Affinage

RFX7

DNA-binding protein RFX7 · UniProt Q2KHR2

Length
1460 aa
Mass
157.4 kDa
Annotated
2026-06-10
15 papers in source corpus 12 papers cited in narrative 12 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

RFX7 is an X-box-binding transcription factor that operates as a downstream effector of p53 to enforce a tumor-suppressive transcriptional program controlling cell metabolism, growth, and immune function (PMID:34907345, PMID:34197623). Activated by p53 and cellular stress, RFX7 directly binds the promoters of established tumor suppressors including PDCD4, PIK3IP1, MXD4, and PNRC1, and sensitizes cells to apoptosis (PMID:34197623, PMID:36864036). A central output of this program is restraint of growth signaling: RFX7 is required for p53-mediated induction of DDIT4 to inhibit mTORC1 and mTORC2-dependent AKT activation (PMID:34907345), and it activates PIK3IP1 to suppress PI3K/AKT signaling, a circuit silenced by RFX7 promoter hypermethylation in glioblastoma where its loss drives metabolic reprogramming and immunosuppression (PMID:42206447). Consistent with its role upstream of mTOR, RFX7 is required in vivo for NK cell homeostasis, with its loss producing enlarged, hyperproliferative, hypermetabolic NK cells rescued by reducing mTOR activity (PMID:29967452). RFX7 acts within a multiprotein DNA-binding complex: mass spectrometry at target promoters identified RFX5, RFXAP, RFXANK, and ANKRA2 as co-binding partners, with ANKRA2—itself a p53 target—serving as a critical cofactor for tumor suppressor gene regulation while RFXANK governs a largely distinct gene set (PMID:39181888). Both ANKRA2 and RFXANK ankyrin domains recognize RFX7 through its PXLPXL motif via hydrophobic contacts (PMID:31864703). RFX7 activity is tuned by phosphorylation, being inhibited through a DYRK1B-mediated negative feedback loop (PMID:41888523) and stimulated by the HCMV kinase pUL97 to drive SOCS3 expression during infection (PMID:36753521). Beyond this core axis, RFX7 also regulates ciliogenesis via RFX4 (PMID:24530844) and contributes to lipid and steroidogenic transcription (PMID:33578049, PMID:39155648).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2014 Medium

    Established the first developmental loss-of-function role for RFX7, placing it atop a transcriptional cascade controlling cilia formation.

    Evidence Morpholino knockdown in Xenopus with Foxj1 epistasis and expression analysis

    PMID:24530844

    Open questions at the time
    • Mechanism of RFX4 regulation by RFX7 not resolved at the DNA-binding level
    • Conservation of the ciliogenesis role in mammals untested
    • No biochemical demonstration of direct promoter occupancy
  2. 2018 High

    Defined RFX7 as a physiological regulator of immune cell metabolism by genetically placing it upstream of mTOR in NK cell homeostasis.

    Evidence Rfx7 knockout mouse with in vivo NK assays and genetic epistasis to mTOR reduction

    PMID:29967452

    Open questions at the time
    • Direct transcriptional targets linking RFX7 to mTOR not identified in this study
    • IL-15/JAK rescue mechanism not connected to specific RFX7 target genes
    • Whether the metabolic role generalizes beyond NK cells unaddressed
  3. 2021 High

    Mapped the RFX7 cistrome and showed it directly activates multiple tumor suppressors downstream of p53 and stress, defining its core gene-regulatory identity.

    Evidence ChIP-seq plus transcriptome in three cell systems with apoptosis viability readout

    PMID:34197623

    Open questions at the time
    • Cofactor requirements for target selection not yet defined
    • Signal that converts p53 activation into RFX7 activation unknown
  4. 2021 High

    Connected RFX7's tumor-suppressive transcription to metabolic control by establishing the p53-RFX7-DDIT4 axis that restrains mTORC1 and AKT.

    Evidence RFX7/DDIT4 loss-of-function, mTOR activity assays under physiological media, genetic epistasis

    PMID:34907345

    Open questions at the time
    • How basal p53/RFX7 activity is maintained under unstressed conditions unclear
    • Whether DDIT4 is the sole metabolic effector of RFX7 not established
  5. 2021 Medium

    Extended the RFX7 regulon to lipid metabolism, showing direct activation of ABCA1 and an upstream lncRNA/miRNA regulatory layer.

    Evidence ChIP and dual-luciferase reporter assays in macrophages with miR-140-5p/PCA3 perturbation

    PMID:33578049

    Open questions at the time
    • Single-lab finding without cistrome-wide validation
    • Relationship to the p53-driven program not examined
  6. 2019 High

    Provided the structural basis for RFX7 cofactor recognition, defining the PXLPXL motif as the docking site for ANKRA2 and RFXANK ankyrin domains.

    Evidence Two X-ray crystal structures of RFX7 fragment bound to ANKRA2 and RFXANK ankyrin domains

    PMID:31864703

    Open questions at the time
    • Functional consequence of differential affinity not tested in cells in this study
    • Full-length complex architecture on DNA not resolved
  7. 2023 High

    Integrated multi-omics in RFX7 knockout cells to confirm RFX7 as the mechanistic link enabling p53-responsive activation and to broaden its target set.

    Evidence CRISPR knockout with transcriptomics, ChIP-seq, and proteomics integration

    PMID:36864036

    Open questions at the time
    • Functional validation of novel neurological-process targets pending
    • Direct vs indirect targets not fully partitioned
  8. 2023 Medium

    Revealed RFX7 as a host substrate hijacked during HCMV infection, with viral kinase pUL97 phosphorylating it to drive SOCS3 expression.

    Evidence Proteomic interaction mapping, RFX7/pUL97 depletion, promoter-luciferase, phosphorylation analysis in NPCs

    PMID:36753521

    Open questions at the time
    • Specific RFX7 residues phosphorylated by pUL97 not mapped
    • Whether phosphorylation alters DNA binding or cofactor assembly unknown
    • Single-lab study
  9. 2024 High

    Resolved the functional composition of the RFX7 DNA-binding complex and identified ANKRA2 as a p53-target cofactor distinct in function from RFXANK.

    Evidence Reporter assay, co-DNA-binding mass spectrometry at PDCD4 promoter, transcriptome in two systems with siRNA

    PMID:39181888

    Open questions at the time
    • Stoichiometry and assembly order of the RFX5/RFXAP/RFXANK/ANKRA2 complex unresolved
    • Determinants directing ANKRA2- vs RFXANK-dependent target choice not defined
  10. 2024 Medium

    Demonstrated a conserved p53/RFX7-driven steroidogenic regulatory pathway and a functional promoter variant affecting RFX7 binding.

    Evidence Promoter-luciferase, ChIP, site-directed mutagenesis in porcine granulosa cells

    PMID:39155648

    Open questions at the time
    • Demonstrated only in porcine cells
    • Human relevance of the NORSF/CYP19A1 axis untested
  11. 2026 Medium

    Defined post-translational down-tuning of RFX7 via a DYRK1B-mediated negative feedback loop closing the p53-RFX7 circuit.

    Evidence Co-IP, kinase-dead mutant, DYRK1 inhibitor rescue, gene expression in multiple cancer lines

    PMID:41888523

    Open questions at the time
    • RFX7 phosphosites targeted by DYRK1B not mapped
    • Mechanism by which phosphorylation suppresses RFX7 activity unknown
    • Single-lab study
  12. 2026 Medium

    Linked RFX7 epigenetic silencing to cancer metabolic-immune reprogramming through the RFX7-PIK3IP1-PI3K/AKT axis in glioblastoma.

    Evidence ChIP-seq, transcriptomics, metabolic analysis, gene perturbation and methylation analysis

    PMID:42206447

    Open questions at the time
    • Causal contribution of RFX7 methylation in patient outcomes not established
    • Generalizability beyond glioblastoma untested
    • Single study

Open questions

Synthesis pass · forward-looking unresolved questions
  • How upstream signals and phosphorylation events are integrated to set RFX7 activity, and how the multiprotein complex selects among its diverse target programs, remain open.
  • No mapped phosphosite-to-activity relationships for DYRK1B or pUL97
  • Rules governing ANKRA2- vs RFXANK-dependent target selection undefined
  • Mechanism converting p53 activation into RFX7 transcriptional activity unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 4 GO:0140110 transcription regulator activity 3
Localization
GO:0005634 nucleus 2
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-168256 Immune System 2 R-HSA-74160 Gene expression (Transcription) 2
Partners
ANKRA2DDIT4DYRK1BP53PIK3IP1RFX5RFXANKRFXAP
Complex memberships
RFX7-ANKRA2-RFX5-RFXAP-RFXANK DNA-binding complex

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2018 Rfx7 deletion in mice leads to decreased NK cell maintenance and immunity in vivo; Rfx7-/- NK cells show increased size, granularity, proliferation, and energetic state, and genetic reduction of mTOR activity mitigated those defects, placing Rfx7 upstream of mTOR in a metabolic regulatory pathway. IL-15 rescue of Rfx7-deficient NK cells occurs through the JAK pathway. Genetic knockout mouse model, genomic/transcriptomic approaches, epistasis with mTOR reduction, in vivo NK cell assays Nature immunology High 29967452
2014 RFX7 in Xenopus laevis is required for ciliogenesis in the neural tube; knockdown of RFX7 causes defects in cilia formation and neural tube closure. RFX7 controls cilia formation by regulating expression of RFX4 (a known ciliogenesis regulator). Foxj1 (master regulator of motile cilia) suppresses RFX4 but not RFX7, placing RFX7 upstream of RFX4 in a ciliogenesis cascade. Morpholino knockdown in Xenopus, epistasis with Foxj1 overexpression, gene expression analysis Mechanisms of development Medium 24530844
2021 p53 activates DDIT4 indirectly through RFX7; RFX7 is required for p53-mediated inhibition of mTORC1, and DDIT4 (downstream of RFX7) is required for p53-mediated inhibition of mTORC2-dependent AKT activation. Under physiological nutrient conditions, basal p53 and RFX7 activity critically restrict mTORC1 activity, establishing a p53-RFX7-DDIT4 axis in metabolic control. Loss-of-function (RFX7 and DDIT4 knockdown/knockout), mTOR activity assays, physiological cell culture media, genetic epistasis Oncogene High 34907345
2021 RFX7 directly binds DNA and controls the transcription of multiple established tumor suppressors including PDCD4, PIK3IP1, MXD4, and PNRC1 across cell types. RFX7 is activated downstream of p53 and stress signals and sensitizes cells to Doxorubicin by promoting apoptosis. ChIP-seq (cistrome mapping), transcriptome analysis in three cell systems, integration of DNA binding landscape with regulated transcriptome, cell viability assays Nucleic acids research High 34197623
2023 Multi-omics integration (transcriptome, cistrome, proteome) in RFX7 knockout cells identifies novel RFX7 target genes linked to tumor suppression and neurological processes, and confirms RFX7 as a mechanistic link enabling p53-responsive activation of these genes. CRISPR knockout, transcriptomics, ChIP-seq, proteomics (multi-omics integration) Cell death discovery High 36864036
2023 During HCMV infection, the viral kinase pUL97 upregulates SOCS3 expression in neural progenitor cells (NPCs) via the transcription factor RFX7. Proteomic analysis identified RFX7 as a pUL97-interacting host protein. pUL97 increases RFX7 phosphorylation, and both pUL97 kinase activity and RFX7 are required for SOCS3 upregulation, as shown by depletion of either pUL97 or RFX7 preventing HCMV-induced SOCS3 upregulation. Proteomics (pUL97-interacting proteins), promoter-luciferase assay, RFX7 depletion, phosphorylation analysis, viral protein screening PLoS pathogens Medium 36753521
2019 Crystal structures of a RFX7 fragment bound to the ANKRA2 ankyrin domain and to the RFXANK ankyrin domain reveal that both ANKRA2 and RFXANK recognize the PXLPXL motif of RFX7 and its flanking sequences via extensive hydrophobic interactions. Structural comparison explains the different RFX7 binding affinities of ANKRA2 and RFXANK. X-ray crystallography (two structures), structural analysis Biochemical and biophysical research communications High 31864703
2024 RFX7 regulates PDCD4 through direct interaction with its X-box promoter motif (reporter gene assay). Mass spectrometry identified RFX5, RFXAP, RFXANK, and ANKRA2 as proteins that bind to DNA together with RFX7 at the PDCD4 promoter. ANKRA2 is a bona fide direct p53 target gene and functions as a critical cofactor of RFX7 for tumor suppressor gene regulation, while RFXANK regulates a largely distinct gene set. Reporter gene assay, mass spectrometry (co-DNA-binding proteomics), transcriptome analysis in two cell systems, siRNA knockdown Cell death discovery High 39181888
2026 DYRK1B expression is induced by p53 via RFX7 in response to cytostatic drugs. DYRK1B physically interacts with RFX7 and counteracts RFX7 activation by p53, establishing a negative feedback loop. The inhibitory effect of DYRK1B on RFX7-dependent gene expression requires DYRK1B catalytic activity and can be blocked by DYRK1 inhibitors. Co-immunoprecipitation (physical interaction), pharmacological inhibition, catalytic-dead mutant analysis, gene expression assays in multiple cancer cell lines Cell death & disease Medium 41888523
2026 In glioblastoma, RFX7 promoter hypermethylation reduces RFX7 expression. Restoration of RFX7 enhances PIK3IP1 expression, suppresses PI3K/AKT activation, and inhibits malignant progression. Loss of PIK3IP1 increases lactate production and histone H4K12 lactylation, upregulates PD-L1 and CSF1, and enhances tumor immunosuppressive features, defining an RFX7-PIK3IP1-PI3K/AKT axis linking metabolic and immune regulation. ChIP-seq, transcriptomic profiling, metabolic analysis, gene perturbation experiments (KO/overexpression), epigenetic (methylation) analysis Advanced science Medium 42206447
2021 RFX7 binds to the ABCA1 promoter and increases ABCA1 expression in macrophages, promoting cholesterol efflux. miR-140-5p downregulates RFX7, and PCA3 lncRNA sponges miR-140-5p to upregulate RFX7 and thereby ABCA1. Chromatin immunoprecipitation assay (RFX7 binding to ABCA1 promoter), dual-luciferase reporter assay, Western blot, qPCR Biochimica et biophysica acta. Molecular and cell biology of lipids Medium 33578049
2024 In pig granulosa cells, RFX7 is transcriptionally activated by p53 and acts as a transcriptional activator of the lncRNA NORSF by binding its promoter. A G-A variant at -478 nt of the NORSF promoter reduces RFX7 binding activity, decreasing NORSF transcription and weakening inhibition of CYP19A1, thereby affecting estradiol synthesis via the p53/RFX7/NORSF/CYP19A1 pathway. Promoter-luciferase assay, chromatin immunoprecipitation, site-directed mutagenesis of RFX7 binding site, gene expression analysis Journal of cellular physiology Medium 39155648

Source papers

Stage 0 corpus · 15 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 The transcription factor Rfx7 limits metabolism of NK cells and promotes their maintenance and immunity. Nature immunology 44 29967452
2014 RFX7 is required for the formation of cilia in the neural tube. Mechanisms of development 39 24530844
2021 p53-mediated AKT and mTOR inhibition requires RFX7 and DDIT4 and depends on nutrient abundance. Oncogene 30 34907345
2021 Transcription factor RFX7 governs a tumor suppressor network in response to p53 and stress. Nucleic acids research 28 34197623
2021 Long non-coding RNA PCA3 inhibits lipid accumulation and atherosclerosis through the miR-140-5p/RFX7/ABCA1 axis. Biochimica et biophysica acta. Molecular and cell biology of lipids 24 33578049
2023 Multi-omics analysis identifies RFX7 targets involved in tumor suppression and neuronal processes. Cell death discovery 9 36864036
2022 Hsa_circ_0030042 Ameliorates Oxidized Low-Density Lipoprotein-Induced Endothelial Cell Injury via the MiR-616-3p/RFX7 Axis. International heart journal 8 35831154
2024 p53 target ANKRA2 cooperates with RFX7 to regulate tumor suppressor genes. Cell death discovery 7 39181888
2023 Human cytomegalovirus pUL97 upregulates SOCS3 expression via transcription factor RFX7 in neural progenitor cells. PLoS pathogens 7 36753521
2022 Phenotype expansion and neurological manifestations of neurobehavioural disease caused by a variant in RFX7. European journal of medical genetics 6 36334883
2019 Structural basis for the recognition of RFX7 by ANKRA2 and RFXANK. Biochemical and biophysical research communications 5 31864703
2024 A variant in long noncoding RNA NORSF affects granulosa cells response to transcription factor RFX7. Journal of cellular physiology 1 39155648
2026 The protein kinase DYRK1B is a p53 target gene and functions as a negative feedback regulator of the transcription factor RFX7. Cell death & disease 0 41888523
2026 Epigenetic Silencing of RFX7 Defines a Transcriptional Axis Linking Lactate Metabolism to Immune Checkpoint Therapy in Glioblastoma. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 0 42206447
2024 Expanding the clinical phenotype and variant spectrum associated with RFX7. American journal of medical genetics. Part A 0 39007708

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