Affinage

CCNA2

Cyclin-A2 · UniProt P20248

Round 2 corrected
Length
432 aa
Mass
48.6 kDa
Annotated
2026-04-28
130 papers in source corpus 37 papers cited in narrative 37 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Cyclin A2 is a master cell-cycle regulator that drives both S-phase DNA replication and mitotic entry by sequentially partnering with CDK2 and CDK1 to phosphorylate substrates that control replication licensing, recombination, and checkpoint signaling. The crystal structure of the cyclin A–CDK2 complex reveals that cyclin A activates CDK2 by repositioning its PSTAIRE helix and T-loop, with full activation requiring T-loop phosphorylation; the activated complex phosphorylates p27Kip1 to trigger its proteasomal degradation, BRCA2-S3291 to suppress RAD51-dependent recombination at mitosis, and AXIN1 to promote β-catenin degradation via WNT pathway modulation (PMID:7630397, PMID:8756328, PMID:9311993, PMID:15800615, PMID:38704137). CCNA2 transcription is activated at the G1/S boundary by E2F1/E2F3 replacing the repressive E2F4/p130 complex, and is additionally regulated by CDCA7 and CREB1 at its promoter; post-transcriptionally, multiple p53-responsive miRNAs (miR-124, miR-29, miR-19-3p) repress CCNA2 to enforce cellular senescence independently of the p53/p21 axis (PMID:10766737, PMID:34737951, PMID:30848072). Cyclin A2 is degraded at mitosis through APC/C-mediated K11-linked polyubiquitination, and its deregulation via Rb pathway loss contributes to chromosomal instability and aneuploidy (PMID:18485873, PMID:15306814).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1990 High

    Identification of the human cyclin A2 gene at an HBV integration site in hepatocellular carcinoma established the existence of a human A-type cyclin, enabling all subsequent functional studies.

    Evidence Molecular cloning and cDNA sequencing from a hepatocellular carcinoma with HBV integration

    PMID:1967822

    Open questions at the time
    • No functional data on the encoded protein at this stage
    • Expression pattern across tissues and cell cycle not yet determined
  2. 1991 High

    Microinjection experiments demonstrated that cyclin A2 protein is required for the initiation of DNA replication, answering whether cyclin A2 has a direct cell-cycle function beyond being a viral integration target.

    Evidence Anti-cyclin A antibody and antisense microinjection with recombinant protein rescue in mammalian fibroblasts

    PMID:1836977

    Open questions at the time
    • Whether cyclin A2 acts at additional cell-cycle stages beyond S-phase entry
    • Identity of the catalytic partner kinase
  3. 1992 High

    Demonstration that cyclin A2 functions at two distinct cell-cycle transitions — S phase and mitotic entry — through association with CDK2 and CDC2/CDK1 respectively, establishing cyclin A2 as a dual-function regulator.

    Evidence Stage-specific microinjection of anti-cyclin A antibodies with kinase activity assays in synchronized human cells

    PMID:1312467

    Open questions at the time
    • Structural basis of cyclin A–CDK activation unknown
    • Substrates of each complex not identified
  4. 1995 High

    The crystal structure of cyclin A–CDK2 at 2.3 Å resolved how cyclin binding activates CDK2 — by repositioning the PSTAIRE helix and T-loop to open the catalytic cleft — providing the atomic framework for all subsequent substrate and inhibitor studies.

    Evidence X-ray crystallography of human cyclin A–CDK2–ATP complex at 2.3 Å

    PMID:7630397

    Open questions at the time
    • Role of T-loop phosphorylation not yet structurally resolved
    • Substrate recognition mechanism unknown
  5. 1995 High

    Identification of p19Skp1 and p45Skp2 as essential accessory subunits of the S-phase cyclin A–CDK2 holoenzyme revealed that the active complex is a higher-order assembly beyond a simple cyclin–CDK dimer.

    Evidence Reconstitution, co-immunoprecipitation, and microinjection of anti-Skp2 antibodies blocking S-phase entry

    PMID:7553852

    Open questions at the time
    • Structural organization of the quaternary complex unknown
    • How Skp1/Skp2 contribute to substrate selection unclear
  6. 1996 High

    Structures of the p27-bound and T-loop-phosphorylated cyclin A–CDK2 complexes explained CKI inhibition (p27 inserts into the catalytic cleft) and full kinase activation (phospho-T-loop remodels the substrate-binding site), completing the structural picture of cyclin A–CDK2 regulation.

    Evidence X-ray crystallography of p27Kip1–cyclin A–CDK2 at 2.3 Å and phospho-CDK2–cyclin A at 2.6 Å

    PMID:8684460 PMID:8756328

    Open questions at the time
    • How the complex selects among diverse substrates not resolved
    • In vivo stoichiometry of CKI-bound vs. free complex unknown
  7. 1997 High

    Discovery that cyclin A–CDK2 phosphorylates p27Kip1 on its TPKK motif to trigger proteasomal degradation established a feed-forward mechanism by which the complex eliminates its own inhibitor, explaining the sharp S-phase onset of CDK2 activity.

    Evidence Site-directed mutagenesis of p27 TPKK motif, retroviral expression, proteasome inhibitor experiments

    PMID:9311993

    Open questions at the time
    • Identity of the E3 ubiquitin ligase for phospho-p27 not determined here
    • Whether other CKIs are similarly phosphorylated by cyclin A–CDK2
  8. 1998 High

    Caspase-3 cleavage of p21/p27 during apoptosis derepresses cyclin A–CDK2, placing this kinase complex as an effector of apoptotic execution downstream of caspase activation.

    Evidence Dominant-negative CDK2 and caspase-resistant p21 mutant suppress apoptosis in endothelial cells

    PMID:9660939

    Open questions at the time
    • Apoptotic substrates of activated cyclin A–CDK2 not identified
    • Generalizability beyond endothelial cells not tested
  9. 2000 High

    ChIP demonstrated that the CCNA2 promoter switches from E2F4/p130 repressive occupancy in quiescence to E2F1/E2F3 activating occupancy in late G1, directly explaining how CCNA2 transcription is coupled to cell-cycle re-entry.

    Evidence Chromatin immunoprecipitation in synchronized human cells

    PMID:10766737

    Open questions at the time
    • Other transcriptional regulators of the CCNA2 promoter not surveyed
    • Epigenetic mechanisms beyond histone acetylation not examined
  10. 2005 High

    Identification of BRCA2-S3291 as a cyclin A–CDK2 substrate that blocks RAD51 binding linked the cell-cycle kinase to cell-cycle-dependent regulation of homologous recombination, explaining how recombination is suppressed outside S phase.

    Evidence In vitro kinase assays, phospho-specific antibodies, co-IP in synchronized cells

    PMID:15800615

    Open questions at the time
    • Whether additional recombination factors are cyclin A–CDK2 substrates
    • Structural basis of phospho-S3291 disrupting RAD51 binding not shown
  11. 2008 High

    Biochemical reconstitution showed that APC/C assembles K11-linked polyubiquitin chains on cyclin A2 for mitotic degradation, defining the ubiquitin chain topology and TEK-box motif requirements for the regulated destruction that terminates cyclin A2 function at mitosis.

    Evidence In vitro ubiquitination reconstitution with mass spectrometry of chain topology and TEK-box mutagenesis

    PMID:18485873

    Open questions at the time
    • How APC/C recognizes cyclin A2 before securin and cyclin B (early mitotic substrate preference) is not structurally explained
    • In vivo chain editing or DUB regulation of ubiquitinated cyclin A2 not characterized
  12. 2019 High

    Multiple p53-responsive miRNAs (miR-124, miR-29a/b/c) were shown to repress CCNA2, driving cellular senescence through a pathway independent of p53/p21, revealing a post-transcriptional layer of CCNA2 regulation that connects proliferation control to aging.

    Evidence miRNA microarrays in aging mice, overexpression/inhibition in human cells, senescence assays in p21-knockout cells

    PMID:30848072

    Open questions at the time
    • Relative quantitative contribution of individual miRNAs to CCNA2 repression in vivo unknown
    • Whether miRNA-mediated CCNA2 repression is reversible during tissue regeneration
  13. 2021 Medium

    CDCA7 was identified as a direct transcriptional activator of CCNA2, expanding the set of known CCNA2 promoter regulators beyond the E2F family and linking CCNA2 upregulation to oncogenic transcription programs.

    Evidence ChIP and luciferase reporter validation of CDCA7 binding to CCNA2 promoter; CCNA2 knockdown rescues CDCA7-driven proliferation in ESCC cells

    PMID:34737951

    Open questions at the time
    • Whether CDCA7 and E2F factors cooperate or act independently at the CCNA2 promoter
    • CDCA7-CCNA2 axis not validated in non-cancer contexts
  14. 2024 Medium

    Cyclin A2–CDK2 was shown to phosphorylate AXIN1, promoting β-catenin ubiquitination and WNT pathway inactivation, extending the substrate repertoire of the complex to a key signaling pathway and linking it to alveolar cell differentiation in lung adenocarcinoma.

    Evidence Single-cell sequencing, CCNA2 inhibition, Western blot for AXIN1 phosphorylation and β-catenin in LUAD models

    PMID:38704137

    Open questions at the time
    • Direct in vitro kinase assay for AXIN1 phosphorylation by cyclin A2–CDK2 not shown
    • Physiological relevance of this axis outside cancer models not established
    • Specific AXIN1 phosphosite(s) not mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of APC/C's preferential recognition of cyclin A2 as an early mitotic substrate, the comprehensive in vivo substrate landscape of cyclin A2–CDK2 versus cyclin A2–CDK1, and whether the miRNA-mediated post-transcriptional network controlling CCNA2 is exploitable therapeutically in senescence-associated diseases.
  • No structural model of APC/C–cyclin A2 recognition explaining early mitotic degradation timing
  • Systematic phosphoproteomics distinguishing cyclin A2–CDK2 from cyclin A2–CDK1 substrates lacking
  • Therapeutic targeting of miRNA–CCNA2 axis not tested in vivo

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0140096 catalytic activity, acting on a protein 3
Localization
GO:0005634 nucleus 2 GO:0005654 nucleoplasm 1
Pathway
R-HSA-1640170 Cell Cycle 6 R-HSA-69306 DNA Replication 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-162582 Signal Transduction 1 R-HSA-5357801 Programmed Cell Death 1 R-HSA-73894 DNA Repair 1
Partners
BRCA2CDK1CDK2CDKN1ACDKN1BE2F1SKP1SKP2
Complex memberships
Cyclin A2–CDK1Cyclin A2–CDK2Cyclin A2–CDK2–p19Skp1–p45Skp2

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1990 The CCNA2 locus was identified as the integration site of hepatitis B virus in a human hepatocellular carcinoma, leading to cloning of human cyclin A2 cDNA encoding a 432-amino-acid protein whose C-terminal half is homologous to A-type cyclins of clam and Drosophila. Molecular cloning, cDNA library screening, sequence homology analysis Nature High 1967822
1991 Cyclin A2 protein is synthesized and translocates to the nucleus at the onset of S phase; microinjection of anti-cyclin A antibodies or antisense cyclin A plasmids during G1 abolishes DNA synthesis, and re-injection of purified cyclin A protein rescues the block, establishing that cyclin A2 is required for the initiation of DNA replication. Microinjection of antibodies/antisense plasmids and recombinant protein rescue in nontransformed mammalian fibroblasts Cell High 1836977
1992 Cyclin A2 is required at two distinct points in the human cell cycle: DNA synthesis (S phase) and entry into mitosis. Cyclin A binds both CDK2 and CDC2, generating two distinct kinase activities — one appearing in S phase and one in G2. Microinjection of anti-cyclin A antibodies at defined cell cycle stages; kinase activity assays The EMBO Journal High 1312467
1995 Crystal structure of the human cyclin A–CDK2–ATP complex at 2.3 Å resolution shows that cyclin A binds one side of CDK2's catalytic cleft, inducing large conformational changes in the PSTAIRE helix and T-loop that activate the kinase by realigning active-site residues and relieving steric blockade at the catalytic cleft entrance. X-ray crystallography at 2.3 Å resolution Nature High 7630397
1995 p19Skp1 and p45Skp2 are essential components of the cyclin A–CDK2 S-phase kinase complex. In many transformed cells, p21 is displaced and cyclin A–CDK2 forms a quaternary complex with p9CKS, p19Skp1, and p45Skp2. Microinjection of antibodies or antisense oligonucleotides against p45Skp2 prevented S-phase entry, identifying p45 as an essential element of the cyclin A–CDK2 activity required for S phase. In vitro reconstitution, microinjection of antibodies and antisense oligonucleotides, co-immunoprecipitation Cell High 7553852
1996 Crystal structure of p27Kip1 kinase-inhibitory domain bound to phosphorylated cyclin A–CDK2 at 2.3 Å shows p27 binds as an extended structure contacting both subunits: on cyclin A it occupies a groove formed by conserved cyclin-box residues, and on CDK2 it rearranges the N-terminal lobe and inserts into the catalytic cleft, mimicking ATP to inhibit kinase activity. X-ray crystallography at 2.3 Å resolution with phosphorylated complex Nature High 8684460
1996 Phosphorylation of CDK2 on its T-loop reorganizes the regulatory loop by up to 7 Å, neutralizes charge via three Arg side chains, creates additional CDK2–cyclin A contacts, and remodels the substrate-binding site, revealing the structural basis by which T-loop phosphorylation fully activates the cyclin A–CDK2 complex. X-ray crystallography of phosphorylated CDK2–cyclin A–ATPγS complex at 2.6 Å Nature Structural Biology High 8756328
1997 p27Kip1 must be phosphorylated by CDK2 on a conserved TPKK site (C-terminal) in order to be targeted for proteasomal degradation. This phosphorylation requires p27 to be in a cyclin-bound but CDK-non-inhibitory conformation (demonstrated by CDK-contact mutant p27(k-) that is rapidly degraded, while mutation of the TPKK site to VPKK stabilizes it), establishing a mechanism whereby cyclin A–CDK2 triggers its own de-inhibition by phosphorylating and destabilizing p27. Site-directed mutagenesis of p27, retroviral expression, proteasome inhibitor experiments, in vivo phosphorylation assays The EMBO Journal High 9311993
1998 During apoptosis of human endothelial cells, caspase CPP32/caspase-3 cleaves the C-termini of p21Cip1 and p27Kip1, causing dissociation from nuclear cyclin A–CDK2 complexes and dramatic induction of CDK2 kinase activity. Dominant-negative CDK2 and a caspase-resistant p21 mutant partially suppress apoptosis, placing cyclin A–CDK2 activation downstream of caspase activation as an effector of apoptotic execution. Caspase cleavage assays, dominant-negative CDK2, caspase-resistant p21 mutant expression, kinase activity assays in apoptotic cells Molecular Cell High 9660939
2000 ChIP analysis in synchronized cells shows that the CCNA2 (cyclin A) promoter is occupied by E2F-4/p130 with low histone acetylation in quiescent cells, and these are replaced by E2F-1/E2F-3 with histone H3/H4 acetylation in late G1, directly regulating cyclin A transcriptional activation as cells enter S phase. Chromatin immunoprecipitation (ChIP) in synchronized living cells Genes & Development High 10766737
2004 Rb inactivation deregulates E2F and aberrantly upregulates Mad2, a mitotic checkpoint protein; cyclin A is identified as a direct E2F target whose deregulated expression (via Rb pathway loss) contributes to mitotic defects and aneuploidy, linking cyclin A2 transcriptional control to chromosomal instability. Retroviral expression, ChIP, RNAi, cell cycle analysis in normal and Rb-deficient cells Nature High 15306814
2005 Cyclin-dependent kinases, including cyclin A–CDK2, phosphorylate BRCA2 at serine 3291 in the C-terminal RAD51-interaction domain. This phosphorylation is low during S phase (when recombination is active) and increases toward mitosis, blocking BRCA2–RAD51 interaction and suppressing homologous recombination; DNA damage reverses this phosphorylation to restore RAD51 binding. In vitro kinase assays with CDK-cyclin complexes, phospho-specific antibodies, co-immunoprecipitation, cell cycle-synchronized analysis Nature High 15800615
2008 Mass spectrometry-based global DUB interactome analysis identified CCNA2 (cyclin A2) as a protein co-purifying with specific deubiquitinating enzyme complexes, placing cyclin A2 in the ubiquitin-proteasome regulatory network. Affinity purification–mass spectrometry (AP-MS) of 75 deubiquitinating enzymes in HEK293 cells Cell Medium 19615732
2008 The human APC/C assembles K11-linked ubiquitin chains on substrates to trigger their degradation during mitosis; cyclin A2 (as an APC/C substrate) is among the cell-cycle regulators whose ubiquitination and degradation is mediated by this K11-linkage mechanism, dependent on TEK-box motifs in substrates. In vitro ubiquitination reconstitution, mass spectrometry of ubiquitin-chain topology, mutagenesis of TEK-box motifs Cell High 18485873
2013 MicroRNA-124 is downregulated in HD striatal mutant cells and in R6/2 mouse brains; this correlates with increased CCNA2 protein expression. Exogenous miR-124 reduces CCNA2, while miR-124 inhibition or CCNA2 knockdown/overexpression reciprocally alters the proportion of cells in S phase, establishing CCNA2 as a functional target of miR-124 in cell cycle regulation in a Huntington's disease cell model. miRNA overexpression/inhibition, CCNA2 knockdown/overexpression, flow cytometry cell cycle analysis, qRT-PCR, in vivo R6/2 mouse model Biochemical and Biophysical Research Communications Medium 23796713
2015 High-throughput AP-MS (BioPlex) identified 23,744 interactions among 7,668 human proteins; CCNA2 was identified with specific interacting partners in 293T cells, extending the known cyclin A2 interaction network. High-throughput affinity-purification mass spectrometry in HEK293T cells Cell Medium 26186194
2015 Quantitative interactome analysis using GFP-tagged proteins at near-endogenous levels in HeLa cells placed CCNA2 in defined stable complexes distinguishable by stoichiometry signatures, with the majority of cyclin A2 interactions being substoichiometric. Quantitative AP-MS with GFP-tagged proteins under near-endogenous promoter control, stoichiometry calculations Cell Medium 26496610
2015 BioID proximity-labeling of 58 centrosome/cilium bait proteins identified CCNA2 as a proximal interactor at the centrosome-cilium interface, linking cyclin A2 to centrosome biology. Proximity-dependent biotinylation (BioID) mass spectrometry Cell Low 26638075
2016 miR-22, induced by farnesoid X receptor (FXR), directly represses CCNA2 in hepatocellular carcinoma cells. Waltonitone induces miR-22 via FXR, reducing CCNA2 expression and arresting cell proliferation; miR-22 silencing or FXR knockdown reverses the CCNA2 downregulation and restores proliferation, and CCNA2 knockdown mimics waltonitone's anti-proliferative effect. miRNA overexpression/knockdown, FXR knockdown, qRT-PCR, Western blot, in vivo xenograft model Oncotarget Medium 27738335
2016 mmu-miR-125b overexpression in macrophages suppresses NO production; CCNA2 (along with eEF2K) is identified as a direct and functional target of miR-125b by luciferase reporter assay, and CCNA2 knockdown phenocopies miR-125b overexpression in reducing NO production, implicating CCNA2 in macrophage iNOS/NO pathway regulation. Luciferase reporter assay, Western blot, siRNA knockdown, NO production assays BMC Cancer Medium 27020049
2017 BioPlex 2.0 AP-MS network (>56,000 interactions) identified CCNA2-containing protein communities with functional co-complex partners, further characterizing the human cyclin A2 interactome at proteome scale. Affinity-purification mass spectrometry at proteome scale, Markov clustering Nature Medium 28514442
2018 CCNA2 knockdown in colorectal cancer cells significantly suppresses cell growth by impairing cell cycle progression (reducing S-phase entry) and inducing apoptosis, establishing CCNA2 as functionally required for CRC cell proliferation. siRNA knockdown, flow cytometry cell cycle and apoptosis assays, colony formation assay Cancer Management and Research Medium 30464611
2018 Sevoflurane exposure upregulates miR-19-3p in neurons, which post-transcriptionally inhibits CCNA2 protein translation. Intracranial injection of adeno-associated virus carrying antisense miR-19-3p rescues CCNA2 expression, restores neuron proliferation, and alleviates learning/memory impairment in neonatal rats, placing CCNA2 as a downstream effector of miR-19-3p in neuronal cell cycle control. Bioinformatic target prediction, luciferase reporter, miR-19-3p antisense AAV injection in neonatal rats, BrdU proliferation, Morris water maze, Western blot Aging Medium 30540563
2019 Multiple p53-responsive miRNAs (miR-124, miR-29a/b/c) target CCNA2 mRNA and downregulate its expression during aging and cellular senescence. CCNA2 silencing triggers senescence while CCNA2 overexpression delays senescence and rescues the senescence induced by miR-124/miR-29. In p21-deficient cells, the p53/miRNA/CCNA2 axis independently drives senescence, identifying a p53/miRNAs/Ccna2 pathway as a senescence regulator that is parallel to and independent of p53/p21. miRNA microarray in aging mice, mRNA microarray, miRNA overexpression/inhibition, CCNA2 knockdown/overexpression, SA-β-gal senescence assay, p21-knockout cells Aging Cell High 30848072
2019 CCNA2 downregulation in first-trimester trophoblast (HTR8/SVneo cells) reduces migration via the RhoA-ROCK signaling pathway and decreases proliferation while increasing apoptosis via the p53 pathway; CCNA2 overexpression produces the opposite effects. DNA damage was identified as a mechanism linking CCNA2 to p53 pathway activation. CCNA2 expression is reduced in chorionic villi from recurrent miscarriage patients. siRNA knockdown, overexpression, migration/invasion assays, flow cytometry, Western blot for RhoA-ROCK and p53 pathway components in HTR8 cells and ex vivo villi American Journal of Reproductive Immunology Medium 31087423
2019 miR-219a-5p is upregulated in traumatic brain injury and in a neuronal injury model; it directly inhibits CCNA2 (and CACUL1) and thereby activates akt/Foxo3a and p53/Bcl-2 signaling, increasing cleaved caspase-3 and causing neuronal apoptosis. TaqMan Low Density Array in patient serum, RT-qPCR validation, predicted target knockdown, Western blot for pathway components in neuronal cell line injury model Journal of Neurochemistry Medium 31077370
2020 miR-29c-3p directly targets the 3′-UTR of CCNA2 (validated by dual-luciferase reporter and RIP assay); miR-29c-3p overexpression reduces CCNA2, activates p53 signaling, and inhibits esophageal carcinoma cell proliferation, migration, and invasion while arresting cells in G0/G1. CCNA2 silencing phenocopies these effects and reverses the promotion caused by low miR-29c-3p levels. Dual-luciferase reporter gene assay, RIP, qRT-PCR, Western blot, MTT, Transwell, flow cytometry in esophageal carcinoma cell lines Frontiers in Bioengineering and Biotechnology Medium 32154226
2020 miR-508-3p directly targets the 3′-UTR of CCNA2 (validated by reporter gene assay), suppressing CCNA2 expression and inhibiting ovarian cancer cell proliferation; high CCNA2 expression is inversely correlated with miR-508-3p levels in ovarian cancer tissues. Luciferase reporter gene assay, miR-508-3p mimic overexpression, Western blot, proliferation assays in ovarian cancer cell lines International Journal of Oncology Medium 32377701
2020 CCNA2 expression is required for sensitivity to polo-like kinase 1 (PLK1) inhibitors (BI-2536 and volasertib) in gastric cancer cells: elevated CCNA2 (particularly in KRAS-mutant lines) increases mitotic catastrophe and apoptosis upon PLK1 inhibition. CCNA2 knockdown reduces sensitivity to PLK1 inhibitors, functionally linking CCNA2 levels to mitotic regulation and PLK1 inhibitor response. Pharmacogenomic screen of 37 gastric cancer cell lines, CCNA2 knockdown, PLK1 inhibitor treatment, flow cytometry for mitotic catastrophe/apoptosis, Western blot Cancers Medium 32486290
2021 YY1 transcription factor directly binds the ROBO1 promoter to promote transcription (validated by luciferase reporter, ChIP, and EMSA); ROBO1 overexpression inhibits pancreatic cancer cell proliferation by reducing CCNA2 and CDK2 expression, arresting cells in S phase. The YY1-ROBO1-CCNA2/CDK2 axis constitutes a regulatory pathway in which YY1-driven ROBO1 transcription suppresses cell cycle progression through CCNA2 downregulation. Luciferase reporter assay, ChIP, EMSA, ROBO1 overexpression, Western blot for CCNA2/CDK2, flow cytometry, subcutaneous xenograft Oncogene Medium 33714986
2021 BioPlex 3.0 (affinity purification of 10,128 human proteins) identified 118,162 interactions including CCNA2 co-complex partners in 293T and HCT116 cell lines, and comparison across cell lines validated core cyclin A2 interactions versus cell-specific interactions. Proteome-scale AP-MS in two human cell lines with cross-cell-line comparison Cell Medium 33961781
2021 CDCA7 directly binds the CCNA2 gene regulatory region (validated by ChIP and luciferase reporter assays) to promote CCNA2 transcription in esophageal squamous cell carcinoma; CCNA2 knockdown reverses the proliferation/colony formation/cell cycle promotion induced by CDCA7 overexpression, establishing CCNA2 as a direct transcriptional target of CDCA7 that mediates its oncogenic function. ChIP, luciferase reporter assay, CCNA2 knockdown rescue assay, proliferation, colony formation, flow cytometry in ESCC cell lines Frontiers in Oncology Medium 34737951
2021 Tanshinone IIA (TSA) down-regulates CCNA2 and CDK2 in lung adenocarcinoma cells, inducing G1/S phase cell cycle arrest and apoptosis. Molecular docking analysis shows TSA has favorable binding energy to the CCNA2–CDK2 complex, and Western blot confirms reduction of CCNA2, CDK2, AURKA, PLK1, and p-ERK, placing CCNA2–CDK2 complex disruption as a mechanism of TSA's anti-LUAD effect. Network pharmacology/molecular docking, MTT, colony formation, flow cytometry, Western blot in A549 and NCI-H1975 cells Scientific Reports Low 34880385
2022 E2F1 directly binds the CCNA2 promoter at the +677 position (validated by luciferase reporter assay) to transcriptionally activate CCNA2 expression in triple-negative breast cancer. E2F1 knockdown reduces CCNA2 expression and impairs cell proliferation and invasion, while CCNA2 overexpression rescues the effects of E2F1 knockdown. Luciferase reporter assay, bioinformatics correlation, E2F1 knockdown, CCNA2 overexpression rescue, Western blot in TNBC cell lines and tissues Cancer Biomarkers Medium 34366326
2022 CREB1 directly binds the proximal promoter region of CCNA2 in bovine myoblasts (validated by dual luciferase reporter assay), promoting CCNA2 transcription and thereby stimulating S-phase entry and cell proliferation. Dual luciferase reporter assay, CREB1 overexpression/knockdown, flow cytometry, EdU incorporation, Western blot in bovine myoblasts International Journal of Biological Macromolecules Medium 35777504
2022 OpenCell endogenous GFP-tagging and live-cell imaging showed that CCNA2 localizes to the nucleus during S and G2 phases; AP-MS from endogenously tagged CCNA2 identified co-complex interactors under physiological expression conditions. CRISPR endogenous GFP tagging, confocal live-cell imaging, AP-MS in human cells Science Medium 35271311
2024 CCNA2 binds CDK2 and the resulting complex phosphorylates AXIN1, promoting ubiquitination-dependent degradation of β-catenin and inactivation of WNT/β-catenin signaling, thereby driving AT2 cell differentiation into AT2-like (cancer stem) cells in smoking-induced lung adenocarcinoma. CCNA2 inhibition reverses smoking-induced AT2-like cell differentiation. Single-cell sequencing analysis, CCNA2 inhibition experiments, Western blot for β-catenin/AXIN1/p-AXIN1, flow cytometry for AT2/AT2-like cell markers in LUAD models Cancer Letters Medium 38704137

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 4238 9054499
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
1992 Cyclin A is required at two points in the human cell cycle. The EMBO journal 1318 1312467
2009 Defining the human deubiquitinating enzyme interaction landscape. Cell 1282 19615732
1995 Mechanism of CDK activation revealed by the structure of a cyclinA-CDK2 complex. Nature 1205 7630397
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2005 The bromodomain protein Brd4 is a positive regulatory component of P-TEFb and stimulates RNA polymerase II-dependent transcription. Molecular cell 1075 16109376
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
1991 Cyclin A is required for the onset of DNA replication in mammalian fibroblasts. Cell 856 1836977
2009 A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene. Cell 843 19490893
1996 Crystal structure of the p27Kip1 cyclin-dependent-kinase inhibitor bound to the cyclin A-Cdk2 complex. Nature 793 8684460
2010 The matricellular protein CCN1 induces fibroblast senescence and restricts fibrosis in cutaneous wound healing. Nature cell biology 780 20526329
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
1990 Hepatitis B virus integration in a cyclin A gene in a hepatocellular carcinoma. Nature 671 1967822
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1997 Phosphorylation-dependent degradation of the cyclin-dependent kinase inhibitor p27. The EMBO journal 602 9311993
1996 Structural basis of cyclin-dependent kinase activation by phosphorylation. Nature structural biology 522 8756328
2000 Analysis of promoter binding by the E2F and pRB families in vivo: distinct E2F proteins mediate activation and repression. Genes & development 517 10766737
1991 Cyclins and cancer. Cell 503 1833062
2004 Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control. Nature 453 15306814
1995 p19Skp1 and p45Skp2 are essential elements of the cyclin A-CDK2 S phase kinase. Cell 445 7553852
2008 Mechanism of ubiquitin-chain formation by the human anaphase-promoting complex. Cell 442 18485873
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2015 A Dynamic Protein Interaction Landscape of the Human Centrosome-Cilium Interface. Cell 433 26638075
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2010 Systematic analysis of human protein complexes identifies chromosome segregation proteins. Science (New York, N.Y.) 421 20360068
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
1998 Cleavage of p21Cip1/Waf1 and p27Kip1 mediates apoptosis in endothelial cells through activation of Cdk2: role of a caspase cascade. Molecular cell 408 9660939
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2005 CDK-dependent phosphorylation of BRCA2 as a regulatory mechanism for recombinational repair. Nature 380 15800615
2011 CCN1/CYR61: the very model of a modern matricellular protein. Cellular and molecular life sciences : CMLS 279 21805345
2006 Mechanical regulation of the Cyr61/CCN1 and CTGF/CCN2 proteins. The FEBS journal 166 16856934
2010 Matricellular protein CCN1 activates a proinflammatory genetic program in murine macrophages. Journal of immunology (Baltimore, Md. : 1950) 142 20164416
2007 Functional properties and intracellular signaling of CCN1/Cyr61. Journal of cellular biochemistry 140 17171641
2015 The matricellular protein CCN1 mediates neutrophil efferocytosis in cutaneous wound healing. Nature communications 138 26077348
2011 Cyr61/CCN1 signaling is critical for epithelial-mesenchymal transition and stemness and promotes pancreatic carcinogenesis. Molecular cancer 101 21232118
2005 The matrix protein CCN1 (CYR61) induces apoptosis in fibroblasts. The Journal of cell biology 100 16275757
2009 Sphingosine-1-phosphate regulates glioblastoma cell invasiveness through the urokinase plasminogen activator system and CCN1/Cyr61. Molecular cancer research : MCR 98 19147534
2006 The matricellular protein CCN1 is essential for cardiac development. Circulation research 97 17023674
2014 CCN1 secretion and cleavage regulate the lung epithelial cell functions after cigarette smoke. American journal of physiology. Lung cellular and molecular physiology 88 24973403
2018 CCNA2 acts as a novel biomarker in regulating the growth and apoptosis of colorectal cancer. Cancer management and research 80 30464611
2014 Matricellular protein CCN1/CYR61: a new player in inflammation and leukocyte trafficking. Seminars in immunopathology 79 24638890
2018 The matricellular protein CCN1 in tissue injury repair. Journal of cell communication and signaling 72 29357009
2016 The matricellular protein CCN1 enhances TGF-β1/SMAD3-dependent profibrotic signaling in fibroblasts and contributes to fibrogenic responses to lung injury. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 70 26884454
2018 The official unified nomenclature adopted by the HGNC calls for the use of the acronyms, CCN1-6, and discontinuation in the use of CYR61, CTGF, NOV and WISP 1-3 respectively. Journal of cell communication and signaling 69 30393824
2005 Increased expression of Cyr61 (CCN1) identified in peritoneal metastases from human pancreatic cancer. Journal of the American College of Surgeons 69 15737847
2019 Shear-Induced CCN1 Promotes Atheroprone Endothelial Phenotypes and Atherosclerosis. Circulation 65 30917686
2019 The p53/miRNAs/Ccna2 pathway serves as a novel regulator of cellular senescence: Complement of the canonical p53/p21 pathway. Aging cell 64 30848072
2006 Decreased expression of the angiogenic regulators CYR61 (CCN1) and NOV (CCN3) in human placenta is associated with pre-eclampsia. Molecular human reproduction 61 16675545
2009 Fas-mediated apoptosis is regulated by the extracellular matrix protein CCN1 (CYR61) in vitro and in vivo. Molecular and cellular biology 59 19364818
2013 Aging increases CCN1 expression leading to muscle senescence. American journal of physiology. Cell physiology 57 24196529
2015 The matricellular protein CCN1 promotes mucosal healing in murine colitis through IL-6. Mucosal immunology 55 25807183
2012 CCN1: a novel inflammation-regulated biphasic immune cell migration modulator. Cellular and molecular life sciences : CMLS 54 22527715
2022 CCN1 interacts with integrins to regulate intestinal stem cell proliferation and differentiation. Nature communications 52 35660741
2012 Extracellular matrix protein CCN1 limits oncolytic efficacy in glioma. Cancer research 52 22282654
2012 The matricellular protein CCN1/Cyr61 is a critical regulator of Sonic Hedgehog in pancreatic carcinogenesis. The Journal of biological chemistry 47 23027863
2014 Oxidant exposure induces cysteine-rich protein 61 (CCN1) via c-Jun/AP-1 to reduce collagen expression in human dermal fibroblasts. PloS one 45 25536346
2007 Cyr61/CCN1 is a tumor suppressor in human hepatocellular carcinoma and involved in DNA damage response. The international journal of biochemistry & cell biology 45 17698398
2015 The matricellular protein CCN1 controls retinal angiogenesis by targeting VEGF, Src homology 2 domain phosphatase-1 and Notch signaling. Development (Cambridge, England) 44 26002917
2008 Functional domains of CCN1 (Cyr61) regulate breast cancer progression. International journal of oncology 44 18575751
2020 CCN1 is an opsonin for bacterial clearance and a direct activator of Toll-like receptor signaling. Nature communications 43 32144270
2015 The matricellular protein CCN1 suppresses hepatocarcinogenesis by inhibiting compensatory proliferation. Oncogene 43 26028023
2022 CCNA2 as an Immunological Biomarker Encompassing Tumor Microenvironment and Therapeutic Response in Multiple Cancer Types. Oxidative medicine and cellular longevity 42 35401923
2016 Waltonitone inhibits proliferation of hepatoma cells and tumorigenesis via FXR-miR-22-CCNA2 signaling pathway. Oncotarget 40 27738335
2014 Role of cysteine-rich 61 protein (CCN1) in macrophage-mediated oncolytic herpes simplex virus clearance. Molecular therapy : the journal of the American Society of Gene Therapy 40 24895995
2018 CCN1 accelerates re-epithelialization by promoting keratinocyte migration and proliferation during cutaneous wound healing. Biochemical and biophysical research communications 39 30361094
2016 Neurofibromatosis 2 (NF2) controls the invasiveness of glioblastoma through YAP-dependent expression of CYR61/CCN1 and miR-296-3p. Biochimica et biophysica acta 39 26923924
2010 Regulation of Cyr61/CCN1 expression by hypoxia through cooperation of c-Jun/AP-1 and HIF-1α in retinal vascular endothelial cells. Experimental eye research 39 21029732
2021 Tanshinone IIA suppresses the progression of lung adenocarcinoma through regulating CCNA2-CDK2 complex and AURKA/PLK1 pathway. Scientific reports 38 34880385
2019 Downregulation of CCNA2 disturbs trophoblast migration, proliferation, and apoptosis during the pathogenesis of recurrent miscarriage. American journal of reproductive immunology (New York, N.Y. : 1989) 37 31087423
2005 Expression, purification, and functional testing of recombinant CYR61/CCN1. Protein expression and purification 37 15878827
2019 CYR61/CCN1 Regulates dCK and CTGF and Causes Gemcitabine-resistant Phenotype in Pancreatic Ductal Adenocarcinoma. Molecular cancer therapeutics 36 30787177
2008 Cyr61/CCN1 and CTGF/CCN2 mediate the proangiogenic activity of VHL-mutant renal carcinoma cells. Carcinogenesis 36 18212329
2022 CCN1 Promotes Inflammation by Inducing IL-6 Production via α6β1/PI3K/Akt/NF-κB Pathway in Autoimmune Hepatitis. Frontiers in immunology 35 35547732
2017 Enhancement of CCL2 expression and monocyte migration by CCN1 in osteoblasts through inhibiting miR-518a-5p: implication of rheumatoid arthritis therapy. Scientific reports 35 28341837
2013 MicroRNA-124 targets CCNA2 and regulates cell cycle in STHdh(Q111)/Hdh(Q111) cells. Biochemical and biophysical research communications 34 23796713
2008 The matrix protein CCN1 (CYR61) promotes proliferation, migration and tube formation of endothelial progenitor cells. Experimental cell research 34 18755182
2018 CYR61/CCN1 Regulates Sclerostin Levels and Bone Maintenance. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 33 29351359
2015 CCN1 (Cyr61) Is Overexpressed in Human Osteoarthritic Cartilage and Inhibits ADAMTS-4 (Aggrecanase 1) Activity. Arthritis & rheumatology (Hoboken, N.J.) 33 25709087
2013 Cysteine-rich protein 61 (CCN1) domain-specific stimulation of matrix metalloproteinase-1 expression through αVβ3 integrin in human skin fibroblasts. The Journal of biological chemistry 33 23504324
2005 Proteolysis of CCN1 by plasmin: functional implications. Cancer research 33 16266990
2020 Scutellarin Ameliorates Renal Injury via Increasing CCN1 Expression and Suppressing NLRP3 Inflammasome Activation in Hyperuricemic Mice. Frontiers in pharmacology 32 33192525
2014 Induction of the matricellular protein CCN1 through RhoA and MRTF-A contributes to ischemic cardioprotection. Journal of molecular and cellular cardiology 32 25106095
2020 Inhibition of cellular communication network factor 1 (CCN1)-driven senescence slows down cartilage inflammaging and osteoarthritis. Bone 30 32622876
2019 Caught between a "Rho" and a hard place: are CCN1/CYR61 and CCN2/CTGF the arbiters of microvascular stiffness? Journal of cell communication and signaling 30 31376071
2017 Biological functions and role of CCN1/Cyr61 in embryogenesis and tumorigenesis in the female reproductive system (Review). Molecular medicine reports 30 29115499
2015 CCN1 secreted by tonsil-derived mesenchymal stem cells promotes endothelial cell angiogenesis via integrin αv β3 and AMPK. Journal of cellular physiology 30 24909560
2017 Lipopolysaccharide-induced CCN1 production enhances interleukin-6 secretion in bronchial epithelial cells. Cell biology and toxicology 29 28638955
2023 Ginsenoside Rg1 ameliorates hypoxia-induced pulmonary arterial hypertension by inhibiting endothelial-to-mesenchymal transition and inflammation by regulating CCN1. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 28 37216706
2016 CYR61/CCN1 stimulates proliferation and differentiation of osteoblasts in vitro and contributes to bone remodeling in vivo in myeloma bone disease. International journal of oncology 28 28035364
2011 Retinoids suppress cysteine-rich protein 61 (CCN1), a negative regulator of collagen homeostasis, in skin equivalent cultures and aged human skin in vivo. Experimental dermatology 28 21488975
2009 Genomic and phenotypic analysis reveals a key role for CCN1 (CYR61) in BAG3-modulated adhesion and invasion. The Journal of pathology 28 19402132
2020 MiR-29c-3p Suppresses the Migration, Invasion and Cell Cycle in Esophageal Carcinoma via CCNA2/p53 Axis. Frontiers in bioengineering and biotechnology 27 32154226
2020 miR‑508‑3p suppresses the development of ovarian carcinoma by targeting CCNA2 and MMP7. International journal of oncology 27 32377701
2017 Interplay between CCN1 and Wnt5a in endothelial cells and pericytes determines the angiogenic outcome in a model of ischemic retinopathy. Scientific reports 27 28469167
2016 CCN1 (CYR61) and CCN3 (NOV) signaling drives human trophoblast cells into senescence and stimulates migration properties. Cell adhesion & migration 27 26744771
2022 E2F1 transcriptionally regulates CCNA2 expression to promote triple negative breast cancer tumorigenicity. Cancer biomarkers : section A of Disease markers 26 34366326
2019 Screening the expression of several miRNAs from TaqMan Low Density Array in traumatic brain injury: miR-219a-5p regulates neuronal apoptosis by modulating CCNA2 and CACUL1. Journal of neurochemistry 26 31077370
2017 Cyr61/CCN1 induces CCL20 production by keratinocyte via activating p38 and JNK/AP-1 pathway in psoriasis. Journal of dermatological science 26 28602508
2015 O-Fucosylation of CCN1 is required for its secretion. FEBS letters 26 26424659
2007 Expression of CCN1 (CYR61) in developing, normal, and diseased human kidney. American journal of physiology. Renal physiology 25 17699553
2020 CCN1 promotes hepatic steatosis and inflammation in non-alcoholic steatohepatitis. Scientific reports 24 32081971
2012 The matrix protein CCN1/CYR61 is required for α(V)β5-mediated cancer cell migration. Cell biochemistry and function 24 22692860
2019 CCN1-Yes-Associated Protein Feedback Loop Regulates Physiological and Pathological Angiogenesis. Molecular and cellular biology 23 31262999
2021 Roundabout homolog 1 inhibits proliferation via the YY1-ROBO1-CCNA2-CDK2 axis in human pancreatic cancer. Oncogene 22 33714986
2016 CCN1 Regulates Chondrocyte Maturation and Cartilage Development. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 21 26363286
2013 Extracellular matrix protein CCN1 regulates cardiomyocyte apoptosis in mice with stress-induced cardiac injury. Cardiovascular research 21 23329650
2024 Cancer-associated Fibroblast-specific Expression of the Matricellular Protein CCN1 Coordinates Neovascularization and Stroma Deposition in Melanoma Metastasis. Cancer research communications 20 38363129
2023 MOTS-c repairs myocardial damage by inhibiting the CCN1/ERK1/2/EGR1 pathway in diabetic rats. Frontiers in nutrition 19 36687680
2022 CREB1 promotes proliferation and differentiation by mediating the transcription of CCNA2 and MYOG in bovine myoblasts. International journal of biological macromolecules 19 35777504
2021 Diabetes Promotes Retinal Vascular Endothelial Cell Injury by Inducing CCN1 Expression. Frontiers in cardiovascular medicine 19 34458333
2020 Pharmacogenomic Analysis Reveals CCNA2 as a Predictive Biomarker of Sensitivity to Polo-Like Kinase I Inhibitor in Gastric Cancer. Cancers 19 32486290
2019 The senescence-associated matricellular protein CCN1 in plasma of human subjects with idiopathic pulmonary fibrosis. Respiratory medicine 19 31765873
2014 Inhibiting CCN1 blocks AML cell growth by disrupting the MEK/ERK pathway. Cancer cell international 19 25187756
2014 Estrogen-induced CCN1 is critical for establishment of endometriosis-like lesions in mice. Molecular endocrinology (Baltimore, Md.) 18 25321413
2022 CCN1/Integrin α5β1 Instigates Free Fatty Acid-Induced Hepatocyte Lipid Accumulation and Pyroptosis through NLRP3 Inflammasome Activation. Nutrients 17 36145246
2021 Induction of Sestrin2 by pterostilbene suppresses ethanol-triggered hepatocyte senescence by degrading CCN1 via p62-dependent selective autophagy. Cell biology and toxicology 17 34405320
2021 CDCA7 Facilitates Tumor Progression by Directly Regulating CCNA2 Expression in Esophageal Squamous Cell Carcinoma. Frontiers in oncology 17 34737951
2020 Dermal Fibroblast CCN1 Expression in Mice Recapitulates Human Skin Dermal Aging. The Journal of investigative dermatology 17 32800875
2018 Sevoflurane impairs learning and memory of the developing brain through post-transcriptional inhibition of CCNA2 via microRNA-19-3p. Aging 17 30540563
2012 CCN1 promotes tumorigenicity through Rac1/Akt/NF-κB signaling pathway in pancreatic cancer. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 17 22752926
2022 Valproic Acid-Induced CCN1 Promotes Osteogenic Differentiation by Increasing CCN1 Protein Stability through HDAC1 Inhibition in Tonsil-Derived Mesenchymal Stem Cells. Cells 16 35159343
2022 Depletion of CCN1/CYR61 reduces triple-negative/basal-like breast cancer aggressiveness. American journal of cancer research 16 35261806
2021 Integrated Profiling Identifies CCNA2 as a Potential Biomarker of Immunotherapy in Breast Cancer. OncoTargets and therapy 16 33859479
2020 Hsa_circ_0003732 promotes osteosarcoma cells proliferation via miR-545/CCNA2 axis. Bioscience reports 16 32537647
2016 Mmu-miR-125b overexpression suppresses NO production in activated macrophages by targeting eEF2K and CCNA2. BMC cancer 16 27020049
2015 The matricellular protein CCN1 regulates TNF-α induced vascular endothelial cell apoptosis. Cell biology international 16 25820828
2024 Smoking-induced CCNA2 expression promotes lung adenocarcinoma tumorigenesis by boosting AT2/AT2-like cell differentiation. Cancer letters 15 38704137
2024 Matricellular protein CCN1 promotes collagen alignment and scar integrity after myocardial infarction. Matrix biology : journal of the International Society for Matrix Biology 15 39098433