hypothalamic LIN28A regulates glucose metabolism through TBK-1 as a direct target mRNA (independent of Let-7); VMH-specific LIN28A overexpression improves glucose tolerance and insulin sensitivity in diet-induced obese mice via altered AKT signaling linked to TBK-1. VMH-targeted viral overexpression/knockdown; glucose tolerance tests; TBK-1 target validation; Let-7 levels measured as control Diabetes Medium 28550108
2016 LARP7 interacts with a poly(A) polymerase Star-PAP to maintain Lin28a mRNA stability in embryonic stem cells; Larp7 knockdown reduces Lin28 levels, priming ESCs for differentiation without affecting pluripotency directly. Co-IP; mRNA stability assays; ESC differentiation assays; KD experiments Cell reports Medium 24768001
2016 Lin28a binds the 3'UTR of Hmga2 mRNA through a conserved element and post-transcriptionally downregulates Hmga2 translation in a let-7-independent manner during ESC differentiation; this prevents inappropriate accumulation of Hmga2 that would alter proliferation and apoptosis. RIP; reporter assays with 3'UTR; Otx2/Hmga2 KO ESCs; protein quantification FASEB journal Medium 27920151
2012 Lin28a directly interacts with ROCK2 (but not ROCK1) in ovarian cancer cells and upregulates ROCK2 expression; Lin28A/ROCK2 interaction promotes cancer cell survival, invasion, and metastasis; binding sites were mapped by truncated mutations and co-IP. Co-IP; truncation/domain-mapping mutations; ROCK2 knockdown rescue experiments; in vivo xenograft Oncogene Medium 30266988
2020 LIN28A directly interacts with MALAT1 lncRNA and facilitates MALAT1-mediated stabilization of Nox4 mRNA, activating the AMPK/mTOR signaling axis in diabetic nephropathy; MALAT1-LIN28A-Nox4 interaction demonstrated by RIP and RNA pulldown assays. RIP assay; RNA pulldown; KD/OE functional assays in HK-2 cells; in vivo DN rat model Frontiers in endocrinology Low 35813614
2020 In zebrafish lateral line, Yap activation upregulates lin28a transcription after severe injury; lin28a is necessary and sufficient to regenerate sox2+ progenitors; mechanistically, let-7 acts downstream of lin28a to activate Wnt pathway for promoting hair cell progenitor regeneration. lin28a and yap mutants; lin28a overexpression; let-7/Wnt epistasis analysis eLife Medium 32352377

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Lin28 promotes transformation and is associated with advanced human malignancies. Nature genetics 704 19483683
2013 Lin28: primal regulator of growth and metabolism in stem cells. Cell stem cell 399 23561442
2017 The LIN28/let-7 Pathway in Cancer. Frontiers in genetics 378 28400788
2012 How does Lin28 let-7 control development and disease? Trends in cell biology 305 22784697
2002 Two genetic circuits repress the Caenorhabditis elegans heterochronic gene lin-28 after translation initiation. Developmental biology 297 11884032
2016 LIN28 Regulates Stem Cell Metabolism and Conversion to Primed Pluripotency. Cell stem cell 264 27320042
2006 Identification and characterization of lin-28 homolog B (LIN28B) in human hepatocellular carcinoma. Gene 253 16971064
2007 Lin-28 binds IGF-2 mRNA and participates in skeletal myogenesis by increasing translation efficiency. Genes & development 249 17473174
2012 LIN28 binds messenger RNAs at GGAGA motifs and regulates splicing factor abundance. Molecular cell 229 22959275
2010 Pluripotency factors Lin28 and Oct4 identify a sub-population of stem cell-like cells in ovarian cancer. Oncogene 212 20101213
2017 H19/let-7/LIN28 reciprocal negative regulatory circuit promotes breast cancer stem cell maintenance. Cell death & disease 203 28102845
2009 Lin28-mediated post-transcriptional regulation of Oct4 expression in human embryonic stem cells. Nucleic acids research 181 19966271
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 180 23884650
2012 Lin28-mediated control of let-7 microRNA expression by alternative TUTases Zcchc11 (TUT4) and Zcchc6 (TUT7). RNA (New York, N.Y.) 176 22898984
2010 LIN28 alters cell fate succession and acts independently of the let-7 microRNA during neurogliogenesis in vitro. Development (Cambridge, England) 163 20179095
2003 Temporally regulated expression of Lin-28 in diverse tissues of the developing mouse. Gene expression patterns : GEP 158 14643679
2014 Lin28/let-7 axis regulates aerobic glycolysis and cancer progression via PDK1. Nature communications 155 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 154 26123544
2015 LIN28: roles and regulation in development and beyond. Development (Cambridge, England) 148 26199409
2014 Lin28 sustains early renal progenitors and induces Wilms tumor. Genes & development 137 24732380
2016 A Small-Molecule Inhibitor of Lin28. ACS chemical biology 124 27548809
2012 Oncomir miR-125b regulates hematopoiesis by targeting the gene Lin28A. Proceedings of the National Academy of Sciences of the United States of America 122 22366319
2011 MiR-181 mediates cell differentiation by interrupting the Lin28 and let-7 feedback circuit. Cell death and differentiation 118 21979467
2018 Lin28 Signaling Supports Mammalian PNS and CNS Axon Regeneration. Cell reports 96 30184489
2013 Mechanisms of Lin28-mediated miRNA and mRNA regulation--a structural and functional perspective. International journal of molecular sciences 96 23939427
2016 MicroRNA-145 Regulates Neural Stem Cell Differentiation Through the Sox2-Lin28/let-7 Signaling Pathway. Stem cells (Dayton, Ohio) 93 26849971
2015 LIN28 cooperates with WNT signaling to drive invasive intestinal and colorectal adenocarcinoma in mice and humans. Genes & development 88 25956904
2019 LIN28/let-7/PD-L1 Pathway as a Target for Cancer Immunotherapy. Cancer immunology research 83 30651289
2011 Evidence that Lin28 stimulates translation by recruiting RNA helicase A to polysomes. Nucleic acids research 82 21247876
2012 A mirror of two faces: Lin28 as a master regulator of both miRNA and mRNA. Wiley interdisciplinary reviews. RNA 79 22467269
2014 Trim25 Is an RNA-Specific Activator of Lin28a/TuT4-Mediated Uridylation. Cell reports 71 25457611
2014 LIN28A marks the spermatogonial progenitor population and regulates its cyclic expansion. Stem cells (Dayton, Ohio) 69 24715688
2014 SET7/9 methylation of the pluripotency factor LIN28A is a nucleolar localization mechanism that blocks let-7 biogenesis in human ESCs. Cell stem cell 69 25479749
2016 RNA-binding protein Lin28 in cancer and immunity. Cancer letters 68 26945970
2012 lin-28 controls the succession of cell fate choices via two distinct activities. PLoS genetics 63 22457637
2012 Lin28 regulates HER2 and promotes malignancy through multiple mechanisms. Cell cycle (Georgetown, Tex.) 63 22713243
2017 LIN28 Zinc Knuckle Domain Is Required and Sufficient to Induce let-7 Oligouridylation. Cell reports 60 28297670
2009 Histone H2a mRNA interacts with Lin28 and contains a Lin28-dependent posttranscriptional regulatory element. Nucleic acids research 59 19443445
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
2021 LIN28 coordinately promotes nucleolar/ribosomal functions and represses the 2C-like transcriptional program in pluripotent stem cells. Protein & cell 51 34331666
2020 The Role of LIN28-let-7-ARID3B Pathway in Placental Development. International journal of molecular sciences 50 32455665
2015 A Single Let-7 MicroRNA Bypasses LIN28-Mediated Repression. Cell reports 48 26440890
2015 Sex-specific regulation of weight and puberty by the Lin28/let-7 axis. The Journal of endocrinology 45 26698568
2013 Lin28a regulates germ cell pool size and fertility. Stem cells (Dayton, Ohio) 45 23378032
2020 H19/let‑7/Lin28 ceRNA network mediates autophagy inhibiting epithelial‑mesenchymal transition in breast cancer. International journal of oncology 42 32124962
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
2017 Knockdown of miR-128a induces Lin28a expression and reverts myeloid differentiation blockage in acute myeloid leukemia. Cell death & disease 37 28569789
2017 Concise Review: LIN28/let-7 Signaling, a Critical Double-Negative Feedback Loop During Pluripotency, Reprogramming, and Tumorigenicity. Cellular reprogramming 36 28846452
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
2014 LIN28 is involved in glioma carcinogenesis and predicts outcomes of glioblastoma multiforme patients. PloS one 36 24475120
2019 The Makorin lep-2 and the lncRNA lep-5 regulate lin-28 to schedule sexual maturation of the C. elegans nervous system. eLife 34 31264582
2015 A novel mechanism of LIN-28 regulation of let-7 microRNA expression revealed by in vivo HITS-CLIP in C. elegans. RNA (New York, N.Y.) 34 25805859
2019 Dual regulation of lin28a by Myc is necessary during zebrafish retina regeneration. The Journal of cell biology 32 30606747
2015 Lin28a protects against cardiac ischaemia/reperfusion injury in diabetic mice through the insulin-PI3K-mTOR pathway. Journal of cellular and molecular medicine 31 25688987
2022 Lin28a induces SOX9 and chondrocyte reprogramming via HMGA2 and blunts cartilage loss in mice. Science advances 30 36026443
2012 Investigation of peripubertal expression of Lin28a and Lin28b in C57BL/6 female mice. Molecular and cellular endocrinology 30 23138112
2024 Development of miRNA-based PROTACs targeting Lin28 for breast cancer therapy. Science advances 29 39292784
2013 Lin28 promotes growth of prostate cancer cells and activates the androgen receptor. The American journal of pathology 29 23790802
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 28 27920151
2021 LINC01451 drives epithelial-mesenchymal transition and progression in bladder cancer cells via LIN28/TGF-β/Smad pathway. Cellular signalling 26 33516780
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
2013 The Lin28/let-7a/c-Myc pathway plays a role in non-muscle invasive bladder cancer. Cell and tissue research 26 24036903
2017 A Rapid Induction Mechanism for Lin28a in Trophic Responses. Molecular cell 25 28132840
2016 Makorin ortholog LEP-2 regulates LIN-28 stability to promote the juvenile-to-adult transition in Caenorhabditis elegans. Development (Cambridge, England) 24 26811380
2022 LncRNA MALAT1 Aggravates Renal Tubular Injury via Activating LIN28A and the Nox4/AMPK/mTOR Signaling Axis in Diabetic Nephropathy. Frontiers in endocrinology 23 35813614
2022 Lin28 Regulates Cancer Cell Stemness for Tumour Progression. Cancers 23 36230562
2018 The interaction of Lin28A/Rho associated coiled-coil containing protein kinase2 accelerates the malignancy of ovarian cancer. Oncogene 23 30266988
2017 Oncogenic mechanisms of Lin28 in breast cancer: new functions and therapeutic opportunities. Oncotarget 23 28147339
2014 Primordial dwarfism gene maintains Lin28 expression to safeguard embryonic stem cells from premature differentiation. Cell reports 23 24768001
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
2016 LIN28: A Stem Cell Factor with a Key Role in Pediatric Tumor Formation. Stem cells and development 22 26692113
2013 Expression of exogenous LIN28 contributes to proliferation and survival of mouse primary cortical neurons in vitro. Neuroscience 22 23806711
2021 Small molecules with tetrahydroquinoline-containing Povarov scaffolds as inhibitors disrupting the Protein-RNA interaction of LIN28-let-7. European journal of medicinal chemistry 21 34883291
2019 Dppa3 is critical for Lin28a-regulated ES cells naïve-primed state conversion. Journal of molecular cell biology 21 30481289
2019 LIN28A-stabilized FBXL19-AS1 promotes breast cancer migration, invasion and EMT by regulating WDR66. In vitro cellular & developmental biology. Animal 21 31140103
2016 MeCP2 suppresses LIN28A expression via binding to its methylated-CpG islands in pancreatic cancer cells. Oncotarget 21 26910839
2015 Intraocular Medulloepitheliomas and Embryonal Tumors With Multilayered Rosettes of the Brain: Comparative Roles of LIN28A and C19MC. American journal of ophthalmology 21 25748578
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
2021 MicroRNA-15a-5p acts as a tumor suppressor in histiocytosis by mediating CXCL10-ERK-LIN28a-let-7 axis. Leukemia 20 34785791
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
2019 The Long Non-Coding RNA lep-5 Promotes the Juvenile-to-Adult Transition by Destabilizing LIN-28. Developmental cell 19 30956008
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
2016 Lin28a protects against postinfarction myocardial remodeling and dysfunction through Sirt1 activation and autophagy enhancement. Biochemical and biophysical research communications 18 27693787
2015 Lin28a protects against diabetic cardiomyopathy via the PKA/ROCK2 pathway. Biochemical and biophysical research communications 18 26626075
2014 Germ cell loss is associated with fading Lin28a expression in a mouse model for Klinefelter's syndrome. Reproduction (Cambridge, England) 18 24298047
2022 Pharmacological inhibition of Lin28 promotes ketogenesis and restores lipid homeostasis in models of non-alcoholic fatty liver disease. Nature communications 17 36572670
2014 Reversible acetylation of Lin28 mediated by PCAF and SIRT1. Biochimica et biophysica acta 17 24631505
2014 Lin-28 regulates oogenesis and muscle formation in Drosophila melanogaster. PloS one 17 24963666
2020 Lin28a/let-7 pathway modulates the Hox code via Polycomb regulation during axial patterning in vertebrates. eLife 16 32479258
2017 Hypothalamic Ventromedial Lin28a Enhances Glucose Metabolism in Diet-Induced Obesity. Diabetes 16 28550108
2021 Identification of RNA-binding proteins that partner with Lin28a to regulate Dnmt3a expression. Scientific reports 15 33504840
2020 SUMOylation modulates the LIN28A-let-7 signaling pathway in response to cellular stresses in cancer cells. Molecular oncology 15 32333719