Affinage

CCNE2

G1/S-specific cyclin-E2 · UniProt O96020

Length
404 aa
Mass
46.8 kDa
Annotated
2026-06-09
29 papers in source corpus 15 papers cited in narrative 15 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/5 claims corpus-supported (80%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CCNE2 (Cyclin E2) is a cell cycle regulator that drives G1/S progression and cell proliferation, and its expression is tightly controlled at both the transcriptional and post-transcriptional levels (PMID:32487779, PMID:34521301, PMID:31689122). Transcription of CCNE2 is directly activated through promoter binding by E2F1 (PMID:34521301), the ETS factor ELF3 (PMID:39572025), and the arginine methyltransferase CARM1, which deposits the activating asymmetric dimethyl marks H3R17me2a and H3R26me2a at the CCNE2 core promoter (PMID:32487779). CCNE2 is also constrained by a converging network of 3'UTR-targeting microRNAs—including miR-30d-5p, miR-30a, and miR-26a—whose loss derepresses CCNE2 and promotes proliferation and cell cycle entry (PMID:25843294, PMID:26818545, PMID:31689122); these miRNAs are in turn titrated by sponging circular RNAs (circCCNB1/miR-449a, circ-CSPP1/miR-577, circHAS2/miR-1244), and circHAS2 additionally elevates CCNE2 by binding USP10 to promote p53 nuclear export and degradation (PMID:31767812, PMID:32514247, PMID:38515149). Consistent with this, CCNE2 is subject to p53-dependent transcriptional repression, yet the cyclin E2 protein itself is unusually long-lived, indicating post-transcriptional stabilization that uncouples protein abundance from mRNA levels (PMID:27611480). Functionally, CCNE2 acts as a proliferative effector across multiple disease contexts: it lies downstream of HMGA1 to promote nuclear localization and activity of YAP via the Hippo kinases MST1/2 and LATS1/2, driving breast cancer invasiveness (PMID:26265440), it contributes to trastuzumab resistance in HER2+ breast cancer (PMID:28120942), and its depletion induces cellular senescence and apoptosis in synovial fibroblasts (PMID:40820921).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2015 Medium

    Established that CCNE2 is a directly repressible target of microRNA control, defining a post-transcriptional brake on its proliferative output.

    Evidence Luciferase reporter and functional rescue with miR-30d-5p in NSCLC cells

    PMID:25843294

    Open questions at the time
    • Does not address how CCNE2 protein abundance translates to CDK activity
    • Single cancer-cell context
  2. 2015 Medium

    Placed CCNE2 in a signaling role beyond core cell-cycle timing, linking it to YAP nuclear localization via Hippo kinases in breast cancer invasion.

    Evidence Genetic epistasis, YAP subcellular fractionation, and CDK inhibitor treatment in basal-like breast cancer cells

    PMID:26265440

    Open questions at the time
    • Molecular mechanism connecting CCNE2/CDK activity to MST1/2-LATS1/2 not resolved
    • No direct CCNE2-YAP biochemical interaction shown
  3. 2016 Medium

    Demonstrated that CCNE2 mRNA is transcriptionally repressed by p53 while the protein is uncoupled from mRNA by post-transcriptional stabilization, revealing dual-layer regulation.

    Evidence p53 siRNA, RT-PCR, cycloheximide chase, and MG-132 in beryllium-treated cells

    PMID:27611480

    Open questions at the time
    • Stabilizing factor and degron not identified
    • Generality of long half-life across cell types unknown
  4. 2016 Medium

    Confirmed direct 3'UTR targeting by miR-26a as a controller of CCNE2-driven cell cycle progression in a non-cancer proliferative setting.

    Evidence Dual-luciferase reporter, flow cytometry, and adenoviral modulation in hepatocytes

    PMID:26818545

    Open questions at the time
    • Does not establish CCNE2's CDK partner or substrate program here
  5. 2019 Medium

    Extended the miRNA-repression model with miR-30a and introduced circRNA sponges as upstream rheostats that maintain CCNE2 expression and forestall senescence.

    Evidence Luciferase, cell cycle analysis, and circCCNB1/miR-449a functional assays with SA-β-gal readouts

    PMID:31689122 PMID:31767812

    Open questions at the time
    • Quantitative contribution of each ceRNA axis to CCNE2 levels unclear
    • Senescence linkage is correlative at the CCNE2 level
  6. 2020 High

    Identified CARM1-deposited histone arginine methylation at the CCNE2 promoter as a direct activating chromatin input, adding an epigenetic layer to CCNE2 transcriptional control.

    Evidence ChIP for H3R17me2a/H3R26me2a, luciferase reporter, shRNA, and in vivo rescue in NSCLC

    PMID:32487779

    Open questions at the time
    • Whether CARM1 acts coordinately with E2F1 at the same promoter not tested
    • Direct CARM1-promoter recruitment mechanism not defined
  7. 2020 Medium

    Reinforced ceRNA control of CCNE2 (circ-CSPP1/miR-577) and connected it to the pRb-E2F1 axis and downstream proliferation in vivo.

    Evidence Luciferase, RIP, FISH, and xenograft in hepatocellular carcinoma

    PMID:32514247

    Open questions at the time
    • Causal ordering of pRb/E2F1 changes relative to CCNE2 not dissected
  8. 2021 Medium

    Defined E2F1 as a direct transcriptional activator of CCNE2 in fibroblast differentiation, generalizing CCNE2's proliferative function beyond cancer.

    Evidence Luciferase reporter, immunoprecipitation, and siRNA in TGF-β1-induced cardiac fibroblasts

    PMID:34483923 PMID:34521301

    Open questions at the time
    • pRB-E2F1/CCNE2 pathway placement in MFA context inferred from Western blot only
    • No direct CCNE2 mechanistic dissection in the fibrosis model
  9. 2024 Medium

    Added ELF3 as a second direct transcriptional activator and revealed a circHAS2 module that elevates CCNE2 both by miRNA sponging and by USP10-mediated p53 degradation, integrating the transcriptional and p53-repression arms.

    Evidence Luciferase promoter assays, RIP, organoids, and xenografts in keratinocyte and colorectal cancer models

    PMID:38515149 PMID:39572025

    Open questions at the time
    • Relative dominance of the miR-1244 versus USP10/p53 axis on CCNE2 unquantified
    • Direct ELF3-CARM1-E2F1 promoter interplay untested
  10. 2026 Medium

    Showed that CCNE2 loss is sufficient to drive senescence and apoptosis in synovial fibroblasts in vitro and in vivo, establishing CCNE2 as a fate-determining proliferative factor in a non-malignant inflammatory disease.

    Evidence shRNA, SA-β-gal, apoptosis flow cytometry, and AAV intra-articular shCCNE2 in CIA mice

    PMID:40820921

    Open questions at the time
    • CDK partner and direct substrates mediating the senescence phenotype not identified
    • Mechanism linking CCNE2 loss to SASP induction unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • The biochemical core of CCNE2 function—its CDK partner, kinase substrates, and how stabilized protein abundance is converted into cell-cycle and Hippo-pathway outputs—remains uncharacterized in this corpus.
  • No direct CDK-CCNE2 complex or substrate phosphorylation reported
  • No structural model
  • Mechanism of CCNE2 protein stabilization unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Pathway
R-HSA-1640170 Cell Cycle 3 R-HSA-74160 Gene expression (Transcription) 3

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 CCNE2 is a direct target of miR-30d-5p; miR-30d-5p binds to CCNE2 and suppresses its expression, thereby inhibiting NSCLC cell proliferation, invasion, and migration. Re-introduction of CCNE2 antagonized the inhibitory effects of miR-30d-5p. Luciferase reporter assay, Western blot, functional rescue experiments in NSCLC cells Cancer letters Medium 25843294
2015 CCNE2 acts downstream of HMGA1 to regulate motility and invasiveness of basal-like breast cancer cells by promoting nuclear localization and activity of YAP (Hippo pathway mediator). MST1/2 and LATS1/2 kinases are required for HMGA1- and CCNE2-mediated regulation of YAP localization. CDK inhibitors induce translocation of YAP from nucleus to cytoplasm. Genetic epistasis (knockdown/overexpression), subcellular fractionation/localization of YAP, CDK inhibitor treatment Oncotarget Medium 26265440
2017 CCNE2 overexpression contributes to acquired trastuzumab resistance in HER2+ breast cancer; silencing CCNE2 in trastuzumab-resistant BT474r cells restored sensitivity to trastuzumab. miR-26a and miR-30b regulate CCNE2 expression and trastuzumab response. siRNA knockdown of CCNE2, cell viability assays, miRNA overexpression in resistant cell lines Scientific reports Medium 28120942
2016 miR-26a directly targets the 3' UTR of CCNE2 (and CCND2) to regulate mouse hepatocyte proliferation and cell cycle progression. Inhibition of miR-26a upregulated CCNE2 expression and increased hepatocyte proliferation. Dual-luciferase reporter assay, Western blot, flow cytometry, adenoviral overexpression/inhibition in hepatocyte cell line Hepatobiliary & pancreatic diseases international Medium 26818545
2016 Beryllium induces p53-dependent transcriptional downregulation of CCNE2 mRNA (~90% reduction). However, reduction in CCNE2 mRNA did not lead to corresponding reductions in cyclin E2 protein, which had an unusually long half-life (>12 hours), indicating post-transcriptional stabilization of CCNE2 protein independent of p53. siRNA knockdown of p53, RT-PCR, Western blot, cycloheximide chase, proteasomal inhibition (MG-132) Cell proliferation Medium 27611480
2020 CARM1, an arginine methyltransferase, is recruited to the CCNE2 gene promoter and activates CCNE2 transcription. Asymmetric di-methylation marks H3R17me2a and H3R26me2a are enriched at the CCNE2 core promoter. Restoration of CCNE2 abolished CARM1-knockdown-mediated inhibition of cell proliferation, placing CCNE2 downstream of CARM1 in NSCLC. ChIP assay, luciferase reporter assay, shRNA knockdown, overexpression rescue experiments in vitro and in vivo Aging High 32487779
2021 E2F1 transcription factor directly targets the CCNE2 promoter and activates its transcription in TGF-β1-induced human cardiac fibroblast differentiation. Luciferase reporter assay and immunoprecipitation confirmed CCNE2 as a direct target gene of E2F1. Silencing CCNE2 decreased cardiac fibroblast differentiation. Luciferase reporter assay, immunoprecipitation, siRNA knockdown, Western blot Bioengineered Medium 34521301
2021 MFA (methyl ferulic acid) attenuates cardiac fibroblast differentiation and myocardial fibrosis by suppressing the pRB-E2F1/CCNE2 pathway (as well as RhoA/ROCK2 pathway), reducing CCNE2-mediated proliferation and migration of human cardiac fibroblasts. Western blot, cell migration/proliferation assays, in vivo myocardial infarction mouse model Frontiers in pharmacology Low 34483923
2019 miR-30a directly interacts with the CCNE2 3'UTR; nicotine-induced upregulation of miR-30a downregulates CCNE2 expression and arrests human periodontal ligament cells in G1 phase. Inhibition of miR-30a restored CCNE2 expression downregulated by nicotine. Luciferase reporter assay, qRT-PCR, cell cycle analysis (flow cytometry), miR-30a inhibitor rescue Biochemistry and cell biology Medium 31689122
2019 CircCCNB1 acts as a sponge for miR-449a to maintain CCNE2 expression; reduced CircCCNB1 inhibits CCNE2 expression via miR-449a, repressing cellular proliferation and triggering cellular senescence (increased SA-β-gal, p21, p53). Whole-transcriptome sequencing, functional knockdown of CircCCNB1, miR-449a activity assays, SA-β-gal assay, Western blot Aging Medium 31767812
2020 circ-CSPP1 acts as a sponge for miR-577, positively regulating CCNE2 (a target of miR-577) in hepatocellular carcinoma. Knockdown of circ-CSPP1 downregulated CCNE2, p-Rb, E2F1, and c-myc. miR-577 inhibitor rescued suppressive effects of circ-CSPP1 knockdown, but was reversed by CCNE2 silencing. Dual luciferase assay, RNA immunoprecipitation, RNA FISH, knockdown/overexpression, xenograft model, Western blot Cancer cell international Medium 32514247
2024 ELF3 (ETS transcription factor) directly activates the CCNE2 promoter; ELF3 overexpression enhances CCNE2 promoter activity. ELF3 silencing reduces CCNE2 expression, induces cell cycle arrest, and suppresses malignant transformation of HPV16 E6/E7-immortalized keratinocytes. Dual luciferase reporter assay (promoter activity), bioinformatics binding site analysis, siRNA knockdown, CCK-8 assay, cell cycle analysis, Western blot Journal of microbiology and biotechnology Medium 39572025
2026 Knockdown of CCNE2 in rheumatoid arthritis synovial fibroblasts (RASFs) induced cellular senescence (elevated p16, p21, p53, SA-β-gal activity, H3K9me3) and apoptosis, and reduced cell viability. In vivo AAV-mediated intra-articular shCCNE2 reduced arthritis index and joint inflammation in CIA mice, also enhancing SASP factor secretion (MMP-3, IL-8). shRNA knockdown, flow cytometry (apoptosis), SA-β-gal assay, Western blot, AAV intra-articular injection in CIA mouse model Modern rheumatology Medium 40820921
2024 CircHAS2 promotes CCNE2 activation via two axes: (1) sponging miR-1244 to relieve repression of CCNE2, and (2) binding USP10 to facilitate p53 nuclear export and degradation, thereby de-repressing CCNE2 expression. This bidirectional regulation promotes colorectal cancer cell proliferation. RNA sequencing, molecular biology (luciferase, RIP), patient-derived organoids, xenograft models Molecular cancer Medium 38515149
2020 Tigecycline suppresses CCNE2 expression in pancreatic ductal adenocarcinoma cells; CCNE2 overexpression significantly rescued tigecycline-inhibited cell proliferation and migration/invasion, placing CCNE2 as a downstream effector of tigecycline's anti-tumor action. Western blot, CCNE2 overexpression rescue, MTT/BrdU/soft agar assay, wound healing, transwell assay, xenograft model Journal of cellular and molecular medicine Low 32141702

Source papers

Stage 0 corpus · 29 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 MicroRNA-30d-5p inhibits tumour cell proliferation and motility by directly targeting CCNE2 in non-small cell lung cancer. Cancer letters 104 25843294
2020 Exosomal microRNA-144 from bone marrow-derived mesenchymal stem cells inhibits the progression of non-small cell lung cancer by targeting CCNE1 and CCNE2. Stem cell research & therapy 76 32102682
2017 The role of miR-26a and miR-30b in HER2+ breast cancer trastuzumab resistance and regulation of the CCNE2 gene. Scientific reports 62 28120942
2015 A novel HMGA1-CCNE2-YAP axis regulates breast cancer aggressiveness. Oncotarget 61 26265440
2018 The Dysregulated Expression of KCNQ1OT1 and Its Interaction with Downstream Factors miR-145/CCNE2 in Breast Cancer Cells. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 57 30157476
2017 Knockdown of Long Non-Coding RNA KCNQ1OT1 Restrained Glioma Cells' Malignancy by Activating miR-370/CCNE2 Axis. Frontiers in cellular neuroscience 54 28381990
2018 miR-3607-3p suppresses non-small cell lung cancer (NSCLC) by targeting TGFBR1 and CCNE2. PLoS genetics 43 30557355
2019 Circular RNA CircCCNB1 sponges micro RNA-449a to inhibit cellular senescence by targeting CCNE2. Aging 33 31767812
2020 Antibiotic tigecycline inhibits cell proliferation, migration and invasion via down-regulating CCNE2 in pancreatic ductal adenocarcinoma. Journal of cellular and molecular medicine 32 32141702
2020 CARM1 promotes non-small cell lung cancer progression through upregulating CCNE2 expression. Aging 26 32487779
2023 Berberine targets KIF20A and CCNE2 to inhibit the progression of nonsmall cell lung cancer via the PI3K/AKT pathway. Drug development research 23 37070571
2021 Vascular endothelial cell-derived exosomal miR-30a-5p inhibits lung adenocarcinoma malignant progression by targeting CCNE2. Carcinogenesis 21 34128973
2024 CircHAS2 activates CCNE2 to promote cell proliferation and sensitizes the response of colorectal cancer to anlotinib. Molecular cancer 19 38515149
2020 Circular RNA circ-CSPP1 regulates CCNE2 to facilitate hepatocellular carcinoma cell growth via sponging miR-577. Cancer cell international 19 32514247
2016 miR-26a regulates mouse hepatocyte proliferation via directly targeting the 3' untranslated region of CCND2 and CCNE2. Hepatobiliary & pancreatic diseases international : HBPD INT 16 26818545
2021 A Novel Androgen-Induced lncRNA FAM83H-AS1 Promotes Prostate Cancer Progression via the miR-15a/CCNE2 Axis. Frontiers in oncology 15 33614501
2021 Methyl Ferulic Acid Attenuates Human Cardiac Fibroblasts Differentiation and Myocardial Fibrosis by Suppressing pRB-E2F1/CCNE2 and RhoA/ROCK2 Pathway. Frontiers in pharmacology 15 34483923
2016 p53-dependent up-regulation of CDKN1A and down-regulation of CCNE2 in response to beryllium. Cell proliferation 14 27611480
2021 E2F transcription factor 1 (E2F1) promotes the transforming growth factor TGF-β1 induced human cardiac fibroblasts differentiation through promoting the transcription of CCNE2 gene. Bioengineered 12 34521301
2020 Clinical significance of CCNE2 protein and mRNA expression in thyroid cancer tissues. Advances in medical sciences 12 33059229
2021 Circular RNA hsa_circ_0000073 Enhances Osteosarcoma Cells Malignant Behavior by Sponging miR-1252-5p and Modulating CCNE2 and MDM2. Frontiers in cell and developmental biology 8 34568326
2019 Nicotine-upregulated miR-30a arrests cell cycle in G1 phase by directly targeting CCNE2 in human periodontal ligament cells. Biochemistry and cell biology = Biochimie et biologie cellulaire 8 31689122
2019 LncRNA MVIH knockdown inhibits the malignancy progression through downregulating miR-505 mediated HMGB1 and CCNE2 in acute myeloid leukemia. Translational cancer research 7 35117009
2020 [MicroRNA-200c-3p inhibits proliferation of nephroblastoma cells by targeting CCNE2]. Nan fang yi ke da xue xue bao = Journal of Southern Medical University 4 32990223
2014 [Evaluation of c-myc and CCNE2 amplification in breast cancer with quantitative multi-gene fluorescence in-situ hybridization]. Zhonghua bing li xue za zhi = Chinese journal of pathology 4 25327794
2026 Targeting CCNE2 to alleviate rheumatoid arthritis through inducing senescence and apoptosis. Modern rheumatology 1 40820921
2020 Correction to: Circular RNA circ-CSPP1 regulates CCNE2 to facilitate hepatocellular carcinoma cell growth via sponging miR-577. Cancer cell international 1 32669969
2024 ELF3 Overexpression Contributes to the Malignant Transformation of HPV16 E6/E7-Immortalized Keratinocytes by Promoting CCNE2 Expression. Journal of microbiology and biotechnology 0 39572025
2023 Retraction: Knockdown of long non-coding RNA KCNQ1OT1 restrained glioma cells' malignancy by activating miR-370/CCNE2 axis. Frontiers in cellular neuroscience 0 37032834

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