Affinage

CCNT2

Cyclin-T2 · UniProt O60583

Length
730 aa
Mass
81.0 kDa
Annotated
2026-06-09
28 papers in source corpus 11 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CCNT2 (Cyclin T2) is the regulatory cyclin subunit of a distinct, non-redundant form of the P-TEFb complex that drives RNA polymerase II transcriptional elongation, controlling a gene program separate from the CycT1-containing complex and required for mammalian embryonic development (PMID:19364821). As part of P-TEFb, CCNT2 promotes release of paused RNA Pol II, functioning as an ally of Aire in the ectopic transcription of autoantigen genes in thymic epithelial cells; in this context it resides in Aire-associated complexes together with the inhibitory 7SK small RNA and HEXIM1, with HNRNPL physically engaging CDK9, CCNT2, HEXIM1, and 7SK to deliver inactive P-TEFb to Aire (PMID:24434558). Consistent with a role in setting elongation kinetics, CCNT2 occupies both the promoter and a distal enhancer of VEGFA, and its loss slows Pol II elongation rate to shift VEGFA alternative splicing (PMID:34316716). Beyond transcription, CCNT2 acts as a functional brake on differentiation: its depletion drives oligodendrocyte progenitor maturation and alters adipogenic gene expression and leptin secretion (PMID:27627980, PMID:26843650). CCNT2 protein levels are post-transcriptionally constrained through its 3'-UTR by multiple microRNAs, including miR-15a and miR-192 (PMID:28409330, PMID:21740905).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2009 High

    Established that CCNT2 is not redundant with CycT1 but defines a functionally distinct P-TEFb complex with its own essential gene program, resolving whether the two cyclin T paralogs are interchangeable.

    Evidence Gene-trap knockout mouse and siRNA knockdown with gene-expression readout in embryonic stem cells

    PMID:19364821

    Open questions at the time
    • The specific CycT2-dependent target genes driving embryonic lethality were not defined
    • No structural or biochemical basis for CycT1 vs CycT2 target selectivity
  2. 2014 High

    Placed CCNT2 mechanistically within Aire-dependent autoantigen transcription, showing P-TEFb release of paused Pol II as the step Aire co-opts, and identified HNRNPL as the factor delivering 7SK-bound inactive P-TEFb.

    Evidence Genome-scale shRNA screen, in vivo knockdown mice, transcriptional reporters, and Co-IP with 7SK RNA and HNRNPL

    PMID:24434558

    Open questions at the time
    • Direct enzymatic activation of CDK9 by Aire engagement not demonstrated
    • HNRNPL interaction (idx 2) rests on Co-IP without reciprocal structural validation
  3. 2021 Medium

    Connected CCNT2's elongation-control activity to co-transcriptional RNA processing, demonstrating that P-TEFb-set Pol II speed governs VEGFA exon inclusion.

    Evidence ChIP at VEGFA promoter and enhancer, siRNA knockdown with splicing RT-PCR, and Pol II ChIP for elongation rate

    PMID:34316716

    Open questions at the time
    • Single lab, not independently replicated
    • Generality to other alternatively spliced genes not established
  4. 2016 Medium

    Extended CCNT2 function beyond transcription per se to cell-fate decisions, showing it restrains oligodendrocyte progenitor differentiation and supports the adipogenic program.

    Evidence siRNA/shRNA knockdown in rat OPCs and human adipocytes with differentiation marker, gene-panel, and secretion readouts; luciferase confirmation of miR-297c-5p targeting

    PMID:26843650 PMID:27627980

    Open questions at the time
    • Mechanism linking CCNT2 transcriptional activity to specific differentiation gene programs unresolved
    • Each phenotype shown in a single lab/model
  5. 2021 Medium

    Built up the picture of CCNT2 as a post-transcriptionally constrained node whose 3'-UTR is targeted by numerous microRNAs across tissues and cancers.

    Evidence Dual-luciferase 3'-UTR reporter assays (wild-type vs mutant), Western blot, and rescue/overexpression in spermatogenesis, AML, gastric cancer, osteosarcoma, and cardiomyocyte models

    PMID:21740905 PMID:28409330 PMID:29849811 PMID:31957815 PMID:33600051 PMID:33817287

    Open questions at the time
    • Whether these miRNAs act on CCNT2 simultaneously or context-specifically is unknown
    • Several individual axes (idx 9, 10, 11) are Low-confidence single-lab miRNA studies
    • Downstream transcriptional consequences of CCNT2 loss in these settings not mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CycT2-containing P-TEFb selects its distinct gene program and how that selectivity is structurally and biochemically distinguished from CycT1 remains open.
  • No structural model of CycT2-CDK9 versus CycT1-CDK9
  • No genome-wide map of CycT2-specific Pol II elongation targets

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 2 GO:0140110 transcription regulator activity 2 GO:0003677 DNA binding 1
Localization
GO:0005634 nucleus 1
Pathway
R-HSA-74160 Gene expression (Transcription) 3 R-HSA-1266738 Developmental Biology 2 R-HSA-8953854 Metabolism of RNA 1
Partners
AIRECDK9HEXIM1HNRNPL
Complex memberships
P-TEFb

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 CycT2 (CCNT2) is a non-redundant component of P-TEFb; genetic inactivation of Ccnt2 in mice causes early embryonic lethality with no surviving homozygous knockouts, and siRNA knockdown in embryonic stem cells reveals that CycT2 regulates a distinct subset of genes from CycT1, demonstrating that P-TEFb complexes containing CycT1 vs CycT2 regulate different gene programs essential for embryonic development. Gene trap knockout mouse (beta-geo insertion), siRNA knockdown in embryonic stem cells, beta-galactosidase expression tracking Molecular and cellular biology High 19364821
2014 CCNT2, as a component of P-TEFb, acts as a functional ally of Aire in releasing paused RNA polymerase II during ectopic transcription of autoantigen genes in thymic epithelial cells; CCNT2 participates in Aire-containing complexes that include the 7SK RNA, and shRNA knockdown of CCNT2 reduces Aire-dependent transcription. Genome-scale lentiviral shRNA screen, lentigenic knockdown mice, transcriptional reporter assays, co-immunoprecipitation with 7SK RNA Proceedings of the National Academy of Sciences of the United States of America High 24434558
2014 HNRNPL physically interacts with P-TEFb components CDK9, CCNT2, HEXIM1, and the 7SK small RNA, and HNRNPL knockdown disrupts the association of 7SK RNA with Aire-containing complexes, suggesting HNRNPL helps deliver inactive P-TEFb to Aire. Co-immunoprecipitation of HNRNPL with CDK9, CCNT2, HEXIM1, and 7SK RNA; shRNA knockdown with transcriptional readout Proceedings of the National Academy of Sciences of the United States of America Medium 24434558
2021 CCNT2 binds both the promoter and the distal enhancer (+157 kb) of VEGFA, and its silencing slows RNA Pol II elongation rate, leading to exclusion of VEGFA exons 6a and 7; this establishes CCNT2 as a regulator of VEGFA alternative splicing via modulation of RNAPII elongation rate. ChIP assay (CCNT2 at VEGFA promoter and enhancer), siRNA knockdown of CCNT2 with RT-PCR analysis of VEGFA splicing isoforms, RNAPII ChIP to assess elongation rate NAR cancer Medium 34316716
2016 CCNT2 silencing in human adipocytes decreases leptin secretion and reduces mRNA expression of adipogenesis-related genes including MGLL, LIPE, PPARG, LEP, and ADIPOQ, establishing a functional role for CCNT2 in adipogenesis. siRNA-mediated CCNT2 knockdown in human adipocytes, qRT-PCR for adipogenesis gene panel, ELISA for leptin secretion Diabetologia Medium 27627980
2016 CCNT2 knockdown in rat oligodendrocyte progenitor cells (OPCs) promotes differentiation into O1+ oligodendrocytes without affecting cell cycle status, identifying CCNT2 as a functional inhibitor of OPC maturation downstream of miR-297c-5p. siRNA/shRNA knockdown of CCNT2 in rat OPCs, flow cytometry for cell cycle analysis, immunostaining for O1+ differentiation marker; luciferase reporter assay confirming miR-297c-5p targeting of CCNT2 3'UTR The Journal of neuroscience : the official journal of the Society for Neuroscience Medium 26843650
2017 CCNT2 is a direct target of miR-192; dual-luciferase reporter assay confirmed miR-192 suppresses the wild-type but not mutated 3'-UTR of CCNT2, and exogenous CCNT2 expression reverses miR-192-induced G0/G1 cell cycle arrest in AML cells. Dual-luciferase reporter assay with wild-type and mutant CCNT2 3'-UTR, Western blot, rescue experiment with CCNT2 overexpression, flow cytometry for cell cycle International journal of hematology Medium 28409330
2011 CCNT2 (Ccnt2) is a direct target of miR-15a in mouse spermatogenesis; miR-15a inhibits Ccnt2 expression post-transcriptionally, and the inverse expression correlation of miR-15a and Ccnt2 during postnatal testis development suggests a role in controlling early spermatogenesis. Luciferase reporter assay for miR-15a targeting of Ccnt2 3'UTR, qRT-PCR and Western blot profiling in developing mouse testes FEBS letters Medium 21740905
2021 NRF2 binds to the promoter of miR-29a-3p (confirmed by ChIP assay), which in turn targets CCNT2 (confirmed by dual-luciferase reporter), establishing an NRF2/miR-29a-3p/CCNT2 axis in myocardial ischemia-reperfusion injury; restoration of NRF2 or miR-29a-3p suppresses CCNT2 and attenuates cardiomyocyte apoptosis. ChIP assay for NRF2 binding to miR-29a-3p promoter, dual-luciferase reporter for miR-29a-3p targeting CCNT2 3'UTR, rat MI/RI model with overexpression plasmids, H/R cardiomyocyte model BioFactors (Oxford, England) Medium 33600051
2018 CCNT2 is a direct target of miR-142-3p in gastric cancer cells; dual-luciferase assay confirmed suppression of wild-type but not mutant CCNT2 3'-UTR, and miR-142-3p overexpression downregulates CCNT2 protein, inhibiting proliferation, invasion, and migration. Dual-luciferase reporter assay, Western blot, miR-142-3p overexpression in gastric cancer cell lines Oncology letters Low 29849811
2020 CCNT2 is a direct target of miR-188-5p in osteosarcoma; dual-luciferase reporter assay confirmed the binding, and exogenous CCNT2 expression partially reverses the anti-proliferative and cell-cycle-arresting effects of miR-188-5p overexpression. Dual-luciferase reporter assay, CCK-8 proliferation assay, flow cytometry, rescue experiment with CCNT2 overexpression European review for medical and pharmacological sciences Low 31957815
2020 miR-212-5p directly targets CCNT2 (confirmed by luciferase reporter), and restoration of CCNT2 attenuates miR-212-5p-induced apoptosis in AML cells; decitabine treatment upregulates miR-212-5p and downregulates CCNT2, linking the drug's anti-leukemic mechanism to the miR-212-5p/CCNT2 axis. Luciferase reporter assay, Western blot, flow cytometry for apoptosis, CCK-8 assay, CCNT2 rescue overexpression Open life sciences Low 33817287

Source papers

Stage 0 corpus · 28 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 An RNAi screen for Aire cofactors reveals a role for Hnrnpl in polymerase release and Aire-activated ectopic transcription. Proceedings of the National Academy of Sciences of the United States of America 55 24434558
2009 Cyclin T2 is essential for mouse embryogenesis. Molecular and cellular biology 44 19364821
2017 MicroRNA-192 regulates cell proliferation and cell cycle transition in acute myeloid leukemia via interaction with CCNT2. International journal of hematology 35 28409330
2016 Remyelinating Oligodendrocyte Precursor Cell miRNAs from the Sfmbt2 Cluster Promote Cell Cycle Arrest and Differentiation. The Journal of neuroscience : the official journal of the Society for Neuroscience 32 26843650
2016 Epigenetic programming of adipose-derived stem cells in low birthweight individuals. Diabetologia 32 27627980
2011 Cyclin T2: a novel miR-15a target gene involved in early spermatogenesis. FEBS letters 30 21740905
2018 Downregulation of microRNA-142-3p and its tumor suppressor role in gastric cancer. Oncology letters 25 29849811
2023 Nanoparticles Mediated circROBO1 Silencing to Inhibit Hepatocellular Carcinoma Progression by Modulating miR-130a-5p/CCNT2 Axis. International journal of nanomedicine 23 37020690
2022 Genome-wide detection of genetic structure and runs of homozygosity analysis in Anhui indigenous and Western commercial pig breeds using PorcineSNP80k data. BMC genomics 23 35581549
2015 Targeting polyamine biosynthetic pathway through RNAi causes the abrogation of MCF 7 breast cancer cell line. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 18 26277788
2020 Hypothalamic proteome changes in response to nicotine and its withdrawal are potentially associated with alteration in body weight. Journal of proteomics 17 31911195
2021 Smoking Modifies Pancreatic Cancer Risk Loci on 2q21.3. Cancer research 15 33574088
2016 Ancestry-based stratified analysis of Immunochip data identifies novel associations with celiac disease. European journal of human genetics : EJHG 15 27650971
2023 Enlightening the path to NSCLC biomarkers: Utilizing the power of XAI-guided deep learning. Computer methods and programs in biomedicine 14 37866126
2020 Potential role of miR-155-5p in fat deposition and skeletal muscle development of chicken. Bioscience reports 14 32441300
2021 Restoration of NRF2 attenuates myocardial ischemia reperfusion injury through mediating microRNA-29a-3p/CCNT2 axis. BioFactors (Oxford, England) 13 33600051
2020 MiRNA-188-5p alleviates the progression of osteosarcoma via target degrading CCNT2. European review for medical and pharmacological sciences 13 31957815
2015 Genetic variants in cell cycle control pathway confer susceptibility to aggressive prostate carcinoma. The Prostate 12 26708993
2022 Long non-coding RNA nuclear-enriched abundant transcript 1 (LncRNA NEAT1) upregulates Cyclin T2 (CCNT2) in laryngeal papilloma through sponging miR-577/miR-1224-5p and blocking cell apoptosis. Bioengineered 10 35012431
2021 VEGFA's distal enhancer regulates its alternative splicing in CML. NAR cancer 8 34316716
2024 Identifying BMI-associated genes via a genome-wide multi-omics integrative approach using summary data. Human molecular genetics 7 38215789
2022 Genome-Wide Detection of Copy Number Variations and Evaluation of Candidate Copy Number Polymorphism Genes Associated With Complex Traits of Pigs. Frontiers in veterinary science 7 35847642
2024 Circ_0007386 Promotes the Progression of Hepatocellular Carcinoma Through the miR-507/ CCNT2 Axis. Journal of hepatocellular carcinoma 4 38887684
2021 Genetic Alterations in Invasive Breast Carcinoma with a Glycogen-Rich Clear Cell Pattern: A Case Report. Case reports in oncology 3 38352277
2020 Decitabine shows anti-acute myeloid leukemia potential via regulating the miR-212-5p/CCNT2 axis. Open life sciences 1 33817287
2018 Short-lived AUF1 p42-binding mRNAs of RANKL and BCL6 have two distinct instability elements each. PloS one 1 30418981
2026 Expanding the Morphological, Immunohistochemical, and Molecular Spectrums of NUT Carcinoma at Rare Sites of Head and Neck Region. Oral diseases 0 41761439
2026 RNA-Binding Proteins Alter Redox Gene Splicing in Biliary Atresia: Insights from Expression Profiling. ACS omega 0 42040470

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