Affinage

RLIM

E3 ubiquitin-protein ligase RLIM · UniProt Q9NVW2

Length
624 aa
Mass
68.5 kDa
Annotated
2026-06-10
57 papers in source corpus 33 papers cited in narrative 33 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RLIM/RNF12 is an X-linked RING-H2 E3 ubiquitin ligase that controls transcriptional programs and developmental cell-fate decisions, originally identified as a corepressor that recruits the Sin3A/histone deacetylase complex to LIM-homeodomain transcription factors (PMID:10431247). Its defining developmental role is as a dose-dependent, trans-acting activator of X chromosome inactivation: extra Rnf12 copies drive ectopic XCI while loss prevents Xist upregulation (PMID:19945382, PMID:21298085), and this activity operates through ubiquitin-dependent proteasomal degradation of the pluripotency factor and Xist repressor REX1 (PMID:22596162). REX1 is the critical effector, since genetic ablation of Rex1 rescues both the XCI defect of Rnf12-null ES cells and the embryonic lethality of Rnf12-null mice (PMID:30420655). RLIM function is allele- and context-specific: maternally transmitted RLIM is required to initiate imprinted XCI in pre-implantation embryos (PMID:20962847, PMID:38113263), yet it is dispensable for random XCI in the embryonic epiblast, where REX1 is downregulated independently of RLIM (PMID:24870238, PMID:38113263). As an E3 ligase RLIM ubiquitinates a broad substrate set to regulate diverse pathways—degrading Smad7 to potentiate TGF-β/BMP/Nodal-Smad signaling (PMID:22560923), MDM2 to stabilize p53 (PMID:26926424), BRF1 to restrain RNA polymerase III transcription (PMID:30413534), and TRF1 to maintain telomere homeostasis (PMID:19164295)—and conversely stabilizes ZC4H2 to support Shh signaling (PMID:35040952). Its activity is regulated at multiple levels: chromatin recruitment via a non-catalytic basic region under N-terminal autoinhibition targets it to REX1-bound promoters (PMID:38199845), a transcriptional feed-forward loop with the deubiquitylase USP26 prevents RLIM autoubiquitylation and sustains its levels in testis (PMID:35857630), and nucleocytoplasmic shuttling controlled by S214 phosphorylation governs its biological output (PMID:23904271). RLIM is essential for milk-producing mammary alveolar cell survival (PMID:22541433), spermiogenesis (PMID:33620316), and energy balance through hypothalamic neurons (PMID:40766619). X-linked intellectual disability/TOKAS patient mutations cluster in the catalytic RING domain or the distal basic regulatory region, abolishing efficient ubiquitin transfer and impairing stem cell maintenance and neural differentiation (PMID:29742418, PMID:33953269).

Mechanistic history

Synthesis pass · year-by-year structured walk · 32 steps
  1. 1999 High

    Established RLIM's founding molecular identity as a transcriptional corepressor that links LIM-homeodomain factors to chromatin-modifying machinery, defining its earliest known mode of action before its enzymatic role was appreciated.

    Evidence Protein interaction and corepressor recruitment assays plus in vivo chick wing overexpression

    PMID:10431247

    Open questions at the time
    • Did not establish E3 ligase activity
    • Relationship between corepressor recruitment and ubiquitination unresolved
  2. 2009 High

    Defined RLIM/RNF12 as a dose-dependent, X-encoded activator of X chromosome inactivation, answering how an autosome-independent trans factor could initiate XCI and revealing dosage as the key trigger.

    Evidence Transgenic ES cell overexpression and heterozygous knockout XCI assays

    PMID:19945382

    Open questions at the time
    • Did not identify the molecular substrate transmitting the signal to Xist
    • Mechanism of dose-sensing unresolved
  3. 2009 Medium

    Identified the first ubiquitination substrate of RLIM, TRF1, connecting its enzymatic activity to telomere length control.

    Evidence Co-IP, in vitro ubiquitination, shRNA knockdown and telomere length measurement

    PMID:19164295

    Open questions at the time
    • Single lab
    • Relationship to XCI role not addressed
  4. 2010 High

    Demonstrated that maternally transmitted RLIM is specifically required for imprinted XCI in vivo, distinguishing imprinted from random XCI and establishing parent-of-origin dependence.

    Evidence Oocyte-specific conditional knockout mouse genetics with Xist FISH and silencing assays

    PMID:20962847

    Open questions at the time
    • Did not explain why random XCI is RLIM-independent
    • Substrate mediating iXCI not yet identified
  5. 2011 Medium

    Placed Rnf12 within the pluripotency regulatory network by showing its repression by Nanog/Oct4/Sox2, linking developmental timing of XCI to the pluripotency state.

    Evidence ChIP, reporter assays and pluripotency factor perturbation in ES cells

    PMID:21544581

    Open questions at the time
    • Single lab
    • Direct vs indirect transcriptional control not fully resolved
  6. 2011 High

    Confirmed RNF12 acts in trans to activate Xist independently of Tsix or Xist intron 1, narrowing the regulatory route for XCI initiation.

    Evidence Rnf12 knockout ES cells with Xist FISH and expression analysis

    PMID:21298085

    Open questions at the time
    • Effector substrate not yet defined
    • Mechanism of trans action unresolved at this stage
  7. 2012 High

    Identified REX1 as a key RNF12 ubiquitination substrate and XCI repressor, providing the molecular bridge between RLIM ligase activity and Xist activation.

    Evidence Co-IP, ubiquitination assay, knockout ES cells, ChIP-seq and REX1 perturbation with Xist FISH

    PMID:22596162

    Open questions at the time
    • Whether REX1 alone accounts for all XCI defects not yet tested
    • Chromatin recruitment mechanism unknown
  8. 2012 High

    Extended RLIM's substrate repertoire to Smad7, establishing it as a positive regulator of TGF-β/BMP/Nodal-Smad signaling with in vivo developmental relevance.

    Evidence Co-IP, ubiquitination assay, ES cell loss-of-function and zebrafish rescue

    PMID:22560923

    Open questions at the time
    • Tissue contexts of Smad7 regulation incomplete
    • Interplay with XCI substrate selectivity unclear
  9. 2012 High

    Revealed a tissue-specific, allele-specific survival function for RLIM in mammary alveolar cells, showing its physiological roles extend beyond embryonic XCI.

    Evidence Mammary-specific conditional knockout with apoptosis, differentiation and allele-specific expression analysis

    PMID:22541433

    Open questions at the time
    • Substrate mediating alveolar survival not defined
    • Mechanism linking XCI status to allele usage incompletely resolved
  10. 2013 Medium

    Showed that S214 phosphorylation-dependent nucleocytoplasmic shuttling is required for RLIM biological function, identifying subcellular trafficking as a regulatory layer.

    Evidence Phospho-site mutagenesis, fractionation, live imaging and rescue in mammary cells

    PMID:23904271

    Open questions at the time
    • Kinase responsible not identified in this study
    • Single lab
  11. 2013 Medium

    Defined upstream transcriptional control of RLIM by the p53-Sp1 axis, connecting RLIM expression to tumor suppressor regulatory circuits.

    Evidence Promoter reporter assays, ChIP and Co-IP with p53 mutants

    PMID:23650532

    Open questions at the time
    • Single lab
    • Physiological contexts of p53-mediated RLIM repression untested
  12. 2014 High

    Demonstrated RLIM is dispensable for random XCI in the embryonic epiblast, sharpening the distinction between imprinted and random XCI mechanisms.

    Evidence Conditional mouse genetics with Xist FISH, H3K27me3 IF and embryo viability

    PMID:24870238

    Open questions at the time
    • Identity of the RLIM-independent Xist activator unknown at this stage
    • Why rXCI bypasses RLIM not yet mechanistically explained
  13. 2014 Medium

    Resolved that XCI proceeds through trans-acting diffusible factors rather than X-X pairing, positioning Rnf12 dosage as acting at sequential initiation and maintenance steps with cis elements.

    Evidence ES cell genetics with Rnf12 dosage manipulation and cis-element deletion

    PMID:24613346

    Open questions at the time
    • Single lab
    • Quantitative integration of cis and trans inputs incomplete
  14. 2014 Low

    Added Stathmin as a proliferation-relevant RLIM substrate, extending its ligase activity to cell cycle and oncoprotein control.

    Evidence Co-IP, ubiquitination assay and siRNA knockdown with proliferation/cell cycle assays

    PMID:24686088

    Open questions at the time
    • Low-confidence single lab with limited mechanistic validation
    • In vivo relevance untested
  15. 2015 Low

    Showed PIWIL1 competitively protects Stathmin1 from RLIM, revealing substrate-level antagonism that modulates RLIM output.

    Evidence Co-IP, ubiquitination and competition binding assays

    PMID:26317901

    Open questions at the time
    • Single set of assays, single lab
    • Physiological context of competition undefined
  16. 2016 Medium

    Established RNF12 as an MDM2 ligase that elevates p53, embedding RLIM in the p53 tumor suppressor axis.

    Evidence Yeast two-hybrid, Co-IP, ubiquitination assay and growth/apoptosis assays

    PMID:26926424

    Open questions at the time
    • Single lab
    • Reconciliation with p53-mediated repression of RLIM not addressed
  17. 2016 Medium

    Showed RLIM ubiquitinates c-Myc without affecting its stability, instead repressing its transcriptional activity, revealing a non-degradative ubiquitination mode.

    Evidence Co-IP, in vivo/in vitro ubiquitination and c-Myc reporter/proliferation assays

    PMID:27684546

    Open questions at the time
    • Ubiquitin linkage type and downstream reader unknown
    • Single lab
  18. 2017 Low

    Identified a MIZ1-binding, non-degradative mechanism by which RLIM disrupts c-MYC-MIZ1 to derepress CDK inhibitors, expanding its transcriptional tumor-suppressive activity.

    Evidence Co-IP, competition binding, reporter and cell cycle assays

    PMID:29137325

    Open questions at the time
    • Low-confidence single lab
    • In vivo validation limited
  19. 2018 High

    Linked RLIM to X-linked intellectual disability by showing patient mutations inactivate the RING domain or a distal basic regulatory region required for ubiquitin transfer, mapping disease mechanism to enzymatic failure.

    Evidence RING mutagenesis, in vitro ubiquitination and ES cell differentiation assays

    PMID:29742418

    Open questions at the time
    • Disease-relevant substrate in neurons not pinpointed here
    • Function of the basic region in catalysis incompletely defined
  20. 2018 High

    Proved by epistasis that REX1 is the prime critical RNF12 target in XCI, since Rex1 deletion rescues both ES cell XCI defects and mouse embryonic lethality.

    Evidence Rnf12;Rex1 double knockout mouse and ES cell genetics with XCI markers

    PMID:30420655

    Open questions at the time
    • Other substrates' contributions to non-XCI phenotypes not excluded
    • Promoter targeting mechanism still open
  21. 2018 Medium

    Identified BRF1 as a substrate subject to Lys27/Lys33 polyubiquitination, connecting RNF12 to negative control of RNA polymerase III transcription.

    Evidence Co-IP, linkage-specific ubiquitination and Pol III transcription/proliferation assays

    PMID:30413534

    Open questions at the time
    • Functional consequence of non-canonical linkages unresolved
    • Single lab
  22. 2020 Medium

    Placed RLIM within a sequential TRIM28→RLIM→MDM2 cascade controlling p53 in tumorigenesis, defining upstream regulation of its ligase activity in cancer.

    Evidence Co-IP, ubiquitination assays, perturbation and xenograft models

    PMID:33328571

    Open questions at the time
    • Single lab
    • Direct vs indirect TRIM28-RLIM regulation incompletely defined
  23. 2020 Medium

    Showed the KSHV LANA protein hijacks RLIM, promoting its autoubiquitination while selectively redirecting substrate degradation, revealing viral modulation of RLIM activity.

    Evidence Co-IP with MG132, ubiquitination assays, RING mutant and substrate stability assays

    PMID:31865802

    Open questions at the time
    • Mechanism of differential substrate selectivity unresolved
    • Single lab
  24. 2021 High

    Revealed a spermiogenesis function for RLIM in round spermatids and Sertoli cells, expanding its physiological roles to male fertility.

    Evidence Systemic and lineage-specific Rlim knockout mice with sperm morphology, motility and IVF assays

    PMID:33620316

    Open questions at the time
    • Substrate driving spermiogenesis defect not identified here
    • Cell-autonomy between germ cells and Sertoli cells unresolved
  25. 2021 Medium

    Showed a disease-associated missense variant adjacent to the basic region destabilizes RLIM and impairs ligase activity and Xist induction, linking protein stability to disease mechanism.

    Evidence Stability and in vitro ubiquitination assays, localization and Xist induction in ES cells

    PMID:33953269

    Open questions at the time
    • Single lab
    • In vivo phenotype of the variant untested
  26. 2022 Medium

    Identified AKT phosphorylation as a driver of RNF12 nuclear localization and stability that accelerates SMAD7 degradation to promote breast cancer metastasis, integrating kinase signaling with RLIM regulation.

    Evidence Co-IP, phosphorylation and fractionation assays, ubiquitination, migration and xenograft metastasis models

    PMID:35013159

    Open questions at the time
    • Phosphorylation site(s) relationship to S214 not reconciled
    • Single lab
  27. 2022 Medium

    Revealed a stabilizing RLIM→ZC4H2→RNF220 cascade supporting Shh signaling in cerebellar progenitors and medulloblastoma, demonstrating a non-degradative, stabilizing ubiquitination output.

    Evidence Co-IP, ubiquitination, stability and Shh signaling assays with patient mutation analysis

    PMID:35040952

    Open questions at the time
    • Mechanism of stabilizing vs degradative ubiquitination unresolved
    • Single lab
  28. 2022 High

    Defined a transcriptional feed-forward loop in which RNF12 relieves REX1 repression of Usp26, and USP26 reciprocally protects RNF12 from autoubiquitylation, providing a testis-specific amplification mechanism.

    Evidence Quantitative proteomics, Co-IP, ubiquitination and reporter assays, germ cell differentiation and disease variant analysis

    PMID:35857630

    Open questions at the time
    • Tissue specificity of the loop mechanistically incomplete
    • Generalization beyond testis untested
  29. 2023 Medium

    Explained the imprinted-versus-random XCI dichotomy by showing the Rlim-Rex1 axis operates in pre-implantation embryos, after which Rex1 is downregulated independently of Rlim in epiblast cells.

    Evidence Mouse embryo genetics with stage-resolved protein analysis and conditional knockouts

    PMID:38113263

    Open questions at the time
    • The Rlim-independent Rex1 downregulation mechanism not defined
    • Single lab
  30. 2024 High

    Established how RNF12 finds its substrate on chromatin, via a DNA-motif-directed, autoinhibited basic region that targets it to REX1-bound promoters for ubiquitylation, resolving the recruitment step central to its gene regulation.

    Evidence ChIP-seq, motif analysis, BioID proximity labeling, domain mutagenesis and ubiquitylation/expression assays

    PMID:38199845

    Open questions at the time
    • Factor relieving N-terminal autoinhibition in vivo unknown
    • Generality of motif-directed recruitment across substrates untested
  31. 2024 Low

    Added PML as an AKT-regulated RLIM degradation substrate in a stromal COMP→PI3K/AKT→RLIM→PML axis driving colon cancer progression.

    Evidence Co-IP, ubiquitination, AKT phosphorylation assays and murine tumor/metastasis models

    PMID:39162054

    Open questions at the time
    • Low-confidence single lab with limited mechanistic detail
    • Direct vs indirect AKT-RLIM regulation unresolved
  32. 2025 Medium

    Implicated RLIM in central control of energy balance through hypothalamic GABAergic and VIP neurons governing thermogenesis and feeding, defining a neuroendocrine physiological role.

    Evidence Systemic and cell-type-specific conditional knockout mice with metabolic phenotyping (preprint)

    PMID:40766619

    Open questions at the time
    • Preprint, not yet peer-reviewed
    • Neuronal substrate mediating metabolic effects not identified
    • Mechanistic link to circadian clock incomplete

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RLIM achieves substrate selectivity and switches between degradative, non-degradative, and stabilizing ubiquitination outcomes across its many substrates and tissues remains unresolved.
  • No unifying structural model linking RING activity, basic-region recruitment, and substrate choice
  • Determinants of ubiquitin linkage type and degradative vs non-degradative fate undefined
  • Tissue-specific substrate prioritization mechanism unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 7 GO:0016874 ligase activity 6 GO:0140110 transcription regulator activity 4 GO:0003677 DNA binding 1
Localization
GO:0005634 nucleus 3 GO:0000228 nuclear chromosome 1 GO:0005829 cytosol 1
Pathway
R-HSA-4839726 Chromatin organization 6 R-HSA-74160 Gene expression (Transcription) 5 R-HSA-1266738 Developmental Biology 4 R-HSA-392499 Metabolism of proteins 4 R-HSA-162582 Signal Transduction 3
Partners
BRF1MDM2MIZ1REX1SMAD7TRF1USP26ZC4H2
Complex memberships
RNF12-USP26 complexSin3A/HDAC corepressor complex

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 RLIM (RING finger LIM domain-binding protein) binds LIM domains and acts as a transcriptional corepressor by recruiting the Sin3A/histone deacetylase complex, thereby inhibiting LIM homeodomain transcription factor activity. Overexpression in chick wing development phenocopies inhibition of LIM-HD factor LHX2. Protein-protein interaction assays, co-repressor recruitment assays, in vivo chick wing overexpression Nature genetics High 10431247
2009 RNF12/RLIM is an X-encoded, dose-dependent activator of X chromosome inactivation (XCI). Additional copies of Rnf12/RNF12 initiate XCI in male ES cells and on both X chromosomes in female ES cells; heterozygous Rnf12+/- female ES cells show markedly reduced XCI initiation. The activity requires an intact open reading frame and correlates with expression level. Transgenic mouse ES cell overexpression, heterozygous knockout ES cells, XCI assays Cell High 19945382
2009 RLIM acts as an E3 ubiquitin ligase for TRF1, physically interacting with TRF1 and promoting its ubiquitin-dependent proteasomal degradation. Depletion of RLIM by shRNA increases TRF1 protein levels and leads to telomere shortening and impaired cell growth. Co-immunoprecipitation, ubiquitination assay, shRNA knockdown, telomere length measurement The Journal of biological chemistry Medium 19164295
2010 Maternal transmission of RLIM/Rnf12 is required for imprinted XCI in mice. Conditional oocyte-specific knockout of Rnf12 results in female embryonic lethality due to failure of imprinted XCI initiation (defective Xist cloud formation and Xp silencing), while RLIM-deficient ES cells can still undergo random XCI. Conditional oocyte-specific knockout mouse genetics, Xist RNA FISH, X-linked gene silencing assays Nature High 20962847
2011 RNF12/RLIM acts in trans to activate Xist transcription; female Rnf12−/− knockout ES cells fail to initiate XCI, demonstrating that RNF12 is essential for Xist upregulation and random XCI initiation. No evidence was found for RNF12-mediated regulation through Tsix or Xist intron 1. Rnf12 knockout ES cells, Xist RNA FISH, gene expression analysis PLoS genetics High 21298085
2011 Rnf12 expression is negatively regulated by the pluripotency factors Nanog, Oct4, and Sox2 in mouse ES cells, linking the XCI-activating role of Rnf12 to the pluripotency network. Chromatin immunoprecipitation, reporter assays, pluripotency factor knockdown/overexpression Human genetics Medium 21544581
2011 RLIM directly binds to Smurf2 and promotes TGF-β-driven cell migration in osteosarcoma U2OS cells, functioning as a positive regulator of TGF-β signaling. Co-immunoprecipitation, stable overexpression cell line, wound healing migration assay Biochemical and biophysical research communications Low 21945933
2012 RNF12 ubiquitinates and promotes proteasomal degradation of REX1 (a pluripotency factor and XCI repressor). RNF12 deficiency increases REX1 levels; REX1 binds Xist and Tsix regulatory regions (by ChIP-seq) and its overexpression inhibits Xist transcription and XCI, while Rex1+/- male ES cells show ectopic XCI. Co-IP, ubiquitination assay, Rnf12 knockout ES cells, ChIP-seq, REX1 overexpression/knockdown, Xist RNA FISH Nature High 22596162
2012 RNF12 functions as an E3 ubiquitin ligase for Smad7, binding Smad7 and inducing its polyubiquitination and proteasomal degradation, thereby potentiating TGF-β/BMP/Nodal-Smad signaling. RNF12-deficient mouse ES cells show elevated Smad7 and reduced TGF-β responses. Gastrulation defects from ectopic or depleted Smad7 in zebrafish are rescued by RNF12 gain/loss of function. Co-IP, ubiquitination assay, RNF12 knockdown/overexpression in mammalian cells, RNF12-deficient ES cells, zebrafish morpholino/rescue experiments Molecular cell High 22560923
2012 Paternal Rnf12/RLIM is a critical survival factor for milk-producing mammary alveolar cells. Mammary gland-specific Rnf12 knockout inhibits alveolar differentiation and milk production, with alveolar cells undergoing apoptosis upon differentiation. This function is mediated primarily by the paternal allele due to nonrandom maternal XCI in mammary epithelial cells. Conditional mammary gland-specific Rnf12 knockout mouse genetics, alveolar differentiation and apoptosis assays, allele-specific expression analysis Cell High 22541433
2013 RLIM/Rnf12 protein shuttles between nucleus and cytoplasm, regulated by phosphorylation of serine S214 within its nuclear localization sequence. Shuttling-deficient nuclear or cytoplasmic RLIM mutants fail to support alveolar cell survival, demonstrating that nucleocytoplasmic shuttling is required for RLIM's biological functions. Phosphorylation-site mutagenesis, nuclear/cytoplasmic fractionation, live-cell imaging, shuttling-deficient mutant rescue assays in mammary cells Molecular biology of the cell Medium 23904271
2013 p53 represses RLIM transcription indirectly through Sp1: p53 physically interacts with Sp1 and prevents Sp1 binding to four Sp1 elements on the RLIM promoter. Wild-type but not mutant p53 represses RLIM promoter activity. Promoter reporter assays, ChIP, co-immunoprecipitation, p53 mutant analysis PloS one Medium 23650532
2014 RLIM ubiquitinates and promotes proteasomal degradation of Stathmin, an oncoprotein. Physical interaction between RLIM and Stathmin was identified; RLIM siRNA knockdown increases Stathmin protein levels, promoting cell proliferation and cell cycle changes in osteosarcoma cells. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, cell proliferation and cell cycle assays Cellular signalling Low 24686088
2014 RLIM is dispensable for random XCI (rXCI) in the mouse embryonic epiblast. Female cells lacking RLIM from pre-implantation stages show hallmarks of XCI (Xist clouds and H3K27me3 foci) and have full embryogenic potential, indicating an RLIM-independent mechanism activates Xist in the embryo proper. RLIM levels are downregulated in embryonic cells undergoing rXCI. Mouse conditional genetics, Xist RNA FISH, H3K27me3 immunofluorescence, embryo development assays Nature High 24870238
2014 XCI does not require X-X pairing but is regulated by trans-acting diffusible factors. RNF12 acts in concert with cis-regulatory elements (Jpx, Ftx, Xpr region) at two sequential steps: two active Rnf12 copies drive XCI initiation, and one copy must remain active to maintain XCI toward Xi establishment. ES cell genetics, Xist RNA FISH, Rnf12 dosage manipulation, cis-regulatory element deletion Molecular cell Medium 24613346
2015 PIWIL1 protects Stathmin1 from RLIM-mediated ubiquitin-dependent degradation by directly binding Stathmin1 and inhibiting its interaction with RLIM, thereby upregulating Stathmin1 levels. Co-immunoprecipitation, ubiquitination assay, protein interaction competition assay Oncotarget Low 26317901
2016 RNF12 targets MDM2 for ubiquitination and proteasomal degradation (independently of MDM2 self-ubiquitination), thereby elevating p53 protein levels and promoting p53-dependent cell growth suppression and DNA damage-induced apoptosis. Yeast two-hybrid, co-immunoprecipitation, ubiquitination assay, cell growth and apoptosis assays Cancer letters Medium 26926424
2016 RLIM associates with c-Myc in vivo and in vitro and promotes c-Myc polyubiquitination (independently of Ser62/Thr58 phosphorylation and independently of E3 ligase activity for the binding itself). However, RLIM-mediated ubiquitination does not affect c-Myc stability; instead, RLIM inhibits c-Myc transcriptional activity and restrains cell proliferation. Co-immunoprecipitation, in vivo/in vitro ubiquitination assay, c-Myc reporter assay, cell proliferation assay PloS one Medium 27684546
2017 RLIM directly binds MIZ1 and disrupts the interaction between c-MYC and MIZ1, thereby enhancing transcription of p15 and p21, suppressing hepatocellular carcinoma cell growth, and arresting cell cycle progression. Co-immunoprecipitation, competition binding assay, reporter assay, cell growth and cell cycle assays Oncotarget Low 29137325
2018 RNF12 XLID (X-linked intellectual disability) patient mutations disrupt E3 ubiquitin ligase activity by either inactivating the catalytic RING domain or impairing a distal basic regulatory region required for efficient ubiquitin transfer. These mutations impair proper stem cell maintenance and neural differentiation in an ES cell model. Site-directed mutagenesis of RING domain, in vitro ubiquitination assays, ES cell differentiation assays, patient-mutation analysis Cell reports High 29742418
2018 REX1 is the prime and critical target of RNF12 in XCI. Genetic ablation of Rex1 rescues the rXCI phenotype of Rnf12−/− ES cells, and Rex1 knockout in Rnf12−/− mice rescues embryonic lethality, yielding viable fertile females with normal iXCI and rXCI. Double knockout mouse genetics (Rnf12−/−;Rex1−/−), ES cell genetic rescue, XCI assays (Xist RNA FISH, gene silencing) Nature communications High 30420655
2018 RNF12 physically interacts with BRF1 (a TFIIIB subunit) and catalyzes Lys27- and Lys33-linked polyubiquitination of BRF1, negatively regulating RNA polymerase III-dependent transcription and cell proliferation. Co-immunoprecipitation, ubiquitination assay with linkage specificity, Pol III transcription assays, cell proliferation assays The Journal of biological chemistry Medium 30413534
2020 TRIM28 regulates RLIM levels, and RLIM in turn ubiquitinates MDM2 as part of a sequential TRIM28→RLIM→MDM2 ubiquitination cascade targeting p53 during lung tumorigenesis. Co-immunoprecipitation, ubiquitination assay, stable overexpression and knockdown, xenograft models Cell death and differentiation Medium 33328571
2020 KSHV LANA protein promotes RLIM autoubiquitination and proteasomal degradation, reducing RLIM protein levels. LANA interaction with RLIM is detectable only with proteasome inhibition. LANA differentially modulates RLIM substrate degradation: it enhances degradation of LDB1 and LMO2 while preventing RLIM-mediated degradation of LHX3 and TRF1. Co-immunoprecipitation (with MG132), ubiquitination assay, RING domain mutant analysis, substrate stability assays Journal of virology Medium 31865802
2021 RLIM is highly expressed in post-meiotic round spermatids and Sertoli cells. Systemic or spermatogenic-lineage-specific Rlim knockout results in lower numbers of mature sperm with excess cytoplasm, decreased sperm motility, and reduced in vitro fertilization rates, revealing a role for Rlim in spermiogenesis. Systemic and conditional (spermatogenic lineage) Rlim knockout mouse genetics, sperm morphology, motility, and IVF assays eLife High 33620316
2021 A novel RLIM missense variant p.(Tyr421Cys) adjacent to the regulatory basic region destabilizes the protein (readily degraded by the proteasome), impairs E3 ubiquitin ligase activity, and disrupts RLIM function in Xist induction. The protein is correctly localized to the nucleus despite instability. Protein stability assay (proteasome inhibition), in vitro ubiquitination assay, nuclear localization assay, Xist induction assay in ES cells Scientific reports Medium 33953269
2022 AKT phosphorylates RNF12, inducing its nuclear localization, maintaining its stability, and accelerating SMAD7 degradation, thereby promoting TGF-β-driven breast cancer metastasis. RNF12 and AKT cooperate functionally in cancer cell migration. Co-immunoprecipitation, phosphorylation assays, nuclear/cytoplasmic fractionation, ubiquitination assay, cell migration and invasion assays, zebrafish and murine xenograft metastasis models Cell death & disease Medium 35013159
2022 RLIM directly ubiquitinates ZC4H2, stabilizing it; ZC4H2 in turn stabilizes RNF220, establishing an RLIM→ZC4H2→RNF220 regulatory cascade that supports full activation of Shh signaling in cerebellar granule neuron progenitors and medulloblastoma progression. Disease-causative RLIM mutations disrupt its interaction with ZC4H2. Co-immunoprecipitation, ubiquitination assay, protein stability assay, Shh signaling assays, patient mutation analysis Journal of molecular cell biology Medium 35040952
2022 RNF12 relieves REX1-mediated repression of Usp26 transcription; USP26 (a deubiquitylase) forms complexes with RNF12 and prevents RNF12 autoubiquitylation and degradation, establishing a transcriptional feed-forward amplification loop. The RNF12-USP26 axis operates specifically in testes and is required for gametogenesis gene expression and germ cell differentiation. This axis is disrupted by RLIM TOKAS variants and USP26 infertility variants. Quantitative proteomics, co-immunoprecipitation, ubiquitination assays, reporter assays, testis-specific expression analysis, in vitro germ cell differentiation Science signaling High 35857630
2023 The Rlim-Rex1 axis is active in pre-implantation embryos governing iXCI. Upon implantation, Rex1 levels are downregulated independently of Rlim specifically in epiblast cells, providing a mechanistic basis for why Rlim-Rex1 regulates iXCI but not rXCI in female mice. Mouse embryo genetics, protein level analysis in pre-implantation and post-implantation stages, conditional Rlim/Rex1 knockouts Proceedings of the National Academy of Sciences of the United States of America Medium 38113263
2024 RNF12 is recruited to specific genomic locations via a consensus DNA sequence motif, enabling co-localization with its substrate REX1 at gene promoters. Chromatin recruitment is mediated by a non-catalytic basic region of RNF12 and is subject to an N-terminal autoinhibitory mechanism. Chromatin targeting is critical for REX1 ubiquitylation and RNF12-dependent gene regulation. ChIP-seq, motif analysis, proximity labeling (BioID), domain mutagenesis, REX1 ubiquitylation assays, gene expression analysis Life science alliance High 38199845
2024 RLIM promotes ubiquitination and proteasomal degradation of PML (promyelocytic leukemia protein). AKT phosphorylates RLIM to regulate its protein stability. The COMP→PI3K/AKT→RLIM→PML axis mediates CAF-induced colon cancer proliferation and metastasis. Co-immunoprecipitation, ubiquitination assay, AKT phosphorylation assay, in vivo murine tumor/metastasis models Journal of gastroenterology and hepatology Low 39162054
2025 Mice lacking Rlim are lean and resistant to diet-induced obesity due to reduced food intake and enhanced brown adipose tissue thermogenesis. Rlim in GABAergic SCN neurons (central circadian clock) mediates diurnal thermogenic rhythms, while Rlim in VIP-expressing neurons modulates diurnal feeding behavior. Systemic and cell-type-specific (RIP-Cre+, VIP-Cre) Rlim conditional knockout mice, metabolic phenotyping, food intake and thermogenesis measurements bioRxiv (preprint)preprint Medium 40766619

Source papers

Stage 0 corpus · 57 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 RNF12 is an X-Encoded dose-dependent activator of X chromosome inactivation. Cell 190 19945382
2012 RNF12 initiates X-chromosome inactivation by targeting REX1 for degradation. Nature 167 22596162
2010 Maternal Rnf12/RLIM is required for imprinted X-chromosome inactivation in mice. Nature 138 20962847
1999 RLIM inhibits functional activity of LIM homeodomain transcription factors via recruitment of the histone deacetylase complex. Nature genetics 128 10431247
2011 RNF12 activates Xist and is essential for X chromosome inactivation. PLoS genetics 119 21298085
2012 RNF12 controls embryonic stem cell fate and morphogenesis in zebrafish embryos by targeting Smad7 for degradation. Molecular cell 80 22560923
2014 The trans-activator RNF12 and cis-acting elements effectuate X chromosome inactivation independent of X-pairing. Molecular cell 60 24613346
2020 Sequential ubiquitination of p53 by TRIM28, RLIM, and MDM2 in lung tumorigenesis. Cell death and differentiation 56 33328571
2014 RLIM is dispensable for X-chromosome inactivation in the mouse embryonic epiblast. Nature 52 24870238
2009 Regulation of estrogen-dependent transcription by the LIM cofactors CLIM and RLIM in breast cancer. Cancer research 52 19117995
2011 The X-inactivation trans-activator Rnf12 is negatively regulated by pluripotency factors in embryonic stem cells. Human genetics 48 21544581
2009 Ubiquitin Ligase RLIM Modulates Telomere Length Homeostasis through a Proteolysis of TRF1. The Journal of biological chemistry 48 19164295
2018 RNF12 X-Linked Intellectual Disability Mutations Disrupt E3 Ligase Activity and Neural Differentiation. Cell reports 32 29742418
2018 REX1 is the critical target of RNF12 in imprinted X chromosome inactivation in mice. Nature communications 32 30420655
2018 Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder. Molecular psychiatry 27 29728705
2015 Syndromic X-linked intellectual disability segregating with a missense variant in RLIM. European journal of human genetics : EJHG 27 25735484
2012 Paternal RLIM/Rnf12 is a survival factor for milk-producing alveolar cells. Cell 26 22541433
2000 Functional characterization of the gene encoding RLIM, the corepressor of LIM homeodomain factors. Genomics 26 11013082
2018 Ldb1- and Rnf12-dependent regulation of Lhx2 controls the relative balance between neurogenesis and gliogenesis in the retina. Development (Cambridge, England) 24 29650591
2013 Functional activity of RLIM/Rnf12 is regulated by phosphorylation-dependent nucleocytoplasmic shuttling. Molecular biology of the cell 24 23904271
2014 Rlim, an E3 ubiquitin ligase, influences the stability of Stathmin protein in human osteosarcoma cells. Cellular signalling 20 24686088
2011 RLIM interacts with Smurf2 and promotes TGF-β induced U2OS cell migration. Biochemical and biophysical research communications 20 21945933
2022 RNF12 is regulated by AKT phosphorylation and promotes TGF-β driven breast cancer metastasis. Cell death & disease 19 35013159
2016 E3 Ubiquitin Ligase RLIM Negatively Regulates c-Myc Transcriptional Activity and Restrains Cell Proliferation. PloS one 18 27684546
2016 RNF12 promotes p53-dependent cell growth suppression and apoptosis by targeting MDM2 for destruction. Cancer letters 17 26926424
2015 PIWIL1 destabilizes microtubule by suppressing phosphorylation at Ser16 and RLIM-mediated degradation of Stathmin1. Oncotarget 17 26317901
2017 Rlim-Dependent and -Independent Pathways for X Chromosome Inactivation in Female ESCs. Cell reports 16 29281819
2021 Deficient spermiogenesis in mice lacking Rlim. eLife 14 33620316
2019 Rlim/Rnf12, Rex1, and X Chromosome Inactivation. Frontiers in cell and developmental biology 12 31737626
2021 A novel RLIM/RNF12 variant disrupts protein stability and function to cause severe Tonne-Kalscheuer syndrome. Scientific reports 11 33953269
1994 Distribution of Rlim, an LIM homeodomain gene, in the rat brain. Neuroscience letters 11 7914684
2022 Sequential stabilization of RNF220 by RLIM and ZC4H2 during cerebellum development and Shh-group medulloblastoma progression. Journal of molecular cell biology 10 35040952
2018 RNF12 catalyzes BRF1 ubiquitination and regulates RNA polymerase III-dependent transcription. The Journal of biological chemistry 10 30413534
2016 Maintenance of Xist Imprinting Depends on Chromatin Condensation State and Rnf12 Dosage in Mice. PLoS genetics 10 27788132
2020 Kaposi's Sarcoma-Associated Herpesvirus LANA Modulates the Stability of the E3 Ubiquitin Ligase RLIM. Journal of virology 8 31801865
2020 RLIM Is a Candidate Dosage-Sensitive Gene for Individuals with Varying Duplications of Xq13, Intellectual Disability, and Distinct Facial Features. American journal of human genetics 8 33159883
2022 An RNF12-USP26 amplification loop drives germ cell specification and is disrupted by disease-associated mutations. Science signaling 7 35857630
2021 RNF12 Promotes Glioblastoma Malignant Proliferation via Destructing RB1 and Regulating MAPK Pathway. Journal of healthcare engineering 7 34900190
2013 p53 Represses transcription of RING finger LIM domain-binding protein RLIM through Sp1. PloS one 7 23650532
2019 TUG1 promotes the development of prostate cancer by regulating RLIM. European review for medical and pharmacological sciences 6 30915735
2001 Expression and regulation of the LIM-class homeobox gene rlim-1 in neuronal progenitors of the rat cerebellum. Journal of neuroscience research 6 11170173
2024 Cancer-associated fibroblasts promote the proliferation and metastasis of colon cancer by mediating the RLIM/PML axis through paracrine COMP. Journal of gastroenterology and hepatology 5 39162054
2023 Roles of the Rlim-Rex1 axis during X chromosome inactivation in mice. Proceedings of the National Academy of Sciences of the United States of America 5 38113263
2012 Inhibiting the inhibitor: the role of RNF12 in TGF-β superfamily signaling. Molecular cell 5 22681885
2019 A novel approach to differentiate rat embryonic stem cells in vitro reveals a role for RNF12 in activation of X chromosome inactivation. Scientific reports 4 30988473
2024 Chromatin targeting of the RNF12/RLIM E3 ubiquitin ligase controls transcriptional responses. Life science alliance 3 38199845
2024 RLIM-specific activity reporters define variant pathogenicity in Tonne-Kalscheuer syndrome. HGG advances 3 39482882
2017 RLIM suppresses hepatocellular carcinogenesis by up-regulating p15 and p21. Oncotarget 3 29137325
2012 Releasing the break on X chromosome inactivation: Rnf12/RLIM targets REX1 for degradation. Cell research 3 22785560
1996 Localization of mRNAs for Rlim-1, the rat Xlim-1 homolog, in the developing rat brain. Brain research. Molecular brain research 2 9011751
2024 How does the Xist activator Rlim/Rnf12 regulate Xist expression? Biochemical Society transactions 1 38747697
2023 Knockout of Rlim Results in a Sex Ratio Shift toward Males but Superovulation Cannot Compensate for the Reduced Litter Size. Animals : an open access journal from MDPI 1 36978620
2021 Knockdown of RLIM inhibits XIST expression and improves developmental competence of cloned male pig embryos. Molecular reproduction and development 1 33650239
2026 The RING E3 ligase RLIM drives oxidative stress-induced stem cell dysfunction through MDM2-p53 signaling. The Journal of biological chemistry 0 41866032
2025 Rlim coordinates diurnal regulation of food intake and thermogenesis. bioRxiv : the preprint server for biology 0 40766619
2025 A novel missense variant at the site of interaction between RLIM and E2 ubiquitin-conjugating enzymes causes Tønne-Kalscheuer syndrome. BMC pediatrics 0 41068697
2023 Retracted: RNF12 Promotes Glioblastoma Malignant Proliferation via Destructing RB1 and Regulating MAPK Pathway. Journal of healthcare engineering 0 38094843

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