Affinage

CIP2A

Protein CIP2A · UniProt Q8TCG1

Length
905 aa
Mass
102.2 kDa
Annotated
2026-04-28
100 papers in source corpus 32 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CIP2A is an oncoprotein that functions primarily as an endogenous inhibitor of protein phosphatase 2A (PP2A), thereby stabilizing multiple phospho-proteins that drive proliferation and survival signaling. Structurally, CIP2A hijacks the PP2A-B56α holoenzyme by displacing the PP2A-A scaffolding subunit through its N-terminal head domain to form a CIP2A–B56α–PP2Ac pseudotrimer, simultaneously occluding the LxxIxE substrate-binding pocket on B56α; this mechanism shields phospho-MYC (S62), phospho-AKT, phospho-E2F1, and phospho-STAT5b from PP2A-mediated dephosphorylation, and additionally potentiates mTORC1 signaling by inhibiting mTORC1-associated PP2A (PMID:36854761, PMID:26235622, PMID:20729919, PMID:24590173, PMID:23306062). Independent of its PP2A-inhibitory role, CIP2A is actively exported from the nucleus during interphase but gains chromatin access upon nuclear envelope breakdown at mitosis, where it forms a complex with MDC1 and TOPBP1 that tethers acentric chromosome fragments and promotes DNA double-strand break repair; disruption of this CIP2A–TOPBP1 axis is synthetically lethal in BRCA-deficient tumors (PMID:35842428, PMID:35121901, PMID:34145035). CIP2A also scaffolds mitotic spindle assembly by recruiting Aurora A and Plk1 to centrosomes via CEP192, directly binds and stabilizes Plk1 through its polo-box domain to prevent APC/C-Cdh1-mediated degradation, and redirects PKM2 to mitochondria to shift metabolism toward oxidative phosphorylation (PMID:28521709, PMID:23983103, PMID:38321019).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2009 Medium

    Establishing that CIP2A expression is induced by upstream oncogenic signaling (H. pylori CagA via Src/MEK/ERK) placed CIP2A downstream of mitogenic kinase cascades and linked it to c-Myc stabilization in a pathological context.

    Evidence H. pylori infection with CagA mutants and signaling inhibitors in gastric epithelial cells

    PMID:19959630

    Open questions at the time
    • Mechanism by which MEK/ERK activation increases CIP2A transcription not yet mapped to specific transcription factors in this study
    • Single pathogen system
  2. 2011 High

    Identification of CIP2A as a direct inhibitor of PP2A activity toward AKT and c-MYC established the core biochemical function of CIP2A as a PP2A inhibitor controlling two major oncogenic nodes.

    Evidence siRNA knockdown and ectopic overexpression with PP2A activity assays in HCC and CML cells, xenograft models

    PMID:20729919 PMID:21490338

    Open questions at the time
    • Which PP2A holoenzyme(s) CIP2A targets was unknown
    • Structural basis of PP2A inhibition unresolved
  3. 2011 High

    Mapping the ETS1 binding site on the proximal CIP2A promoter resolved how EGFR-MEK signaling transcriptionally activates CIP2A, closing the loop between growth factor signaling and CIP2A induction.

    Evidence ChIP for ETS1, promoter-luciferase with site-directed mutagenesis, MEK1/2 siRNA

    PMID:21445343

    Open questions at the time
    • Contribution of other ETS-family members (e.g., Elk-1) not yet dissected
    • Post-transcriptional regulation not addressed
  4. 2013 High

    Discovery of a CIP2A–E2F1 positive feedback loop (E2F1 drives CIP2A transcription; CIP2A inhibits PP2A to stabilize phospho-E2F1) revealed how CIP2A amplifies oncogenic signaling and suppresses senescence.

    Evidence siRNA/overexpression, PP2A activity assays, CIP2A-deficient mammary tumor mouse model

    PMID:23306062

    Open questions at the time
    • Direct PP2A-B subunit mediating E2F1 S364 dephosphorylation not identified
    • Whether this loop operates outside breast cancer unknown
  5. 2013 High

    Demonstrating that CIP2A directly binds Plk1's polo-box domain and shields Plk1 from APC/C-Cdh1 proteolysis established a PP2A-independent mitotic function for CIP2A in spindle regulation.

    Evidence Co-IP with domain mapping, Plk1 kinase activity assays, live-cell imaging of mitotic progression upon CIP2A knockdown

    PMID:23983103

    Open questions at the time
    • Phosphorylation site(s) on CIP2A mediating Plk1 binding not mapped
    • Unclear whether Plk1 stabilization feeds back to regulate CIP2A
  6. 2014 High

    Linking CIP2A to mTORC1 as an allosteric inhibitor of mTORC1-associated PP2A, with reciprocal autophagic degradation of CIP2A upon mTORC1 inhibition, revealed a bistable switch coupling CIP2A levels to nutrient/growth signaling.

    Evidence Co-IP with mTORC1, PP2A activity assays, autophagy/ubiquitination assays, c-Myc stability measurements

    PMID:24590173

    Open questions at the time
    • Identity of the E3 ligase for CIP2A ubiquitination unknown
    • Structural details of CIP2A-mTORC1 interface unresolved
  7. 2015 High

    Genetic proof in CIP2A-knockout mice that CIP2A is required for MYC serine 62 phosphorylation and MYC-driven proliferation in vivo cemented the CIP2A–PP2A–MYC axis as a physiological signaling module.

    Evidence CIP2A-knockout mouse intestinal regeneration model, immunofluorescence for MYC-S62 on Lamin A/C structures

    PMID:26235622

    Open questions at the time
    • How CIP2A targets PP2A specifically to MYC-S62 rather than other substrates not explained
    • Nuclear vs. cytoplasmic action of CIP2A on MYC unclear
  8. 2017 High

    Identifying CIP2A as a scaffold for CEP192-mediated MTOC assembly, phosphorylated by Plk1 at S904, broadened CIP2A's mitotic role from Plk1 stabilization to active centrosome/spindle pole organization.

    Evidence Co-IP of CIP2A with CEP192, phospho-site mutagenesis, immunofluorescence in mouse oocytes

    PMID:28521709

    Open questions at the time
    • Whether this scaffolding function operates in somatic mitosis not tested
    • Other Plk1 phosphosites on CIP2A not surveyed
  9. 2018 High

    Overexpression of CIP2A in mouse hippocampus caused PP2A inhibition leading to tau and APP hyperphosphorylation, Aβ production, and cognitive deficits, extending CIP2A's PP2A-inhibitory function to neurodegeneration.

    Evidence AAV-CIP2A injection in mouse hippocampus, PP2A activity assays, LTP electrophysiology, behavioral testing

    PMID:30021167

    Open questions at the time
    • Whether endogenous CIP2A contributes to AD pathology in human brain not addressed
    • Specific PP2A-B subunit involved in neuronal context unknown
  10. 2019 High

    Discovery of CIP2A-BP, a micropeptide that directly binds CIP2A and displaces B56γ to reactivate PP2A, identified the first endogenous protein antagonist of CIP2A's PP2A-inhibitory function.

    Evidence Co-IP and pulldown of CIP2A-BP with CIP2A, PP2A activity rescue, MMTV-PyMT mouse tumor model

    PMID:31755573

    Open questions at the time
    • Whether CIP2A-BP displaces B56α (in addition to B56γ) not tested
    • CIP2A-BP expression regulation beyond TGF-β/4E-BP1 axis unknown
  11. 2021 High

    CRISPR synthetic lethality screens revealed that the CIP2A–TOPBP1 complex prevents lethal chromosome mis-segregation in BRCA-deficient cells, establishing a genome-stability function for CIP2A independent of PP2A inhibition.

    Evidence Genome-scale CRISPR screen in BRCA1/2-deficient cells, co-IP, live-cell imaging of acentric chromosome tethering

    PMID:35121901

    Open questions at the time
    • Structural basis of CIP2A–TOPBP1 interaction not determined
    • Whether this function extends to other HR-deficient backgrounds untested
  12. 2022 High

    Elucidation of CIP2A's cell-cycle-dependent nuclear access — cytoplasmic in interphase via active export, chromatin-bound after nuclear envelope breakdown — explained how CIP2A gains access to mitotic DSBs and forms the CIP2A–MDC1–TOPBP1 complex at DNA lesions.

    Evidence Live-cell imaging, subcellular fractionation, CIP2A knockout phenotyping for radiosensitivity and micronuclei

    PMID:35842428

    Open questions at the time
    • Nuclear export signal on CIP2A not mapped
    • Whether interphase nuclear exclusion is solely CRM1-dependent not confirmed
  13. 2023 High

    Cryo-EM/structural determination of the CIP2A–B56α–PP2Ac pseudotrimer resolved the decades-old question of how CIP2A inhibits PP2A: the N-terminal head domain displaces the A-subunit and blocks the LxxIxE substrate pocket simultaneously.

    Evidence Structural biology, CRISPR single-amino-acid mutagenesis of head domain, TNBC xenograft tumor growth

    PMID:36854761

    Open questions at the time
    • Whether CIP2A employs the same mechanism for B56γ as for B56α
    • Full-length CIP2A structure including C-terminal dimerization domain not resolved
  14. 2024 High

    CIP2A's direct binding to PKM2 inducing tetramer formation and mitochondrial relocalization revealed a metabolic reprogramming function, shifting cells from glycolysis toward oxidative phosphorylation.

    Evidence Co-IP, pulldown, S287 mutagenesis on PKM2, mitochondrial fractionation, metabolic flux assays, xenograft

    PMID:38321019

    Open questions at the time
    • Whether CIP2A-PKM2 interaction is PP2A-dependent or independent not fully resolved
    • Applicability beyond NSCLC not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • The full-length structure of CIP2A including its C-terminal dimerization domain, the precise mechanisms governing CIP2A's cell-cycle-dependent nuclear-cytoplasmic shuttling, and whether the PP2A-inhibitory and genome-stability functions are coordinated or fully independent remain unresolved.
  • Full-length CIP2A structure lacking
  • Nuclear export signal not mapped
  • No unified model linking PP2A inhibition and CIP2A-TOPBP1 genome stability functions

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 9 GO:0060090 molecular adaptor activity 3
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 3 GO:0005694 chromosome 2 GO:0005815 microtubule organizing center 2 GO:0005739 mitochondrion 1
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-73894 DNA Repair 4 R-HSA-1640170 Cell Cycle 3 R-HSA-1430728 Metabolism 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-9612973 Autophagy 2
Partners
CEP192MDC1PKMPLK1PPP2CAPPP2R5APPP2R5CTOPBP1
Complex memberships
CIP2A-B56α-PP2Ac pseudotrimerCIP2A-MDC1-TOPBP1 complexmTORC1-associated CIP2A complex

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2023 CIP2A inhibits PP2A-B56α through a multi-step mechanism: upon direct binding to the PP2A-B56α trimer, CIP2A displaces the PP2A-A subunit to form a CIP2A-B56α-PP2Ac pseudotrimer, and simultaneously blocks the LxxIxE-motif substrate binding pocket on B56α. The N-terminal head domain of CIP2A mediates interaction with B56α and stabilizes CIP2A protein itself. CRISPR/Cas9 single amino acid mutagenesis of the head domain blunted MYC expression and MEK phosphorylation and abrogated triple-negative breast cancer tumor growth in vivo. Structural biology, CRISPR/Cas9 mutagenesis, biochemical interaction assays, in vivo tumor growth assay Nature communications High 36854761
2021 CIP2A is cytoplasmic in interphase but accumulates at DNA lesions during mitosis as part of a complex with TOPBP1. In BRCA-deficient cells, the CIP2A-TOPBP1 complex prevents lethal mis-segregation of acentric chromosomes arising from impaired DNA synthesis. Physical disruption of the CIP2A-TOPBP1 complex is highly deleterious in BRCA-deficient tumors. CRISPR-Cas9 synthetic lethality screens, live-cell imaging, co-immunoprecipitation, functional rescue experiments Nature cancer High 35121901
2022 CIP2A is actively exported from the nucleus during interphase but, upon nuclear envelope breakdown at mitosis onset, gains access to chromatin where it forms a complex with MDC1 and TOPBP1 to promote TOPBP1 recruitment to sites of mitotic DSBs. Cells lacking CIP2A display increased radio-sensitivity, micronuclei formation and chromosomal instability. Live-cell imaging, co-immunoprecipitation, CIP2A knockout/knockdown, subcellular fractionation, immunofluorescence Nature communications High 35842428
2021 CIP2A directly interacts with TopBP1; CIP2A deficiency results in enhanced DNA damage-induced TopBP1 and RAD51 recruitment to chromatin in mammary epithelial cells. CIP2A is selectively essential for mitotic progression of DNA-damaged cells and drives proliferative MYC and E2F1 signaling in basal-like triple-negative breast cancer. Co-immunoprecipitation, CIP2A-deficient mouse model, chromatin fractionation, cell survival assays, patient-derived xenograft Cancer research High 34145035
2014 CIP2A associates with mTORC1 and acts as an allosteric inhibitor of mTORC1-associated PP2A, thereby enhancing mTORC1-dependent growth signaling and inhibiting autophagy. CIP2A itself is degraded via ubiquitination and p62/SQSTM1-dependent autophagy upon mTORC1 inhibition, which in turn leads to destabilization of c-Myc. Co-immunoprecipitation, RNAi screen, PP2A activity assays, autophagy assays, c-Myc stability assays The Journal of cell biology High 24590173
2013 CIP2A is required for mitotic progression by directly interacting with the polo-box domain of Plk1 during mitosis. This interaction blocks APC/C-Cdh1-dependent proteolysis of Plk1, thereby maintaining Plk1 stability and enhancing its kinase activity. CIP2A translocates from the cytoplasm to the nucleus upon mitotic entry, enriching at spindle poles. Co-immunoprecipitation, siRNA knockdown, kinase activity assays, live-cell imaging, subcellular fractionation Cancer research High 23983103
2019 CIP2A-BP (a micropeptide encoded by LINC00665) directly binds CIP2A and displaces PP2A's B56γ subunit from CIP2A, thereby releasing PP2A activity. This inhibits PI3K/AKT/NFκB signaling, decreasing MMP-2, MMP-9, and Snail expression. TGF-β/Smad-induced 4E-BP1 suppresses eIF4E-dependent translation of CIP2A-BP. Co-immunoprecipitation, pulldown assays, PP2A activity assays, siRNA/overexpression, mouse MMTV-PyMT model The EMBO journal High 31755573
2015 CIP2A is required for serine 62 phosphorylation of MYC, which promotes MYC accumulation on Lamin A/C-associated nuclear structures. CIP2A is critical for serum-induced MYC S62 phosphorylation and MYC-elicited proliferation induction in vitro and in vivo in an intestinal regeneration model. CIP2A-knockout mouse model, transgenic approaches, co-immunoprecipitation, immunofluorescence, intestinal regeneration assays Cell reports High 26235622
2013 E2F1 overexpression (due to p53/p21 inactivation) promotes CIP2A expression; CIP2A in turn inhibits PP2A activity, increasing stabilizing serine 364 phosphorylation of E2F1, forming a positive E2F1-CIP2A feedback loop that renders breast cancer cells resistant to senescence induction. CIP2A-deficient mouse mammary tumors display markers of senescence. siRNA/overexpression experiments, PP2A activity assays, CIP2A-deficient mouse model, phosphorylation assays Cancer discovery High 23306062
2011 CIP2A negatively regulates PP2A activity toward Akt; CIP2A overexpression increases phospho-Akt and protects HCC cells from bortezomib-induced apoptosis. Bortezomib downregulates CIP2A in a dose- and time-dependent manner, increasing PP2A activity and inducing apoptosis in sensitive cells. siRNA knockdown, ectopic overexpression, PP2A activity assays, flow cytometry, in vivo xenograft Oncogene High 20729919
2011 In CML, CIP2A knockdown results in increased PP2A activity, decreased c-Myc levels, and decreased BCR-ABL1 tyrosine kinase activity, indicating CIP2A stabilizes c-Myc and supports BCR-ABL1 activity via PP2A inhibition. siRNA knockdown, PP2A activity assay, immunoblotting for c-Myc and BCR-ABL1 phosphorylation Blood Medium 21490338
2011 CIP2A expression is transcriptionally regulated by the EGFR-MEK1/2-ETS1 pathway; ETS1 binds the proximal CIP2A promoter region (-27 to -107) and mediates MEK-dependent stimulation of CIP2A expression, as determined by promoter-luciferase assays, mutagenesis, and chromatin immunoprecipitation. Promoter-luciferase assays, site-directed mutagenesis, chromatin immunoprecipitation (ChIP), siRNA for MEK1/2 PloS one High 21445343
2009 H. pylori CagA upregulates CIP2A expression through Src and MEK/ERK (Ras/MEK/ERK) signaling pathways in a manner dependent on CagA phosphorylation. CIP2A depletion partially attenuates H. pylori infection-induced c-Myc stabilization. Plasmid-mediated CagA expression, H. pylori infection, signaling inhibitors, immunoblotting, siRNA knockdown Journal of medical microbiology Medium 19959630
2017 CIP2A acts as a scaffold for CEP192-mediated MTOC assembly by recruiting aurora A and Plk1 to spindle poles during mouse oocyte meiotic maturation. CIP2A is phosphorylated by Plk1 at S904, which targets CIP2A to MTOCs. CIP2A associates with CEP192 and depletion of CIP2A impairs MTOC organization and chromosome alignment. Co-immunoprecipitation, siRNA/morpholino knockdown, phosphorylation assays, immunofluorescence in mouse oocytes Development High 28935709
2023 In mouse oocytes, DSB induction triggers microtubule-dependent chromosomal recruitment of the CIP2A-MDC1-TOPBP1 complex from spindle poles to chromosomes via kinetochore/centromere structures. This transport is regulated by PLK1 but not ATM activity and is required for DSB repair during meiosis I. Live-cell imaging, immunofluorescence, microtubule depolymerization, CIP2A/CENP-A/HEC1 depletion in mouse oocytes, PLK1/ATM inhibitor experiments Nucleic acids research High 36999590
2024 CIP2A binds directly to PKM2 and induces PKM2 tetramer formation, with serine 287 identified as a novel phosphorylation site essential for PKM2 dimer-tetramer switching. CIP2A redirects PKM2 to mitochondria, leading to upregulation of Bcl2 via phosphorylation at threonine 69, inhibiting glycolysis and promoting oxidative phosphorylation in NSCLC cells. Co-immunoprecipitation, pulldown, mutagenesis, mitochondrial fractionation, metabolic assays, in vivo xenograft Cell discovery High 38321019
2018 CIP2A overexpression in neurons causes PP2A inhibition, leading to tau and APP hyperphosphorylation, increased APP β-cleavage and Aβ production, tau mislocalization to dendrites and spines, and synaptic degeneration. AAV-CIP2A injection into mouse hippocampus induces AD-like cognitive deficits and LTP impairment. AAV injection in mouse hippocampus, PP2A activity assays, phosphorylation immunoblotting, LTP electrophysiology, behavioral tests Cell reports High 30021167
2022 Chk1 overexpression induces CIP2A upregulation, which in turn inhibits PP2A and activates STAT3, leading to reactive astrogliosis. Chk1 inhibitor (GDC0575) increases PP2A activity and decreases tau phosphorylation in AD cell models and reverses cognitive deficits in APP/PS1 mice. GFAP-ChK1-AAV mouse brain injection, ChK1 overexpression, CIP2A immunoblotting, PP2A activity assays, behavioral tests Neurotherapeutics Medium 35286657
2012 CIP2A depletion promotes proliferation of spermatogonial progenitor cells (SPCs) and spermatogenesis in mice. CIP2A mutant mice show fewer PLZF-positive SPCs and reduced sperm counts. Spermatogonia-specific restoration of CIP2A expression rescues PLZF expression and sperm production, placing CIP2A upstream of PLZF in the SPC self-renewal pathway. CIP2A mutant mouse model, genetic rescue experiments, immunofluorescence, RT-PCR for self-renewal genes PloS one High 22461891
2016 CIP2A promotes T-cell activation during adaptive immune response. CIP2A expression is induced during T-cell activation in a Zap70-dependent manner. CIP2A-deficient mice show decreased frequency of CD4+ and CD8+ effector T-cells upon Listeria monocytogenes challenge. CIP2A-deficient mouse model (CIP2AHOZ), Listeria challenge, flow cytometry, Zap70 inhibitor experiments PloS one Medium 27100879
2014 Erlotinib and its derivative TD52 downregulate CIP2A transcription by reducing the binding of Elk-1 transcription factor to the proximal CIP2A promoter, thereby decreasing CIP2A expression and increasing PP2A activity and apoptosis in HCC cells. Chromatin immunoprecipitation, promoter reporter assays, PP2A activity assay, overexpression/knockdown Cell death & disease Medium 25077545
2022 lncRNA TP53TG1 interacts with CIP2A protein and triggers its ubiquitination-mediated degradation, resulting in inhibition of the PI3K/AKT pathway in gastric cancer cells. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, immunoblotting Cancer science Medium 36114757
2017 CIP2A mediates fibronectin-induced bladder cancer cell proliferation by stabilizing β-catenin. The CIP2A-β-catenin interaction was confirmed by co-immunoprecipitation and immunofluorescence; CIP2A enhances β-catenin stability (shown by cycloheximide chase). Co-immunoprecipitation, immunofluorescence co-localization, cycloheximide chase, siRNA knockdown, xenograft model Journal of experimental & clinical cancer research Medium 28521777
2021 In a CIP2A splicing variant NOCIVA, the first 13 exons of CIP2A are fused to a 349-nucleotide intronic sequence encoding a novel 13-amino acid C-terminal peptide. NOCIVA retains B56α binding capacity but translocates to the nucleus (unlike cytoplasmic CIP2A). NOCIVA is overexpressed in myeloid malignancies. RACE (rapid amplification of cDNA ends), structural analysis, B56α binding assays, subcellular localization by immunofluorescence Clinical cancer research Medium 33674272
2014 CIP2A regulates cancer cell metabolism by promoting glycolysis (LDH-A expression and lactate production) and regulating CREB phosphorylation in response to serum in NSCLC cells, identified through 2D-electrophoresis proteomics followed by functional validation. 2D-electrophoresis proteomics, metabolic assays (LDH-A activity, lactate, NADH/NAD+), siRNA knockdown, CREB phosphorylation immunoblotting Molecular bioSystems Low 25325377
2018 CIP2A promotes G1/S cell cycle transition in HPV-16 E6-expressing cells through transcription factor B-Myb (not c-Myc), regulating CDK1 and CDK2 expression. HPV-16 E6 upregulates CIP2A in a p53-degradation-dependent manner. siRNA knockdown, immunoblotting, cell cycle analysis, luciferase assay Journal of cellular and molecular medicine Medium 29893470
2014 Estradiol (E2) enhances CIP2A expression at the translational level through EGFR → MAPK/PI3K → p70 S6 kinase (S6K) → eIF4B phosphorylation axis, independently of c-MYC. siRNA knockdown, kinase inhibitors, translational assays, phosphorylation immunoblotting Endocrine-related cancer Medium 24280132
2016 In JAK2V617F-mutated cells, CIP2A levels are elevated and the PI3K/mTOR-dependent phosphorylation of STAT5b serine residues involves PP2A inhibition by CIP2A; PI3K/mTOR inhibitors decrease CIP2A levels and thereby restore PP2A-mediated dephosphorylation of STAT5b. CIP2A knockdown, PP2A activity assays, phospho-STAT5 immunoblotting, primary patient cells, JAK2V617F knock-in mice Oncotarget Medium 29228564
2013 miR-375 directly targets the CIP2A coding sequence at five functional binding sites near the C-terminal domain, suppressing CIP2A expression, which reduces MYC protein levels. This was established by luciferase assays with target sequence mutagenesis. Luciferase reporter assay, target site mutagenesis, miR-375 transfection, immunoblotting Molecular biology of the cell Medium 23552692
2016 An oncogenic feedforward loop exists in TNBC consisting of pERK/pElk-1/CIP2A/PP2A: ERK activation drives Elk-1-mediated CIP2A transcription, CIP2A inhibits PP2A, which further activates ERK. This loop was validated by PP2A knockdown and ectopic Elk-1 expression showing reciprocal changes in loop members. Knockdown/overexpression of pathway components, PP2A activity assays, ChIP for Elk-1 at CIP2A promoter, xenograft model EBioMedicine Medium 30651219
2019 CIP2A promotes Cip2a/miR-301a feedback in TNBC: CIP2A increases E2F1 expression which transcriptionally activates miR-301a by occupying the SKA2 promoter; miR-301a in turn promotes CIP2A expression via ERK/CREB signaling. miRNA microarray, chromatin immunoprecipitation, miRNA mimic/inhibitor transfection, immunoblotting Journal of Cancer Low 31762806
2018 SFXN1 promotes TNBC progression by inhibiting autophagy receptor TOLLIP-mediated autophagic degradation of CIP2A, thereby stabilizing CIP2A protein and maintaining CIP2A/PP2A/p-AKT signaling. Label-free quantitative proteomics, immunoblotting, immunofluorescence, RT-qPCR, siRNA knockdown, in vivo xenograft Cancer letters Medium 38849012

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 Micropeptide CIP2A-BP encoded by LINC00665 inhibits triple-negative breast cancer progression. The EMBO journal 203 31755573
2010 CIP2A mediates effects of bortezomib on phospho-Akt and apoptosis in hepatocellular carcinoma cells. Oncogene 142 20729919
2008 CIP2A is overexpressed in gastric cancer and its depletion leads to impaired clonogenicity, senescence, or differentiation of tumor cells. Clinical cancer research : an official journal of the American Association for Cancer Research 130 18559589
2011 Cancerous inhibitor of PP2A (CIP2A) at diagnosis of chronic myeloid leukemia is a critical determinant of disease progression. Blood 115 21490338
2013 Senescence sensitivity of breast cancer cells is defined by positive feedback loop between CIP2A and E2F1. Cancer discovery 114 23306062
2022 m6A modification-mediated lncRNA TP53TG1 inhibits gastric cancer progression by regulating CIP2A stability. Cancer science 103 36114757
2021 The CIP2A-TOPBP1 axis safeguards chromosome stability and is a synthetic lethal target for BRCA-mutated cancer. Nature cancer 88 35121901
2013 Tumor suppressor miR-375 regulates MYC expression via repression of CIP2A coding sequence through multiple miRNA-mRNA interactions. Molecular biology of the cell 87 23552692
2014 miR-375 activates p21 and suppresses telomerase activity by coordinately regulating HPV E6/E7, E6AP, CIP2A, and 14-3-3ζ. Molecular cancer 83 24708873
2011 Overexpression and small molecule-triggered downregulation of CIP2A in lung cancer. PloS one 83 21655278
2018 CIP2A Causes Tau/APP Phosphorylation, Synaptopathy, and Memory Deficits in Alzheimer's Disease. Cell reports 80 30021167
2013 CIP2A modulates cell-cycle progression in human cancer cells by regulating the stability and activity of Plk1. Cancer research 66 23983103
2012 CIP2A signature reveals the MYC dependency of CIP2A-regulated phenotypes and its clinical association with breast cancer subtypes. Oncogene 66 22249265
2014 Oncogenic nexus of cancerous inhibitor of protein phosphatase 2A (CIP2A): an oncoprotein with many hands. Oncotarget 64 25015035
2014 CIP2A oncoprotein controls cell growth and autophagy through mTORC1 activation. The Journal of cell biology 63 24590173
2013 IL-10 promotes tumor aggressiveness via upregulation of CIP2A transcription in lung adenocarcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research 63 23743567
2018 Polyphyllin I inhibits growth and invasion of cisplatin-resistant gastric cancer cells by partially inhibiting CIP2A/PP2A/Akt signaling axis. Journal of pharmacological sciences 59 30119963
2012 CIP2A-mediated Akt activation plays a role in bortezomib-induced apoptosis in head and neck squamous cell carcinoma cells. Oral oncology 59 22342571
2011 ETS1 mediates MEK1/2-dependent overexpression of cancerous inhibitor of protein phosphatase 2A (CIP2A) in human cancer cells. PloS one 58 21445343
2017 The role of CIP2A in cancer: A review and update. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 57 29035828
2014 Erlotinib derivative inhibits hepatocellular carcinoma by targeting CIP2A to reactivate protein phosphatase 2A. Cell death & disease 56 25077545
2012 CIP2A overexpression is associated with c-Myc expression in colorectal cancer. Cancer biology & therapy 56 22310977
2021 SP1-induced lncRNA DUBR promotes stemness and oxaliplatin resistance of hepatocellular carcinoma via E2F1-CIP2A feedback. Cancer letters 55 34958891
2011 CIP2A is over-expressed in acute myeloid leukaemia and associated with HL60 cells proliferation and differentiation. International journal of laboratory hematology 55 21219591
2012 CIP2A promotes proliferation of spermatogonial progenitor cells and spermatogenesis in mice. PloS one 51 22461891
2016 Lapatinib inhibits CIP2A/PP2A/p-Akt signaling and induces apoptosis in triple negative breast cancer cells. Oncotarget 50 26824320
2015 Label-free quantitative phosphoproteomics with novel pairwise abundance normalization reveals synergistic RAS and CIP2A signaling. Scientific reports 50 26278961
2011 Increase in CIP2A expression is associated with doxorubicin resistance. FEBS letters 50 21241697
2016 Oridonin inhibits gefitinib-resistant lung cancer cells by suppressing EGFR/ERK/MMP-12 and CIP2A/Akt signaling pathways. International journal of oncology 49 27082429
2013 Fusogenic-oligoarginine peptide-mediated delivery of siRNAs targeting the CIP2A oncogene into oral cancer cells. PloS one 49 24019920
2019 Cucurbitacin B Induces the Lysosomal Degradation of EGFR and Suppresses the CIP2A/PP2A/Akt Signaling Axis in Gefitinib-Resistant Non-Small Cell Lung Cancer. Molecules (Basel, Switzerland) 47 30759826
2022 The CIP2A-TOPBP1 complex safeguards chromosomal stability during mitosis. Nature communications 46 35842428
2015 Serine 62-Phosphorylated MYC Associates with Nuclear Lamins and Its Regulation by CIP2A Is Essential for Regenerative Proliferation. Cell reports 46 26235622
2012 Inhibition of CIP2A determines erlotinib-induced apoptosis in hepatocellular carcinoma. Biochemical pharmacology 46 23178652
2017 Cucurbitacin B induces autophagy and apoptosis by suppressing CIP2A/PP2A/mTORC1 signaling axis in human cisplatin resistant gastric cancer cells. Oncology reports 43 28534965
2015 Afatinib induces apoptosis in NSCLC without EGFR mutation through Elk-1-mediated suppression of CIP2A. Oncotarget 43 25537503
2010 CIP2A expression and localization in oral carcinoma and dysplasia. Cancer biology & therapy 43 21068540
2010 CIP2A is overexpressed in esophageal squamous cell carcinoma. Medical oncology (Northwood, London, England) 43 21140243
2018 Polyphyllin I inhibits invasion and epithelial-mesenchymal transition via CIP2A/PP2A/ERK signaling in prostate cancer. International journal of oncology 41 29956727
2018 Enhanced expression of MycN/CIP2A drives neural crest toward a neural stem cell-like fate: Implications for priming of neuroblastoma. Proceedings of the National Academy of Sciences of the United States of America 40 30021854
2019 Targeting SET to restore PP2A activity disrupts an oncogenic CIP2A-feedforward loop and impairs triple negative breast cancer progression. EBioMedicine 39 30651219
2021 CIP2A Interacts with TopBP1 and Drives Basal-Like Breast Cancer Tumorigenesis. Cancer research 38 34145035
2016 EGFR-independent Elk1/CIP2A signalling mediates apoptotic effect of an erlotinib derivative TD52 in triple-negative breast cancer cells. European journal of cancer (Oxford, England : 1990) 38 28027514
2013 Ethoxysanguinarine Induces Inhibitory Effects and Downregulates CIP2A in Lung Cancer Cells. ACS medicinal chemistry letters 38 24900782
2009 Helicobacter pylori CagA upregulation of CIP2A is dependent on the Src and MEK/ERK pathways. Journal of medical microbiology 38 19959630
2024 CIP2A induces PKM2 tetramer formation and oxidative phosphorylation in non-small cell lung cancer. Cell discovery 36 38321019
2011 Bortezomib sensitizes HCC cells to CS-1008, an antihuman death receptor 5 antibody, through the inhibition of CIP2A. Molecular cancer therapeutics 36 21393428
2013 CIP2A influences survival in colon cancer and is critical for maintaining Myc expression. PloS one 35 24098375
2015 Second generation tyrosine kinase inhibitors prevent disease progression in high-risk (high CIP2A) chronic myeloid leukaemia patients. Leukemia 34 25765543
2014 CIP2A mediates erlotinib-induced apoptosis in non-small cell lung cancer cells without EGFR mutation. Lung cancer (Amsterdam, Netherlands) 34 24954871
2012 CIP2A is a predictor of survival and a novel therapeutic target in bladder urothelial cell carcinoma. Medical oncology (Northwood, London, England) 33 23275123
2023 Structural mechanism for inhibition of PP2A-B56α and oncogenicity by CIP2A. Nature communications 32 36854761
2019 Inhibitory effects of polyphyllins I and VII on human cisplatin-resistant NSCLC via p53 upregulation and CIP2A/AKT/mTOR signaling axis inhibition. Chinese journal of natural medicines 32 31703757
2012 Development of erlotinib derivatives as CIP2A-ablating agents independent of EGFR activity. Bioorganic & medicinal chemistry 32 22980218
2017 Celastrol inhibits chondrosarcoma proliferation, migration and invasion through suppression CIP2A/c-MYC signaling pathway. Journal of pharmacological sciences 31 28522217
2017 Inhibitors of the PI3K/mTOR pathway prevent STAT5 phosphorylation in JAK2V617F mutated cells through PP2A/CIP2A axis. Oncotarget 31 29228564
2019 Cucurbitacin B induces inhibitory effects via the CIP2A/PP2A/C-KIT signaling axis in t(8;21) acute myeloid leukemia. Journal of pharmacological sciences 30 30852180
2014 CIP2A regulates cell proliferation via the AKT signaling pathway in human lung cancer. Oncology reports 28 25109354
2010 CIP2A increases self-renewal and is linked to Myc in neural progenitor cells. Differentiation; research in biological diversity 28 20447748
2019 Polyphyllin I and VII potentiate the chemosensitivity of A549/DDP cells to cisplatin by enhancing apoptosis, reversing EMT and suppressing the CIP2A/AKT/mTOR signaling axis. Oncology letters 27 31612051
2018 Chronic Cigarette Smoke Exposure Subdues PP2A Activity by Enhancing Expression of the Oncogene CIP2A. American journal of respiratory cell and molecular biology 26 30011381
2017 Arctigenin inhibits triple-negative breast cancers by targeting CIP2A to reactivate protein phosphatase 2A. Oncology reports 26 28560452
2014 Temsirolimus enhances the efficacy of cetuximab in colon cancer through a CIP2A-dependent mechanism. Journal of cancer research and clinical oncology 25 24493623
2022 Chk1 Inhibition Ameliorates Alzheimer's Disease Pathogenesis and Cognitive Dysfunction Through CIP2A/PP2A Signaling. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 24 35286657
2018 CIP2A Promotes Proliferation, Invasion and Chemoresistance to Cisplatin in Renal Cell Carcinoma. Journal of Cancer 24 30410608
2015 CIP2A is a candidate therapeutic target in clinically challenging prostate cancer cell populations. Oncotarget 24 25965834
2014 KIAA1524/CIP2A promotes cancer growth by coordinating the activities of MTORC1 and MYC. Autophagy 24 24905455
2017 CIP2A mediates fibronectin-induced bladder cancer cell proliferation by stabilizing β-catenin. Journal of experimental & clinical cancer research : CR 23 28521777
2016 Cucurbitacin B reverses multidrug resistance by targeting CIP2A to reactivate protein phosphatase 2A in MCF-7/adriamycin cells. Oncology reports 23 27350399
2015 CIP2A overexpression induces autoimmune response and enhances JNK signaling pathway in human lung cancer. BMC cancer 22 26560124
2019 Cip2a/miR-301a feedback loop promotes cell proliferation and invasion of triple-negative breast cancer. Journal of Cancer 21 31762806
2018 Cucurbitacin B induces inhibitory effects via CIP2A/PP2A/Akt pathway in glioblastoma multiforme. Molecular carcinogenesis 21 29393542
2018 CIP2A-promoted astrogliosis induces AD-like synaptic degeneration and cognitive deficits. Neurobiology of aging 21 30594047
2023 CIP2A coordinates phosphosignaling, mitosis, and the DNA damage response. Trends in cancer 20 37793965
2018 Synergistic Interaction of HOXB13 and CIP2A Predisposes to Aggressive Prostate Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 20 30181389
2023 Oocytes can repair DNA damage during meiosis via a microtubule-dependent recruitment of CIP2A-MDC1-TOPBP1 complex from spindle pole to chromosomes. Nucleic acids research 19 36999590
2017 CIP2A acts as a scaffold for CEP192-mediated microtubule organizing center assembly by recruiting Plk1 and aurora A during meiotic maturation. Development (Cambridge, England) 19 28935709
2014 Autoantibody response to a novel tumor-associated antigen p90/CIP2A in breast cancer immunodiagnosis. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 19 24399648
2022 Mechanism Analysis of LINC00665 and Its Peptides CIP2A-BP in Hepatocellular Carcinoma. Frontiers in genetics 18 35350239
2016 Cross Talk between Wnt/β-Catenin and CIP2A/Plk1 Signaling in Prostate Cancer: Promising Therapeutic Implications. Molecular and cellular biology 18 27090640
2016 CIP2A Promotes T-Cell Activation and Immune Response to Listeria monocytogenes Infection. PloS one 18 27100879
2015 Role of "oncogenic nexus" of CIP2A in breast oncogenesis: how does it work? American journal of cancer research 18 26609493
2015 Knockdown of CIP2A sensitizes ovarian cancer cells to cisplatin: an in vitro study. International journal of clinical and experimental medicine 18 26629248
2013 Expression and biological role of CIP2A in human astrocytoma. Molecular medicine reports 18 23467938
2017 Activation of cancerous inhibitor of PP2A (CIP2A) contributes to lapatinib resistance through induction of CIP2A-Akt feedback loop in ErbB2-positive breast cancer cells. Oncotarget 17 28938602
2015 Fusogenic-oligoarginine peptide-mediated silencing of the CIP2A oncogene suppresses oral cancer tumor growth in vivo. Journal of controlled release : official journal of the Controlled Release Society 17 26386438
2016 Gambogenic acid induces proteasomal degradation of CIP2A and sensitizes hepatocellular carcinoma to anticancer agents. Oncology reports 16 27779687
2014 Estradiol enhances CIP2A expression by the activation of p70 S6 kinase. Endocrine-related cancer 16 24280132
2014 Role of CIP2A in the antitumor effect of bortezomib in colon cancer. Molecular medicine reports 16 24789441
2022 ChK1 activation induces reactive astrogliosis through CIP2A/PP2A/STAT3 pathway in Alzheimer's disease. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 15 35195302
2020 Effect of CIP2A and its mechanism of action in the malignant biological behavior of colorectal cancer. Cell communication and signaling : CCS 15 32321509
2018 CIP2A facilitates the G1/S cell cycle transition via B-Myb in human papillomavirus 16 oncoprotein E6-expressing cells. Journal of cellular and molecular medicine 15 29893470
2018 Euxanthone suppresses tumor growth and metastasis in colorectal cancer via targeting CIP2A/PP2A pathway. Life sciences 15 30144452
2014 CIP2A regulates cancer metabolism and CREB phosphorylation in non-small cell lung cancer. Molecular bioSystems 15 25325377
2018 miR-548b-3p Regulates Proliferation, Apoptosis, and Mitochondrial Function by Targeting CIP2A in Hepatocellular Carcinoma. BioMed research international 14 30671469
2021 Discovery of a Novel CIP2A Variant (NOCIVA) with Clinical Relevance in Predicting TKI Resistance in Myeloid Leukemias. Clinical cancer research : an official journal of the American Association for Cancer Research 13 33674272
2019 Genistein Decreases APP/tau Phosphorylation and Ameliorates Aβ Overproduction Through Inhibiting CIP2A. Current Alzheimer research 13 31470788
2015 CIP2A is associated with multidrug resistance in cervical adenocarcinoma by a P-glycoprotein pathway. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 13 26404133
2011 CIP2A expression is associated with synovial hyperplasia and invasive function of fibroblast-like synoviocytes in rheumatoid arthritis. Rheumatology international 13 21479604
2024 Sideroflexin-1 promotes progression and sensitivity to lapatinib in triple-negative breast cancer by inhibiting TOLLIP-mediated autophagic degradation of CIP2A. Cancer letters 12 38849012