Cyclin-F · UniProt P41002
Cyclin F (CCNF/FBXO1) is the substrate-recognition subunit of an SCF(Cyclin F) E3 ubiquitin ligase that controls protein homeostasis through K48-linked ubiquitination and proteasomal turnover of its substrates (PMID:27080313, PMID:36607545). It binds the E2F1/E2F2/E2F3a transcription factors via R/I and R/V degron motifs in their dimerization domains and targets them for K48-linked degradation, with MEK/ERK-mediated phosphorylation near these degrons regulating the interaction and thereby gating the G1/S cell cycle transition (PMID:36607545); it also recognizes RRM2 as a substrate (PMID:34201347) and, in an antiviral role, binds and degrades HIV-1 Vif through a Vif C-terminal motif to restore APOBEC3G and suppress virion infectivity (PMID:28184007). Beyond its ligase activity, Cyclin F directly binds VCP through its N-terminal region and colocalizes with VCP in the nucleus, enhancing VCP ATPase activity without ubiquitylating it (PMID:31577344). Cyclin F is itself a degradation target of the FBXL8 and FZR1 ligases (PMID:34201347). ALS/FTD-associated CCNF mutations (notably S621G) disrupt this homeostatic machinery: they drive cytoplasmic mislocalization of Cyclin F, increase VCP ATPase activity, promote cytoplasmic TDP-43 aggregation, and perturb Lys48-ubiquitylation and free-ubiquitin balance in a manner requiring intact SCF ligase activity (PMID:27080313, PMID:31577344, PMID:37220877). Mutant Cyclin F impairs autophagosome-lysosome fusion and physically interacts with p62/SQSTM1 (PMID:28852778), activates caspase-3-mediated apoptosis (PMID:28444311, PMID:33986643), and—through a non-cell-autonomous astrocyte mechanism—suppresses motor neuron excitability and sodium currents (PMID:42069601), establishing CCNF as a causative gene in ALS/FTD pathogenesis.
Established CCNF as a distinct cyclin-family gene, defining the molecule whose function would later be dissected.
Evidence cDNA sequencing and Northern blot mapping CCNF to chromosome 16p13.3
Connected CCNF to neurodegeneration by showing mutant Cyclin F disrupts ubiquitination homeostasis, addressing how an SCF subunit could drive disease.
Evidence Transfection of mutant CCNF in neuronal cells with ubiquitination and substrate-accumulation assays
Defined the consequences of mutant Cyclin F on autophagy and on a viral substrate, broadening the substrate landscape of SCF(Cyclin F).
Evidence Lys48-ubiquitylation proteomics, Co-IP with p62 and autophagy-marker analysis (Neuro-2A/SH-SY5Y); Co-IP, degron mutagenesis, and ubiquitination assays for HIV-1 Vif; zebrafish caspase-3 and motor-axon readouts
PMID:28184007 PMID:28444311 PMID:28852778 PMID:29102476
Identified a ligase-independent function of Cyclin F as a VCP ATPase enhancer and tied mutation-driven mislocalization to TDP-43 aggregation.
Evidence Co-IP, deletion mapping, in vitro ATPase assay, subcellular fractionation, and TDP-43 aggregation assays
Placed Cyclin F within its own regulatory turnover circuit and added RRM2 as a substrate, clarifying upstream control of Cyclin F levels.
Evidence Pulldown and double-knockdown of FBXL8/FZR1, plus RRM2 pulldown and overexpression protein-level analysis
Generalized mutation-driven apoptosis activation across multiple ALS variants and patient-derived cells.
Evidence Label-free quantitative proteomics in HEK293 and iPSC-derived cells with immunoblot validation
Demonstrated that SCF(Cyclin F) ligase activity is required for ubiquitin homeostasis and mapped the E2F degron mechanism, linking Cyclin F to both proteostasis and cell-cycle control.
Evidence iPSC-derived motor neurons with ligase-dead rescue mutants and proteasome/free-ubiquitin assays; Co-IP, degron mutagenesis, half-life, kinase-inhibitor and cell-cycle analyses for E2F1/2/3a
Established an endogenous developmental requirement for CCNF in motor neurons and a specific sensitivity to ER stress via loss-of-function.
Evidence CRISPR/TALEN ccnf knockout in zebrafish with motor neuron morphology and stress-response assays
Revealed a non-cell-autonomous astrocyte mechanism by which the S621G mutation suppresses motor neuron excitability, reframing CCNF pathology beyond neuron-intrinsic effects.
Evidence CRISPR knock-in CcnfS621G mice, iPSC-derived astrocyte/motor-neuron co-culture, mitochondrial and electrophysiology assays
| Year | Finding | Method | Journal | Conf | PMIDs |
|---|---|---|---|---|---|
| 2016 | Cyclin F is a component of an SCF(Cyclin F) E3 ubiquitin-protein ligase complex; expression of mutant CCNF in neuronal cells caused abnormal ubiquitination and accumulation of ubiquitinated proteins, including TDP-43 and an SCF(Cyclin F) substrate, implicating protein homeostasis disruption in neurodegeneration. | Transfection of mutant CCNF in neuronal cells, ubiquitination assays, identification of ubiquitinated substrates | Nature communications | High | 27080313 |
| 2017 | ALS/FTD-causing mutant cyclin F (S621G) causes increased Lys48-specific ubiquitylation in neuronal cells, and proteomic analysis identified p62/SQSTM1 and autophagy-related proteins as elevated Lys48-ubiquitylated substrates; mutant cyclin F impairs autophagosome-lysosome fusion and cyclin F physically interacts with p62. | Transfection in Neuro-2A and SH-SY5Y cells, Lys48-specific ubiquitylation assays, immunoprecipitation of Lys48-ubiquitylated proteins, proteomics, autophagy marker analysis (p62, LC3, Lamp2) | Cellular and molecular life sciences : CMLS | Medium | 28852778 |
| 2017 | Cyclin F (FBXO1) physically interacts with HIV-1 Vif protein and mediates its ubiquitination and proteasomal degradation through the SCF(Cyclin F) E3 ligase machinery, thereby restoring APOBEC3G expression and reducing progeny virion infectivity; a cyclin F-specific C-terminal motif in Vif is required for this interaction. | Co-immunoprecipitation, gene overexpression and knockdown, ubiquitination assays, mutational analysis of Vif degron motif, APOBEC3G expression analysis | The Journal of biological chemistry | Medium | 28184007 |
| 2017 | ALS-linked CCNF mutations disrupt cellular pathways including caspase-3-mediated apoptosis; mutant CCNF expression in zebrafish caused increased activated caspase-3, increased spinal cord cell death, shortened primary motor axons, and aberrant axonal branching. | Proteomic analysis of in vitro models, transient overexpression of human CCNF in zebrafish embryos, immunostaining for cleaved caspase-3, motor axon morphology assessment, photomotor response assay | Human molecular genetics | Medium | 28444311 |
| 2017 | Two novel ALS-associated CCNF missense mutations (p.S222P and p.S532R) result in dysfunction of the cyclin F-mediated ubiquitin-proteasome pathway in vitro. | In vitro functional studies of ubiquitin-proteasome pathway activity with mutant CCNF constructs | Neurobiology of aging | Low | 29102476 |
| 2019 | Cyclin F binds to VCP (valosin-containing protein) via its N-terminal region and colocalizes with VCP in the nucleus; VCP is not ubiquitylated by SCF(Cyclin F) but instead its ATPase activity is enhanced by Cyclin F in vitro; ALS-associated CCNF mutations increase Cyclin F binding to VCP, enhance VCP ATPase activity, cause cytoplasmic mislocalization of Cyclin F, and promote cytoplasmic TDP-43 aggregation. | Co-immunoprecipitation, deletion mapping, in vitro ATPase assay, subcellular fractionation/localization, transfection experiments, TDP-43 aggregation assay | Human molecular genetics | High | 31577344 |
| 2021 | Cyclin F is targeted for proteasomal degradation by FBXL8 and FZR1 E3 ligases (both pull down CCNF; double knockdown causes CCNF accumulation); CCNF itself pulls down RRM2 and CCNF overexpression reduces RRM2 protein levels, indicating RRM2 is a substrate of SCF(Cyclin F). | Pulldown assays, double knockdown experiments, overexpression studies, protein level analysis | Cancers | Medium | 34201347 |
| 2021 | Multiple ALS-linked CCNF mutations (K97R, S195R, S509P, R574Q, S621G) activate apoptosis pathways in HEK293 cells and iPSC-derived cells, as revealed by label-free quantitative proteomics and validated by immunoblot. | Label-free quantitative proteomics of HEK293 cells and patient-derived iPSCs, immunoblot validation | Frontiers in molecular neuroscience | Medium | 33986643 |
| 2023 | ALS-linked CCNF S621G mutation causes ubiquitin-proteasome system dysfunction in iPSC-derived motor neurons; both wild-type and S621G CCNF overexpression alter free ubiquitin levels; double mutants designed to abolish E3 ligase complex formation improved UPS function and increased free monomeric ubiquitin, demonstrating that SCF(Cyclin F) ligase activity is required for normal ubiquitin homeostasis. | iPSC-derived motor neuron model, proteasome activity assays, ubiquitin level measurement, overexpression of E3 ligase-dead double mutants in NSC-34 cells | Human molecular genetics | Medium | 37220877 |
| 2023 | FBXO1 (Cyclin F) binds E2F1, E2F2, and E2F3a through R/I and R/V degron motifs in their dimerization domains and mediates K48-linked ubiquitination and proteasomal degradation of these transcription factors; MEK/ERK signaling-mediated phosphorylation of threonine residues near these motifs regulates the FBXO1-E2F interaction and E2F protein stability, thereby controlling G1/S cell cycle transition. | Co-immunoprecipitation, ubiquitination assays, half-life measurement, binding domain/degron mutagenesis (RI/AA, RV/AA), specific kinase inhibitor analysis, FBXO1 knockdown, cell cycle analysis | Archives of pharmacal research | High | 36607545 |
| 2024 | Loss of ccnf in zebrafish (CRISPR/TALEN knockout) causes abnormal motor neuron development and axonal outgrowth defects, and ccnf-deficient zebrafish are specifically sensitized to endoplasmic reticulum stress, identifying a role for CCNF in motor neuron development and ER stress response. | CRISPR/Cas9 and TALEN-mediated genome editing in zebrafish, motor neuron morphology analysis, stress response assays | Cells | Medium | 38474336 |
| 2026 | Endogenous knock-in CcnfS621G mice (generated by CRISPR/Cas9) show no motor decline or neuronal loss at 18 months but display increased hippocampal astrocyte ramification; CCNFS621G iPSC-derived astrocytes exhibit impaired mitochondrial membrane potential and altered network morphology; CCNFS621G astrocytes suppress repetitive motor neuron firing, reduce voltage-gated sodium currents, and increase the proportion of neurons unable to fire action potentials when co-cultured with motor neurons, demonstrating a non-cell-autonomous astrocyte-driven mechanism. | CRISPR/Cas9 knock-in mouse model, immunohistochemistry, proteomics, iPSC-derived astrocyte and motor neuron co-culture, mitochondrial membrane potential assay, electrophysiology (action potential and voltage-gated sodium current recording) | Journal of neuroinflammation | High | 42069601 |
| 1994 | CCNF encodes a new member of the cyclin family (Cyclin F) located on chromosome 16p13.3; it is related to A- and B-type cyclins by sequence; its function was not determined at this time. | cDNA sequencing, exon-intron boundary determination, Northern blot analysis | Genomics | Low | 7896286 |
| Year | Title | Journal | Citations | PMID |
|---|---|---|---|---|
| 2016 | CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia. | Nature communications | 179 | 27080313 |
| 2017 | Pathogenic mutation in the ALS/FTD gene, CCNF, causes elevated Lys48-linked ubiquitylation and defective autophagy. | Cellular and molecular life sciences : CMLS | 44 | 28852778 |
| 2017 | Expression of ALS/FTD-linked mutant CCNF in zebrafish leads to increased cell death in the spinal cord and an aberrant motor phenotype. | Human molecular genetics | 40 | 28444311 |
| 2019 | Pathogenic mutations in the ALS gene CCNF cause cytoplasmic mislocalization of Cyclin F and elevated VCP ATPase activity. | Human molecular genetics | 28 | 31577344 |
| 2017 | Cyclin F/FBXO1 Interacts with HIV-1 Viral Infectivity Factor (Vif) and Restricts Progeny Virion Infectivity by Ubiquitination and Proteasomal Degradation of Vif Protein through SCFcyclin F E3 Ligase Machinery. | The Journal of biological chemistry | 25 | 28184007 |
| 2021 | A Novel Signature of CCNF-Associated E3 Ligases Collaborate and Counter Each Other in Breast Cancer. | Cancers | 17 | 34201347 |
| 2017 | Mutations of CCNF gene is rare in patients with amyotrophic lateral sclerosis and frontotemporal dementia from Mainland China. | Amyotrophic lateral sclerosis & frontotemporal degeneration | 17 | 28281833 |
| 2017 | Investigating CCNF mutations in a Taiwanese cohort with amyotrophic lateral sclerosis. | Neurobiology of aging | 17 | 29102476 |
| 2023 | The Skp1-Cullin1-FBXO1 complex is a pleiotropic regulator required for the formation of gametes and motile forms in Plasmodium berghei. | Nature communications | 15 | 36898988 |
| 2021 | Unbiased Label-Free Quantitative Proteomics of Cells Expressing Amyotrophic Lateral Sclerosis (ALS) Mutations in CCNF Reveals Activation of the Apoptosis Pathway: A Workflow to Screen Pathogenic Gene Mutations. | Frontiers in molecular neuroscience | 14 | 33986643 |
| 1994 | A novel cyclin gene (CCNF) in the region of the polycystic kidney disease gene (PKD1). | Genomics | 14 | 7896286 |
| 2023 | MEKs/ERKs-mediated FBXO1/E2Fs interaction interference modulates G1/S cell cycle transition and cancer cell proliferation. | Archives of pharmacal research | 9 | 36607545 |
| 2019 | Generation and characterization of a human induced pluripotent stem cell line UOWi005-A from dermal fibroblasts derived from a CCNFS621G familial amyotrophic lateral sclerosis patient using mRNA reprogramming. | Stem cell research | 8 | 31445393 |
| 2023 | Genetic and Phenotypic Spectrum of Amyotrophic Lateral Sclerosis Patients with CCNF Variants from a Large Chinese Cohort. | Molecular neurobiology | 7 | 37171577 |
| 2023 | ALS-linked CCNF variant disrupts motor neuron ubiquitin homeostasis. | Human molecular genetics | 6 | 37220877 |
| 2018 | Screening for CCNF Mutations in a Chinese Amyotrophic Lateral Sclerosis Cohort. | Frontiers in aging neuroscience | 6 | 30008669 |
| 2023 | CCNF is a potential pancancer biomarker and immunotherapy target. | Frontiers in oncology | 3 | 37168372 |
| 2024 | Zebrafish CCNF and FUS Mediate Stress-Specific Motor Responses. | Cells | 2 | 38474336 |
| 2023 | Behavioural Variant Frontotemporal Dementia due to CCNF Gene Mutation: A Case Report. | Current Alzheimer research | 1 | 37872794 |
| 2026 | ALS-FTD-linked CCNFS621G drives increased hippocampal astrocyte ramification and mitochondrial dysfunction and impairs motor neuron excitability. | Journal of neuroinflammation | 0 | 42069601 |
| 2025 | Expanding the genetic spectrum of corticobasal syndrome: novel CCNF p.M394L variant from a South Asian cohort. | Neurocase | 0 | 41069067 |
| 2024 | Exploring the Role of CCNF Variants in Italian ALS Patients. | Genes | 0 | 39766833 |
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