Affinage

PCNP

PEST proteolytic signal-containing nuclear protein · UniProt Q8WW12

Length
178 aa
Mass
18.9 kDa
Annotated
2026-06-10
58 papers in source corpus 10 papers cited in narrative 10 extracted findings
Cross-family judge faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PCNP is a short-lived PEST-containing nuclear protein that functions as a context-dependent modulator of major proliferative and survival signaling pathways and, in turn, of cell proliferation, migration, invasion, apoptosis, and angiogenesis (PMID:29716528, PMID:41381593). Its abundance is set post-translationally: PCNP is a cotranslational N-terminal acetylation substrate of the NatA complex, a modification dependent on the chaperone HYPK (PMID:20154145), and it is ubiquitinated by the RING-finger E3 ligase NIRF, with which it physically interacts in the nucleus (PMID:12176013, PMID:14741369). Functionally, PCNP engages canonical growth-control circuits — it binds β-catenin directly to drive its nuclear translocation and activate Wnt/β-catenin signaling (PMID:32548978), shifts the balance of MAPK (ERK/JNK/p38) versus PI3K/Akt/mTOR and STAT3/5 signaling in a cell-type-dependent manner (PMID:29716528, PMID:30872582, PMID:35813472), and transcriptionally upregulates UHRF2 to engage ErbB3/Ras/Raf1 signaling (PMID:41271959). PCNP expression is itself induced when LINC00858 recruits RAD21 to its promoter (PMID:35468892), and overexpressed PCNP acts as a negative regulator of endothelial angiogenesis independent of intracellular VEGF levels (PMID:41381593). No structural model or catalytic activity for PCNP itself has been characterized in the available corpus; its described roles are those of a regulatory adaptor and transcriptional modulator.

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2002 High

    Established the first molecular partner of PCNP, linking this nuclear protein to a RING-finger protein and implying involvement in ubiquitin-related regulation.

    Evidence Yeast and mammalian two-hybrid, GST pull-down, and nuclear co-localization with NIRF

    PMID:12176013

    Open questions at the time
    • Did not define which domain or residues mediate the PCNP-NIRF interaction
    • Functional consequence of the interaction not yet addressed
  2. 2004 High

    Resolved the functional meaning of the PCNP-NIRF interaction by showing NIRF is an E3 ligase that ubiquitinates PCNP, explaining its short half-life.

    Evidence In vitro ubiquitination reconstitution plus in vivo ubiquitination in 293 and COS-7 cells

    PMID:14741369

    Open questions at the time
    • Did not establish whether ubiquitination targets PCNP for degradation versus non-degradative signaling
    • Lysine acceptor sites on PCNP not mapped
  3. 2010 Medium

    Defined a co-translational modification of PCNP, showing it is N-terminally acetylated by NatA in a HYPK-dependent manner.

    Evidence siRNA knockdown of HYPK with NatA substrate acetylation readout

    PMID:20154145

    Open questions at the time
    • PCNP is a secondary substrate within a broader NatA/HYPK study
    • Functional consequence of PCNP N-terminal acetylation not tested
  4. 2018 Medium

    Moved PCNP from a binding partner to a signaling modulator, showing it bidirectionally tunes MAPK versus PI3K/Akt/mTOR signaling and apoptosis to suppress neuroblastoma growth.

    Evidence shRNA knockdown and overexpression with pathway Western blots and xenograft in neuroblastoma cells

    PMID:29716528

    Open questions at the time
    • Direct molecular link between PCNP and the kinases is not defined
    • Single tumor type and single lab
  5. 2019 Medium

    Revealed cell-type dependence of PCNP signaling output, with PCNP activating STAT3/5 and PI3K/Akt/mTOR to favor autophagy and survival in lung adenocarcinoma.

    Evidence shRNA knockdown and overexpression, Western blotting, xenograft in lung adenocarcinoma cells

    PMID:30872582

    Open questions at the time
    • Opposite pathway effect versus neuroblastoma unexplained mechanistically
    • No direct binding to STAT or PI3K components shown
  6. 2020 Medium

    Provided a direct molecular mechanism for PCNP's effect on Wnt signaling by showing it binds β-catenin and promotes its nuclear translocation.

    Evidence Co-immunoprecipitation, nuclear fractionation, bidirectional perturbation in ovarian cancer cells

    PMID:32548978

    Open questions at the time
    • Co-IP without reciprocal or structural validation of the interaction interface
    • How PCNP promotes translocation mechanistically not resolved
  7. 2022 Medium

    Identified an upstream transcriptional control of PCNP, showing LINC00858 recruits RAD21 to the PCNP promoter to drive its expression and downstream STAT3/5 activation.

    Evidence RNA pull-down, RIP, ChIP, siRNA, and xenograft in colon cancer cells

    PMID:35468892

    Open questions at the time
    • Whether RAD21 directly activates transcription or acts via chromatin architecture not distinguished
    • Single tumor context
  8. 2022 Medium

    Extended PCNP's tumor-suppressive signaling profile, linking ERK/JNK/p38 activation and reduced Wnt/β-catenin activity to cell cycle arrest, apoptosis, and autophagy in thyroid cancer.

    Evidence shRNA knockdown and overexpression, cell cycle analysis, Western blotting, xenograft in thyroid cancer cells

    PMID:35813472

    Open questions at the time
    • Identity of the cell cycle regulatory genes modified not fully resolved
    • Direct effectors downstream of PCNP not defined
  9. 2025 Medium

    Provided a transcriptional/effector mechanism for PCNP's oncogenic output by showing it upregulates UHRF2 to activate ErbB3/Ras/Raf1 signaling in hepatocellular carcinoma.

    Evidence Correlation analysis, bidirectional perturbation, proliferation/invasion assays, xenograft

    PMID:41271959

    Open questions at the time
    • Mechanism by which PCNP upregulates UHRF2 transcription not defined
    • Whether PCNP binds the UHRF2 locus directly unknown
  10. 2025 Medium

    Identified a non-tumor role for PCNP as a negative regulator of endothelial angiogenesis acting independently of intracellular VEGF.

    Evidence Overexpression and knockdown, proliferation/migration/tube-formation assays, transcriptome sequencing in HUVECs

    PMID:41381593

    Open questions at the time
    • Effector linking PCNP to inflammatory IL-17/TNF/NF-κB enrichment not identified
    • VEGF-independent mechanism not positively defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • The intrinsic biochemical activity of PCNP and the molecular basis for its opposite, cell-type-dependent signaling outputs remain unresolved.
  • No catalytic activity or structural domain function defined for PCNP itself
  • Mechanism switching PCNP between tumor-suppressive and oncogenic signaling across tissues unknown
  • Functional consequences of NatA acetylation and NIRF ubiquitination on PCNP signaling untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0140110 transcription regulator activity 2
Localization
GO:0005634 nucleus 1
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-392499 Metabolism of proteins 2
Partners
CTNNB1HYPKNIRF

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 PCNP (PEST-containing nuclear protein) interacts with NIRF (a novel Np95/ICBP90-like RING finger protein) as identified by yeast two-hybrid screening, confirmed by mammalian two-hybrid system, GST pull-down assay, and nuclear co-localization. Yeast two-hybrid screening, mammalian two-hybrid assay, GST pull-down, nuclear co-localization Biochemical and biophysical research communications High 12176013
2004 NIRF ubiquitinates PCNP both in vitro and in vivo (in 293 and COS-7 cells), establishing NIRF as an E3 ubiquitin ligase with PCNP as its substrate. NIRF also displays auto-ubiquitination activity. In vitro ubiquitination assay, in vivo ubiquitination in 293 and COS-7 cells FEBS letters High 14741369
2010 HYPK is required for N-terminal acetylation of PCNP, a known NatA substrate, as demonstrated by HYPK knockdown reducing PCNP acetylation. This establishes PCNP as a cotranslational N-terminal acetylation substrate of the NatA complex. siRNA knockdown of HYPK with NatA substrate acetylation assay Molecular and cellular biology Medium 20154145
2018 PCNP overexpression in human neuroblastoma cells increases phosphorylation of ERK1/2, p38, and JNK (MAPK pathway) while decreasing phosphorylation of PI3K, Akt, and mTOR, mediating inhibition of proliferation, migration, and invasion. PCNP knockdown shows opposite effects. PCNP overexpression also activates caspase-3, -8, -9, and PARP cleavage, promoting apoptosis. shRNA knockdown and overexpression, Western blotting for pathway markers, xenograft tumor assay BMC cancer Medium 29716528
2019 PCNP overexpression in lung adenocarcinoma cells activates STAT3 and STAT5 phosphorylation and promotes PI3K/Akt/mTOR signaling (increased p-PI3K, p-Akt, p-mTOR), enhancing autophagy and reducing apoptosis; PCNP knockdown reverses these effects. shRNA knockdown and overexpression, Western blotting, xenograft tumor assay Oncogenesis Medium 30872582
2020 PCNP binds directly to β-catenin and promotes its nuclear translocation, thereby activating Wnt/β-catenin signaling, which promotes ovarian cancer cell proliferation, migration, invasion, and epithelial-to-mesenchymal transition (EMT). Co-immunoprecipitation, Western blotting, nuclear fractionation, shRNA knockdown and overexpression Journal of cellular and molecular medicine Medium 32548978
2022 LINC00858 recruits the transcription factor RAD21 to the PCNP promoter region, upregulating PCNP expression, which in turn activates STAT3/5 phosphorylation to promote colon cancer cell proliferation; silencing RAD21 or PCNP reverses these effects. RNA pull-down, RIP, ChIP, siRNA knockdown, Western blotting, xenograft tumor model Cell death discovery Medium 35468892
2022 PCNP overexpression in thyroid cancer cells reduces proliferation, migration, and invasion, induces cell cycle arrest by modifying cell cycle regulatory gene expression, promotes apoptosis via ERK/JNK/p38 activation, and promotes autophagy by reducing Wnt/β-catenin pathway activity; knockdown shows opposite effects. shRNA knockdown and overexpression, Western blotting, cell cycle analysis, xenograft tumor assay International journal of biological sciences Medium 35813472
2025 PCNP transcriptionally upregulates UHRF2 expression; ectopic PCNP overexpression activates the ErbB3/Ras/Raf1 signaling pathway through UHRF2 upregulation, promoting hepatocellular carcinoma cell proliferation, invasion, and tumor formation in vivo. Pearson correlation analysis, Western blotting, shRNA knockdown and overexpression, in vitro proliferation/invasion assays, xenograft tumor model Scientific reports Medium 41271959
2025 PCNP overexpression in HUVECs inhibits endothelial cell proliferation, migration, and tube formation (angiogenesis), while PCNP knockdown promotes these processes. Transcriptome analysis reveals enrichment of inflammatory signaling pathways (IL-17, TNF, NF-κB) in PCNP-overexpressing cells. The mechanism does not involve direct modulation of intracellular VEGF levels. Overexpression and shRNA knockdown, CCK-8 proliferation assay, wound healing assay, tube formation assay, ELISA, Western blot, transcriptome sequencing Scientific reports Medium 41381593

Source papers

Stage 0 corpus · 58 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 The chaperone-like protein HYPK acts together with NatA in cotranslational N-terminal acetylation and prevention of Huntingtin aggregation. Molecular and cellular biology 120 20154145
2002 NIRF, a novel RING finger protein, is involved in cell-cycle regulation. Biochemical and biophysical research communications 72 12176013
2004 NIRF is a ubiquitin ligase that is capable of ubiquitinating PCNP, a PEST-containing nuclear protein. FEBS letters 55 14741369
2016 'Artilysation' of endolysin λSa2lys strongly improves its enzymatic and antibacterial activity against streptococci. Scientific reports 54 27775093
2011 Polyacrylamide nanoparticles as a delivery system in photodynamic therapy. Molecular pharmaceutics 53 21410233
2021 Platelet-Tumor Cell Hybrid Membrane-Camouflaged Nanoparticles for Enhancing Therapy Efficacy in Glioma. International journal of nanomedicine 44 35002237
2021 Alginate/chitosan-based hydrogel loaded with gene vectors to deliver polydeoxyribonucleotide for effective wound healing. Biomaterials science 40 34241614
1994 ANF-C-receptor-mediated inhibition of aortic smooth muscle cell proliferation and thymidine kinase activity. The American journal of physiology 39 8304541
2018 PEST-containing nuclear protein mediates the proliferation, migration, and invasion of human neuroblastoma cells through MAPK and PI3K/AKT/mTOR signaling pathways. BMC cancer 37 29716528
2017 Glioma and microenvironment dual targeted nanocarrier for improved antiglioblastoma efficacy. Drug delivery 32 28933201
2001 Vasoactivity of the ventral aorta of the American eel (Anguilla rostrata), Atlantic hagfish ( Myxine glutinosa), and sea lamprey (Petromyzon marinus). The Journal of experimental zoology 32 11241398
2022 Long-term anti-inflammatory effects of injectable celecoxib nanoparticle hydrogels for Achilles tendon regeneration. Acta biomaterialia 30 35331938
2018 Role of zein incorporation on hydrophobic drug-loading capacity and colloidal stability of phospholipid nanoparticles. Colloids and surfaces. B, Biointerfaces 30 30096472
1987 So-called "papillary and cystic neoplasm of the pancreas." An immunohistochemical and ultrastructural study. Acta pathologica japonica 30 3307289
2017 Increased Loading, Efficacy and Sustained Release of Silibinin, a Poorly Soluble Drug Using Hydrophobically-Modified Chitosan Nanoparticles for Enhanced Delivery of Anticancer Drug Delivery Systems. Nanomaterials (Basel, Switzerland) 28 29117121
2020 PCNP promotes ovarian cancer progression by accelerating β-catenin nuclear accumulation and triggering EMT transition. Journal of cellular and molecular medicine 25 32548978
1996 The H295R human adrenocortical cell line contains functional atrial natriuretic peptide receptors that inhibit aldosterone biosynthesis. Molecular and cellular endocrinology 24 8735599
2019 PEST-containing nuclear protein regulates cell proliferation, migration, and invasion in lung adenocarcinoma. Oncogenesis 23 30872582
1994 Cloning and functional expression of the bovine natriuretic peptide receptor-B (natriuretic factor R1c subtype. Molecular and cellular biochemistry 23 7845391
2022 p-Coumaric Acid Nanoparticles Ameliorate Diabetic Nephropathy via Regulating mRNA Expression of KIM-1 and GLUT-2 in Streptozotocin-Induced Diabetic Rats. Metabolites 22 36557204
2017 Phycocyanin-based nanocarrier as a new nanoplatform for efficient overcoming of cancer drug resistance. Journal of materials chemistry. B 21 32264396
2019 Praseodymium-Cobaltite-Reinforced Collagen as Biomimetic Scaffolds for Angiogenesis and Stem Cell Differentiation for Cutaneous Wound Healing. ACS applied bio materials 20 35030734
2020 Increased Cytotoxic Efficacy of Protocatechuic Acid in A549 Human Lung Cancer Delivered via Hydrophobically Modified-Chitosan Nanoparticles As an Anticancer Modality. Polymers 18 32872307
1995 Localisation and characteristics of natriuretic peptide receptors in the gills of the Atlantic hagfish Myxine glutinosa (Agnatha). The Journal of experimental biology 18 7891031
2022 A zebrafish HCT116 xenograft model to predict anandamide outcomes on colorectal cancer. Cell death & disease 15 36564370
2019 Taking a holistic view of PEST-containing nuclear protein (PCNP) in cancer biology. Cancer medicine 14 31487123
2012 Interleukin-1β, tumour necrosis factor-α and lipopolysaccharide induce C-type natriuretic peptide from canine aortic endothelial cells. Research in veterinary science 14 23141169
1997 Distribution and characterization of natriuretic peptide receptors in the gills of the spiny dogfish, Squalus acanthias. General and comparative endocrinology 14 9204367
1994 Localization and analysis of natriuretic peptide receptors in the gills of the toadfish, Opsanus beta (teleostei). The American journal of physiology 14 7810750
2022 PCNP is a novel regulator of proliferation, migration, and invasion in human thyroid cancer. International journal of biological sciences 13 35813472
2020 LncRNA np_5318 promotes renal ischemia-reperfusion injury through the TGF-β/Smad signaling pathway. Experimental and therapeutic medicine 11 32256767
2023 KCl Nanoparticles as Potential Inducer of Immunogenic Cell Death for Cancer Immunotherapy. ACS applied bio materials 10 37192493
2022 Biology of PEST-Containing Nuclear Protein: A Potential Molecular Target for Cancer Research. Frontiers in oncology 10 35186732
2021 Concise Nanoplatform of Phycocyanin Nanoparticle Loaded with Docetaxel for Synergetic Chemo-sonodynamic Antitumor Therapy. ACS applied bio materials 10 35006949
1995 Natriuretic peptide receptors in the kidney and the ventral and dorsal aortae of the Atlantic hagfish Myxine glutinosa (Agnatha). The Journal of experimental biology 10 7595160
1993 Localization and characteristics of atrial natriuretic peptide receptors in prenatal and postnatal rat brain. European journal of pharmacology 10 8243555
2022 LINC00858 promotes colon cancer progression through activation of STAT3/5 signaling by recruiting transcription factor RAD21 to upregulate PCNP. Cell death discovery 8 35468892
2017 TIPE2 expression is increased in peripheral blood mononuclear cells from patients with rheumatoid arthritis. Oncotarget 8 29152095
2000 Evidence of a guanylyl cyclase natriuretic peptide receptor in the gills of the new zealand hagfish Eptatretus cirrhatus (Class Agnatha). The Journal of experimental biology 8 10933996
1992 Identification of the atrial natriuretic factor-R1C receptor subtype (B-clone) in cultured rat aortic smooth muscle cells. FEBS letters 8 1352262
2024 Identification of Tumor-Suppressive miR-30a-3p Controlled Genes: ANLN as a Therapeutic Target in Breast Cancer. Non-coding RNA 6 39728605
1994 Ultracytochemical localization of particulate guanylate cyclase after stimulation with natriuretic peptides in lamb olfactory mucosa. The Histochemical journal 6 7883588
2023 Increased radical scavenging activity of thymoquinone and l-ascorbic acid dual encapsulated in palmitoyl-chitosan nanoparticles in a human normal lung fibroblast, MRC-5 due to synergistic antioxidative effects. RSC advances 5 37736560
2022 siAKR1C3@PPA complex nucleic acid nanoparticles inhibit castration-resistant prostate cancer in vitro. Frontiers in oncology 5 36591491
2025 A biomimetic manganese-phycocyanin nanodrug-carrying system and its sonodynamic-immunological anti-tumor therapy. International journal of pharmaceutics 4 40300722
2021 TIPE2 and PCNP expression abnormalities in peripheral blood mononuclear cells associated with disease activity in rheumatoid arthritis: a meta-analysis. European review for medical and pharmacological sciences 4 33629294
2021 Phycocyanin Nanoparticle as a Novel Sonosensitizer for Tumor Sonodynamic Therapy of Michigan Cancer Foundation-7 Cells In Vitro. Journal of nanoscience and nanotechnology 3 33653477
2025 Acid-Responsive Disassembly of Nanomedicines for Extracellular Drug Delivery Reversing Glioblastoma Immunosuppressive Microenvironment by Targeting the Adenosine-A2AR Pathway. Small (Weinheim an der Bergstrasse, Germany) 2 40289458
2025 Regulation of PEST-containing nuclear proteins in cancer cells: implications for cancer biology and therapy. Frontiers in oncology 2 40330830
1993 [Papillary and cystic tumors of the pancreas. Clinico-pathological, cytopathological, immunohistochemical, and nuclear ploidy study]. Medicina 2 8084243
2025 PCNP promotes hepatocellular carcinoma progression by upregulating UHRF2 to activate ErbB3/Ras/Raf pathway. Scientific reports 1 41271959
2024 Recent Insights into the Roles of PEST-Containing Nuclear Protein. Molecular biotechnology 1 38762838
2023 Tissue mechanics modulate PCNP expression in oral squamous cell carcinomas with different differentiation. Frontiers in oncology 1 36703786
2026 Study on biomarkers of homocysteine-induced transformation of vascular smooth muscle cells into foam cells. Scientific reports 0 41644998
2026 Frequency and Etiologies of Peripheral Type Cranial Neuropathy in the Neurology Inpatient Clinic. Noro psikiyatri arsivi 0 41777495
2025 PEST-containing nuclear protein in eye health and disease: A review. Experimental eye research 0 40414338
2025 The role and potential mechanism of PEST-containing nuclear protein (PCNP) in endothelial cell angiogenesis in vitro. Scientific reports 0 41381593
2024 Plasma Proteome-Wide Mendelian Randomization Analysis Reveals Biomarkers and Therapeutic Targets for Different Stages of COVID-19. Transboundary and emerging diseases 0 40303168

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