Affinage

PHIP

PH-interacting protein · UniProt Q8WWQ0

Length
1821 aa
Mass
206.7 kDa
Annotated
2026-06-10
100 papers in source corpus 13 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PHIP (DCAF14/RepID/BRWD2) is a chromatin-associated WD40 scaffold that functions as a substrate receptor for the CRL4 (CUL4-RING) ubiquitin E3 ligase, coupling histone-mark recognition to ubiquitin-dependent control of genome replication and cell division (PMID:29089422, PMID:30018425, PMID:34819353). It engages chromatin through a trivalent reader module — a CryptoTudor domain reading H3K4 methylation together with two bromodomains reading H3K14ac (BD1) and H4K12ac (BD2) — and this reader activity, modulated by COMPASS-family H3K4 methyltransferases, positions PHIP genome-wide and is required for CRL4 recruitment to chromatin; disease-associated mutations in BD1, BD2, and the linker disrupt chromatin binding (PMID:29089422, PMID:34819353). Through CRL4 recruitment, PHIP licenses replication origins prior to S phase, and its loss forces dependence on the alternative SKP2/SCF pathway and triggers genome re-replication (PMID:30018425). PHIP also localizes rapidly to stalled replication forks, where CRL4-DCAF14 protects nascent DNA from MRE11 and DNA2 nucleases in a RAD51-dependent manner to prevent fork collapse (PMID:33503431), and it drives the metaphase-to-anaphase transition by enabling CRL4-RBBP7-mediated ubiquitination and degradation of the spindle-assembly-checkpoint mediator BUB3 (PMID:31911655). Independently of its replication roles, nuclear PHIP directly enhances POMC transcription to regulate energy homeostasis (PMID:32492392), and it modulates focal adhesion dynamics and actin organization through a direct interaction with vinculin to promote cancer cell migration and invasion (PMID:32273388). An earlier-characterized activity links PHIP to insulin/IGF-1 signaling via the IRS-1 PH domain, promoting beta-cell proliferation and survival through AKT and cyclin D2 (PMID:11018022, PMID:17636024). Haploinsufficiency of PHIP causes an intellectual disability-overweight (Chung-Jansen) syndrome (PMID:29209020).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2000 Medium

    Established PHIP's founding biochemical identity as a PH-domain-interacting partner that couples to insulin signaling, answering what protein selectively binds the IRS-1 PH domain.

    Evidence In vitro binding, co-IP, and dominant-negative overexpression with IRS-1 phosphorylation and MAPK readouts

    PMID:11018022

    Open questions at the time
    • Does not define a catalytic activity for PHIP
    • Connection to chromatin/CRL4 functions not yet known
    • Single lab, in vitro binding
  2. 2007 Medium

    Identified a nuclear WD40 isoform and linked PHIP to beta-cell proliferation and survival, extending its signaling role into transcriptional and cytoprotective outputs.

    Evidence Isoform cloning, RNAi, cyclin D2 promoter reporter, dominant-negative PKB, and caspase cleavage assays in beta-cells

    PMID:17636024

    Open questions at the time
    • Mechanism linking PHIP to cyclin D2 promoter not resolved
    • Whether nuclear function depends on CRL4 not addressed
    • Single cell-type focus
  3. 2012 Medium

    Demonstrated that PHIP is functionally required for cancer metastasis, motivating later mechanistic dissection of how it drives invasion.

    Evidence Systemic and stable shRNA suppression in melanoma cell lines with metastasis and survival assays in mice

    PMID:22511720

    Open questions at the time
    • No molecular mechanism for the metastatic phenotype defined
    • Effector pathway unidentified at this stage
  4. 2016 Low

    Genotype-phenotype analysis pinned the PHIP/DCAF14 isoform as the cause of an intellectual disability-overweight syndrome and implicated the CRL4 pathway in the neurodevelopmental phenotype.

    Evidence MIP-based targeted sequencing and isoform-specific phenotypic correlation across 23 individuals

    PMID:29209020

    Open questions at the time
    • Pathway placement inferred, not experimentally reconstituted
    • No functional assay on the specific isoform
    • Causality at the molecular level not established
  5. 2017 High

    Defined PHIP as a chromatin reader that binds H3K4 methylation through a novel CryptoTudor domain and associates with CRL4, reframing PHIP as a chromatin-coupled E3 ligase adaptor.

    Evidence Genome-wide ChIP-seq, direct histone binding assay, CRL4 Co-IP, CRISPR knockout of COMPASS members, and cross-species genetic depletion

    PMID:29089422

    Open questions at the time
    • CRL4 substrates downstream of chromatin recruitment not yet identified
    • Full PTM combinatorics of the reader module not resolved here
  6. 2018 High

    Showed PHIP recruits CRL4 to replication origins to license DNA replication, establishing its architectural role in origin function and an epistatic relationship with the SKP2/SCF pathway.

    Evidence RepID depletion, chromatin fractionation, origin firing and re-replication assays, SKP2 inhibitor sensitivity

    PMID:30018425

    Open questions at the time
    • The relevant CRL4 substrate at origins not defined
    • How RepID and SKP2 partition distinct origins mechanistically unclear
  7. 2018 Medium

    Confirmed PHIP's bromodomain reads an acetyl mark (H4K91ac) and linked PHIP loss to coordinate suppression of pAKT, cyclin D1, and talin1, connecting chromatin reading to proliferation and invasion.

    Evidence Bromodomain binding assay and shRNA knockdown with proliferation/invasion and immunoblot readouts across multiple cancer lines

    PMID:29866840

    Open questions at the time
    • Direct causal chain from bromodomain binding to pAKT/cyclin D1/talin1 not reconstituted
    • Limited structural detail
  8. 2020 High

    Revealed a mitotic role: CRL4 switches partner from RepID to RBBP7 to ubiquitinate and degrade BUB3, driving the metaphase-to-anaphase transition.

    Evidence Co-IP, reconstituted BUB3 ubiquitination, live-cell mitotic timing, RepID/RBBP7 perturbation, PML body fractionation

    PMID:31911655

    Open questions at the time
    • Signal controlling the RepID-to-RBBP7 handoff unknown
    • How PML bodies sequester BUB3 in interphase mechanistically unclear
  9. 2020 Medium

    Established a direct transcriptional role for nuclear PHIP at the POMC locus, providing a molecular route from PHIP to energy homeostasis and the obesity phenotype.

    Evidence Cell-based transcription assays comparing wild-type and obesity-associated PHIP variants

    PMID:32492392

    Open questions at the time
    • Direct vs chromatin-mediated mechanism at POMC not dissected
    • Limited methodological detail
    • In vivo relevance not shown here
  10. 2020 High

    Placed PHIP at focal adhesions in direct contact with vinculin, defining a cytoskeletal mechanism for PHIP-driven cancer cell migration and invasion.

    Evidence Confocal localization, Co-IP with vinculin, shRNA knockdown with TLN1/ZYX rescue, and intracranial tumor model

    PMID:32273388

    Open questions at the time
    • How a chromatin reader also operates at focal adhesions structurally unresolved
    • Whether CRL4 participates at adhesions unknown
  11. 2021 High

    Resolved the full trivalent reader module (CryptoTudor + BD1 + BD2 reading H3K4me/H3K14ac/H4K12ac) and showed it is required for CRL4 chromatin recruitment, with disease mutations disrupting binding.

    Evidence Semisynthetic nucleosome binding with defined PTMs, mutagenesis of BD1/BD2/linker, and CRL4 recruitment assay

    PMID:34819353

    Open questions at the time
    • High-resolution structure of the assembled module not reported
    • Combinatorial PTM dependence in vivo not fully mapped
  12. 2021 High

    Defined PHIP's role in fork protection: CRL4-DCAF14 localizes to stalled forks and shields nascent DNA from MRE11/DNA2 nucleases in a RAD51-dependent manner.

    Evidence Fork localization assay, DNA fiber and DSB measurements, RAD51 epistasis, and nuclease inhibition

    PMID:33503431

    Open questions at the time
    • Relevant CRL4-DCAF14 ubiquitination substrate at forks not identified
    • How RAD51 and PHIP cooperate mechanistically unresolved
  13. 2023 Medium

    Linked PHIP to CDK2 turnover, showing PHIP promotes CDK2 ubiquitination/degradation and G0/G1 arrest, and is itself controlled by a TRIM25/Sp1/DNMT3B promoter-methylation axis.

    Evidence Protein degradation assay, western blot, luciferase reporter, RNA-IP/pulldown, EdU/soft agar, and xenograft in colorectal cancer cells

    PMID:37742010

    Open questions at the time
    • Whether CDK2 degradation is CRL4-dependent not established
    • Direct vs indirect role of PHIP in CDK2 ubiquitination unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single chromatin reader/CRL4 adaptor coordinates its distinct nuclear (replication, mitosis, transcription) and cytoplasmic (focal adhesion, IRS-1 signaling) activities, and which CRL4 substrates execute the replication and fork-protection roles, remains unresolved.
  • CRL4-DCAF14 substrates at origins and stalled forks unidentified
  • Mechanistic basis for cytoplasmic vs nuclear partitioning unknown
  • Whether disease phenotypes arise from chromatin-reading or signaling defects undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0042393 histone binding 3 GO:0060090 molecular adaptor activity 3 GO:0140110 transcription regulator activity 2 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005694 chromosome 3 GO:0005634 nucleus 2 GO:0005886 plasma membrane 1
Pathway
R-HSA-1640170 Cell Cycle 2 R-HSA-392499 Metabolism of proteins 2 R-HSA-4839726 Chromatin organization 2 R-HSA-69306 DNA Replication 1 R-HSA-73894 DNA Repair 1 R-HSA-74160 Gene expression (Transcription) 1
Partners
BUB3CUL4DDB1IRS-1ITGB1RBBP7TLN1VCL
Complex memberships
CRL4 (CUL4-RING) ubiquitin ligasefocal adhesion complex

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 PHIP (PH-interacting protein) selectively binds to the pleckstrin homology (PH) domain of IRS-1 in vitro and stably associates with IRS-1 in vivo. Mutants of the IRS-1 PH domain that disrupt the PH fold fail to bind PHIP. Overexpression of the PH-binding region of PHIP (dominant-negative) inhibits insulin-induced IRS-1 tyrosine phosphorylation and attenuates insulin-stimulated MAP kinase activity. In vitro binding assay, co-immunoprecipitation, dominant-negative overexpression with phosphotyrosine immunoblotting and MAPK activity assay The Journal of biological chemistry Medium 11018022
2007 A larger 1,821-aa WD40 repeat-containing isoform of PHIP (PHIP1) is expressed prominently in the nucleus of pancreatic beta-cells. PHIP1 overexpression stimulates IGF-1-dependent and -independent beta-cell proliferation via transcriptional upregulation of the cyclin D2 promoter. RNAi knockdown of PHIP1 abrogates IRS2-mediated DNA synthesis. PHIP1 overexpression blocks free fatty acid-induced apoptosis through activation of PKB/AKT and inhibition of caspase-9 and caspase-3; this cytoprotective effect is attenuated by dominant-negative PKB. Cloning and expression of novel isoform, immunoblotting, immunohistochemistry, RNA interference, cyclin D2 promoter reporter assay, dominant-negative PKB overexpression, caspase cleavage assays Molecular and cellular biology Medium 17636024
2017 BRWD2/PHIP colocalizes with histone H3K4 methylation genome-wide in human cells, mouse ESCs, and Drosophila. PHIP binds directly to H3K4 methylation through a novel chromatin-binding module related to Royal Family Tudor domains (named CryptoTudor domain). PHIP associates biochemically with the CUL4-RING ubiquitin E3 ligase (CRL4) complex, nucleosomes, and chromatin remodelers. CRISPR-Cas9 knockout of COMPASS H3K4 methyltransferase family members differentially regulates BRWD2/PHIP chromatin occupancy. Depletion of the Drosophila homolog dBRWD3 results in altered gene expression and aberrant H3K27 acetylation patterns at enhancers and promoters. Genome-wide ChIP-seq, biochemical pulldown/Co-IP of CRL4 complex, CRISPR-Cas9 knockout, direct histone binding assay, Drosophila genetic depletion with RNA-seq and ChIP-seq Genes & development High 29089422
2018 RepID/DCAF14/PHIP (a WD-40 protein) recruits the CRL4 ubiquitin ligase complex to chromatin prior to DNA synthesis, playing an architectural role in licensing chromosomes for replication. In the absence of RepID, cells rely on the alternative SKP2-containing SCF ubiquitin ligase to progress through the cell cycle. RepID depletion markedly increases cellular sensitivity to SKP2 inhibitors, triggering massive genome re-replication. RepID and SKP2 interact with distinct, non-overlapping groups of replication origins. RepID depletion (knockdown/knockout), chromatin fractionation, origin firing analysis, SKP2 inhibitor sensitivity assays, genome re-replication assay Nature communications High 30018425
2020 The RepID/DCAF14/PHIP-CRL4 ubiquitin ligase complex regulates the metaphase-to-anaphase transition. During mitosis, CRL4 dissociates from RepID and associates with RBBP7, which ubiquitinates the SAC mediator BUB3 to enable mitotic exit. During interphase, BUB3 is protected from CRL4-mediated degradation by association with PML nuclear bodies. Deficiencies in RepID, CRL4, or RBBP7 delay mitotic exit, increase genomic instability, and enhance sensitivity to paclitaxel. Co-immunoprecipitation, ubiquitination assay, live-cell imaging, RepID/RBBP7 knockdown/knockout with mitotic exit timing, genomic instability assays, PML body fractionation Nature communications High 31911655
2020 Nuclear PHIP directly enhances transcription of pro-opiomelanocortin (POMC), a neuropeptide that suppresses appetite. Obesity-associated PHIP variants repress POMC transcription in cell-based assays. Cell-based transcription assays with wild-type and mutant PHIP variants, nuclear localization of PHIP confirmed Cell metabolism Medium 32492392
2020 PHIP localizes to the leading edge of glioblastoma cells and to the force transduction layer of the focal adhesion complex together with vinculin (VCL), talin 1 (TLN1), integrin beta 1 (ITGB1), phospho-paxillin, and phospho-FAK. Immunoprecipitation revealed a direct physical interaction between PHIP and VCL. Suppression of PHIP downregulates focal adhesion proteins and disorganizes stress fibers. PHIP silencing significantly suppresses glioblastoma migration and invasion, partially restored by TLN1 or ZYX cDNA overexpression. Immunofluorescence, confocal microscopy, co-immunoprecipitation, shRNA knockdown, live-cell imaging with ZYX-GFP, cDNA rescue, intracranial implantation tumor model Proceedings of the National Academy of Sciences of the United States of America High 32273388
2021 PHIP/BRWD2 is a chromatin-associated CRL4 ubiquitin ligase substrate receptor and is required for CRL4 recruitment to chromatin. PHIP binds chromatin through a trivalent reader module: a CryptoTudor domain that reads H3K4 methylation, bromodomain 1 (BD1) that reads H3K14ac, and bromodomain 2 (BD2) that reads H4K12ac, characterized using semisynthetic nucleosomes with defined histone PTMs. Human disease-associated mutations in BD1, BD2, and the linker region disrupt chromatin binding. Semisynthetic nucleosome binding assays with defined histone PTMs, mutagenesis of BD1/BD2/linker, CRL4 chromatin recruitment assay, structural/domain analysis Genes & development High 34819353
2021 DCAF14/PHIP localizes rapidly to stalled replication forks and promotes genome integrity by preventing fork collapse into double-strand breaks. CRL4-DCAF14 mediates stalled fork protection in a RAD51-dependent manner, protecting nascent DNA from MRE11 and DNA2 nucleases. iPOND (isolation of proteins on nascent DNA) or proximity ligation assay for fork localization, DNA fiber assay for fork protection, DSB measurement, RAD51 epistasis, nuclease inhibition experiments Cell reports High 33503431
2018 PHIP's bromodomain is functional and specifically binds the histone modification H4K91ac. Suppression of PHIP inhibits tumor cell proliferation and invasion, coordinately suppressing phosphorylated AKT, cyclin D1, and talin1 in melanoma, breast, and lung cancer cell lines. Bromodomain binding assay (H4K91ac specificity), shRNA knockdown with proliferation and invasion assays, immunoblotting for pAKT, cyclin D1, talin1 Proceedings of the National Academy of Sciences of the United States of America Medium 29866840
2012 Systemic shRNA-mediated suppression of Phip inhibited metastatic progression of melanoma in vivo. Stable suppression of Phip in melanoma cell lines suppressed metastatic potential and prolonged survival of tumor-bearing mice. Plasmid-based shRNA in vivo, stable shRNA knockdown in melanoma cell lines, metastasis assays, survival analysis in tumor-bearing mice Proceedings of the National Academy of Sciences of the United States of America Medium 22511720
2023 PHIP promotes ubiquitination and degradation of CDK2, leading to G0/G1 growth arrest in colorectal cancer cells. PHIP transcription is regulated by DNMT3B-mediated promoter methylation downstream of the TRIM25/Sp1/DNMT3B axis. Western blotting, protein degradation assay, luciferase reporter, RNA-IP, RNA pulldown, EdU and soft agar assays, xenograft model BMC cancer Medium 37742010
2016 Genotype-phenotype analysis of individuals with PHIP haploinsufficiency points toward PHIP/DCAF14 isoform (not NDRP) as the cause of the intellectual disability-overweight syndrome, implicating the CUL4-DDB1 ubiquitin ligase pathway (PHIP1/DCAF14 is a substrate receptor of this complex) in the neurodevelopmental phenotype. MIP-based targeted sequencing, phenotypic correlation of 23 individuals with PHIP mutations, isoform-specific genotype-phenotype analysis European journal of human genetics : EJHG Low 29209020

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 PhIP-Seq characterization of serum antibodies using oligonucleotide-encoded peptidomes. Nature protocols 154 30190553
1994 Metabolic activation pathway for the formation of DNA adducts of the carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in rat extrahepatic tissues. Carcinogenesis 147 8055652
1992 Reaction of the N2-acetoxy derivative of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) with 2'-deoxyguanosine and DNA. Synthesis and identification of N2-(2'-deoxyguanosin-8-yl)-PhIP. Carcinogenesis 128 1576716
2003 Sulforaphane and quercetin modulate PhIP-DNA adduct formation in human HepG2 cells and hepatocytes. Carcinogenesis 94 12949046
1993 32P-postlabeling analysis of IQ, MeIQx and PhIP adducts formed in vitro in DNA and polynucleotides and found in vivo in hepatic DNA from IQ-, MeIQx- and PhIP-treated monkeys. Carcinogenesis 93 8330355
1993 Enzymatic phase II activation of the N-hydroxylamines of IQ, MeIQx and PhIP by various organs of monkeys and rats. Carcinogenesis 82 8222059
1990 Activation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) to mutagenic metabolites. Carcinogenesis 78 2197012
1995 Protection by chlorophyllin and indole-3-carbinol against 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced DNA adducts and colonic aberrant crypts in the F344 rat. Carcinogenesis 76 8603466
2003 Effect of dietary constituents with chemopreventive potential on adduct formation of a low dose of the heterocyclic amines PhIP and IQ and phase II hepatic enzymes. Nutrition and cancer 72 14690798
1993 Mutagenic activation of IQ, PhIP and MeIQx by hepatic microsomes from rat, monkey and man: low mutagenic activation of MeIQx in cynomolgus monkeys in vitro reflects low DNA adduct levels in vivo. Carcinogenesis 69 8425272
2020 Exome Sequencing Identifies Genes and Gene Sets Contributing to Severe Childhood Obesity, Linking PHIP Variants to Repressed POMC Transcription. Cell metabolism 65 32492392
2001 N-glucuronidation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and N_hydroxy-PhIP by specific human UDP-glucuronosyltransferases. Carcinogenesis 63 11408353
2020 Identification of novel, clinically correlated autoantigens in the monogenic autoimmune syndrome APS1 by proteome-wide PhIP-Seq. eLife 59 32410729
1996 DNA adduct formation, cell proliferation and aberrant crypt focus formation induced by PhIP in male and female rat colon with relevance to carcinogenesis. Carcinogenesis 59 8565143
1994 Effect of glutathione depletion and inhibition of glucuronidation and sulfation on 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) metabolism, PhIP-DNA adduct formation and unscheduled DNA synthesis in primary rat hepatocytes. Carcinogenesis 59 8055653
2017 A cryptic Tudor domain links BRWD2/PHIP to COMPASS-mediated histone H3K4 methylation. Genes & development 58 29089422
2010 NADPH oxidase overexpression in human colon cancers and rat colon tumors induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). International journal of cancer 58 20715105
2016 De novo PHIP-predicted deleterious variants are associated with developmental delay, intellectual disability, obesity, and dysmorphic features. Cold Spring Harbor molecular case studies 57 27900362
2007 Grilled meat consumption and PhIP-DNA adducts in prostate carcinogenesis. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 57 17416774
1997 Metabolism of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) by human cytochrome P4501B1. Carcinogenesis 56 9328177
2002 Protection by beverages, fruits, vegetables, herbs, and flavonoids against genotoxicity of 2-acetylaminofluorene and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in metabolically competent V79 cells. Mutation research 55 12438004
2007 Bcl-2 overexpression in PhIP-induced colon tumors: cloning of the rat Bcl-2 promoter and characterization of a pathway involving beta-catenin, c-Myc and E2F1. Oncogene 54 17404573
2002 Molecular and genetic toxicology of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Mutation research 54 12351148
2007 Glucuronidation of PhIP and N-OH-PhIP by UDP-glucuronosyltransferase 1A10. Carcinogenesis 51 17638922
1995 Possible mechanisms for PhIP-DNA adduct formation in the mammary gland of female Sprague-Dawley rats. Carcinogenesis 51 7586192
2014 Ammonia and formaldehyde participate in the formation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in addition to creati(ni)ne and phenylacetaldehyde. Food chemistry 49 24594156
2005 Modeling human colon cancer in rodents using a food-borne carcinogen, PhIP. Cancer science 49 16232193
2000 Cloning and characterization of PHIP, a novel insulin receptor substrate-1 pleckstrin homology domain interacting protein. The Journal of biological chemistry 49 11018022
1994 Mutation and repair induced by the carcinogen 2-(hydroxyamino)-1-methyl-6-phenylimidazo[4,5-b]pyridine (N-OH-PhIP) in the dihydrofolate reductase gene of Chinese hamster ovary cells and conformational modeling of the dG-C8-PhIP adduct in DNA. Chemical research in toxicology 47 8199311
2017 A genotype-first approach identifies an intellectual disability-overweight syndrome caused by PHIP haploinsufficiency. European journal of human genetics : EJHG 46 29209020
2007 Identification of a WD40 repeat-containing isoform of PHIP as a novel regulator of beta-cell growth and survival. Molecular and cellular biology 44 17636024
2000 Indole-3-carbinol as a chemopreventive agent in 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) carcinogenesis: inhibition of PhIP-DNA adduct formation, acceleration of PhIP metabolism, and induction of cytochrome P450 in female F344 rats. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 44 10685010
1998 Immunohistochemical demonstration of carcinogen-DNA adducts in tissues of rats given 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP): detection in paraffin-embedded sections and tissue distribution. Cancer research 43 9766658
2022 Autoantibody discovery across monogenic, acquired, and COVID-19-associated autoimmunity with scalable PhIP-seq. eLife 42 36300623
2012 Pleckstrin homology domain-interacting protein (PHIP) as a marker and mediator of melanoma metastasis. Proceedings of the National Academy of Sciences of the United States of America 42 22511720
2002 Response of Apc(min) and A33 (delta N beta-cat) mutant mice to treatment with tea, sulindac, and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Mutation research 42 12351151
2018 The replication initiation determinant protein (RepID) modulates replication by recruiting CUL4 to chromatin. Nature communications 41 30018425
2016 δ- and γ-tocopherols inhibit phIP/DSS-induced colon carcinogenesis by protection against early cellular and DNA damages. Molecular carcinogenesis 41 27175800
1990 Effects of the food mutagens MeIQx and PhIP on the expression of cytochrome P450IA proteins in various tissues of male and female rats. Carcinogenesis 41 1702369
2000 Tea as a potential chemopreventive agent in PhIP carcinogenesis: effects of green tea and black tea on PhIP-DNA adduct formation in female F-344 rats. Nutrition and cancer 38 10798216
1991 Azido- and nitro-PhIP, relatives of the heterocyclic arylamine and food mutagen PhIP--mechanism of their mutagenicity in Salmonella. Carcinogenesis 38 2044190
1994 In vitro formation and degradation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) protein adducts. Carcinogenesis 37 7955104
2008 Consumption of Brussels sprouts protects peripheral human lymphocytes against 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and oxidative DNA-damage: results of a controlled human intervention trial. Molecular nutrition & food research 35 18293303
1991 The effect of dose and enzyme inducers on the metabolism of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in rats. Carcinogenesis 35 1747929
2016 DNA damage response curtails detrimental replication stress and chromosomal instability induced by the dietary carcinogen PhIP. Nucleic acids research 34 27599846
2003 Carcinogenesis of the food mutagen PhIP in mice is independent of CYP1A2. Carcinogenesis 34 12663521
1998 Genetic analysis of PHIP intestinal mutations in MutaMouse. Mutagenesis 34 9862191
2006 Mechanisms of action of the carcinogenic heterocyclic amine PhIP. Toxicology letters 33 17156947
2002 A rat colon cancer model induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, PhIP. Mutation research 33 12351153
2020 The RepID-CRL4 ubiquitin ligase complex regulates metaphase to anaphase transition via BUB3 degradation. Nature communications 32 31911655
2020 PHIP drives glioblastoma motility and invasion by regulating the focal adhesion complex. Proceedings of the National Academy of Sciences of the United States of America 32 32273388
2015 Curcumin inhibits PhIP induced cytotoxicity in breast epithelial cells through multiple molecular targets. Cancer letters 32 26004342
2003 Genetic polymorphisms and modulation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-DNA adducts in human lymphocytes. International journal of cancer 32 14601045
2002 Inhibition of conjugated fatty acids derived from safflower or perilla oil of induction and development of mammary tumors in rats induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Cancer letters 32 11867197
2021 A trivalent nucleosome interaction by PHIP/BRWD2 is disrupted in neurodevelopmental disorders and cancer. Genes & development 31 34819353
1992 Dose-dependent formation of preneoplastic foci and DNA adducts in rat liver with 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeA alpha C) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Carcinogenesis 31 1499093
2003 Effect of chrysin, a flavonoid compound, on the mutagenic activity of 2-amino-1-methyl-6-phenylimidazo[4,5- b]pyridine (PhIP) and benzo(a)pyrene (B(a)P) in bacterial and human hepatoma (HepG2) cells. Archives of toxicology 30 12856103
1994 DNA adduct levels of 2-amino-1-methyl-6-phenylimidazo-[4,5-b]pyridine (PhIP) in tissues of cynomolgus monkeys after single or multiple dosing. Carcinogenesis 30 8001231
1999 Comparative biotransformation studies of MeIQx and PhIP in animal models and humans. Cancer letters 29 10503897
2001 Intestinal toxicity and carcinogenic potential of the food mutagen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in DNA repair deficient XPA-/- mice. Carcinogenesis 28 11285198
1996 Effects of phenethyl isothiocyanate on metabolism and on genotoxicity of dimethylnitrosamine and 2-amino-1-methyl-6-phenylimidazo[4, 5-beta]pyridine (PhIP). Mutation research 28 8657203
2018 PHIP as a therapeutic target for driver-negative subtypes of melanoma, breast, and lung cancer. Proceedings of the National Academy of Sciences of the United States of America 26 29866840
2008 Protective versus promotional effects of white tea and caffeine on PhIP-induced tumorigenesis and beta-catenin expression in the rat. Carcinogenesis 26 18283038
2006 Cytochrome P450 expression and metabolic activation of cooked food mutagen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in MCF10A breast epithelial cells. Chemico-biological interactions 26 16527260
2002 One dose of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) or 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) induces tumours in Min/+ mice by truncation mutations or LOH in the Apc gene. Mutation research 26 12034317
2006 Mouse lung CYP1A1 catalyzes the metabolic activation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Carcinogenesis 25 17052995
2005 PhIP carcinogenicity in breast cancer: computational and experimental evidence for competitive interactions with human estrogen receptor. Chemical research in toxicology 25 16533016
2019 Clinical and genetic characterization of individuals with predicted deleterious PHIP variants. Cold Spring Harbor molecular case studies 23 31167805
1996 Validation in rats of two biomarkers of exposure to the food-borne carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP): PhIP-DNA adducts and urinary PhIP. Carcinogenesis 23 8565139
2021 Cyanidin-3-O-glucoside and its metabolite protocatechuic acid ameliorate 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) induced cytotoxicity in HepG2 cells by regulating apoptotic and Nrf2/p62 pathways. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 22 34582963
2000 Association between acetylator genotype and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) DNA adduct formation in colon and prostate of inbred Fischer 344 and Wistar Kyoto rats. Cancer letters 22 10737708
1995 Identification of aprt gene mutations induced in repair-deficient and P450-expressing CHO cells by the food-related mutagen/carcinogen, PhIP. Carcinogenesis 22 7767987
2006 Detection of 2-amino-1-methyl-6-phenylimidazo [4,5-b]-pyridine (PhIP)-DNA adducts in human pancreatic tissues. Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals 21 16908439
2022 Phage ImmunoPrecipitation Sequencing (PhIP-Seq): The Promise of High Throughput Serology. Pathogens (Basel, Switzerland) 20 35631089
2014 The cooked meat-derived mammary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) elicits estrogenic-like microRNA responses in breast cancer cells. Toxicology letters 20 24877718
2011 Protective effects of xanthohumol against the genotoxicity of heterocyclic aromatic amines MeIQx and PhIP in bacteria and in human hepatoma (HepG2) cells. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 20 22138251
2000 Mass spectrometric detection and measurement of N2-(2'-deoxyguanosin-8-yl)PhIP adducts in DNA. Journal of chromatography. B, Biomedical sciences and applications 20 10985566
1994 Adduction of the heterocyclic amine food mutagens IQ and PhIP to mitochondrial and nuclear DNA in the liver of Fischer-344 rats. Carcinogenesis 20 8149474
2023 PHIP-associated Chung-Jansen syndrome: Report of 23 new individuals. Frontiers in cell and developmental biology 19 36726590
2002 Resveratrol modulates human mammary epithelial cell O-acetyltransferase, sulfotransferase, and kinase activation of the heterocyclic amine carcinogen N-hydroxy-PhIP. Cancer letters 19 12175520
1995 DNA-binding and disposition of 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine (PhIP) in the rat. Carcinogenesis 19 7586200
2007 Racial differences in clinical and pathological associations with PhIP-DNA adducts in prostate. International journal of cancer 18 17487839
1998 Inhibition of DNA adduct formation of PhIP in female F344 rats by dietary conjugated linoleic acid. Nutrition and cancer 18 10050262
1995 Metabolic activation and DNA adduct detection of PhIP in dogs, rats, and humans in relation to urinary bladder and colon carcinogenesis. Princess Takamatsu symposia 18 8844812
2023 Real-Time Pyruvate Chemical Conversion Monitoring Enabled by PHIP. Journal of the American Chemical Society 17 36857108
2022 PhIP-Seq Reveals Autoantibodies for Ubiquitously Expressed Antigens in Viral Myocarditis. Biology 17 36101433
2013 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-DNA adducts in benign prostate and subsequent risk for prostate cancer. International journal of cancer 17 23400709
2001 Msh2 DNA mismatch repair gene deficiency and the food-borne mutagen 2-amino-1-methy1-6-phenolimidazo [4,5-b] pyridine (PhIP) synergistically affect mutagenesis in mouse colon. Oncogene 17 11593414
1998 Effects of dietary conjugated linoleic acid on DNA adduct formation of PhIP and IQ after bolus administration to female F344 rats. Nutrition and cancer 17 10050263
2006 Hydroxyl-specific fluorescence labeling of ABP-deoxyguanosine, PhIP-deoxyguanosine, and AFB1-formamidopyrimidine with BODIPY-FL. Analytical biochemistry 16 17081492
1997 Pancreatic DNA adducts formed in vitro and in vivo by the food mutagens 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeA alphaC). Mutation research 16 9288881
2023 LINC00955 suppresses colorectal cancer growth by acting as a molecular scaffold of TRIM25 and Sp1 to Inhibit DNMT3B-mediated methylation of the PHIP promoter. BMC cancer 15 37742010
2021 DCAF14 promotes stalled fork stability to maintain genome integrity. Cell reports 15 33503431
2018 A comparison of mutagenic PhIP and beneficial 8-C-(E-phenylethenyl)quercetin and 6-C-(E-phenylethenyl)quercetin formation under microwave and conventional heating. Food & function 15 29953158
2008 The microbial PhIP metabolite 7-hydroxy-5-methyl-3-phenyl-6,7,8,9-tetrahydropyrido[3',2':4,5]imidazo[1,2-a]pyrimidin-5-ium chloride (PhIP-M1) induces DNA damage, apoptosis and cell cycle arrest towards Caco-2 cells. Toxicology letters 15 18375078
1999 Dietary omega-3 fatty acids as potential inhibitors of carcinogenesis: effect on DNA adduct formation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in mice and rats. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 15 10418945
2019 6-Shogaol Suppresses 2-Amino-1-Methyl-6-Phenylimidazo [4,5-b] Pyridine (PhIP)-Induced Human 786-O Renal Cell Carcinoma Osteoclastogenic Activity and Metastatic Potential. Nutrients 14 31569368
2013 Effects of 2-amino-1-methyl-6-phenylimidazo [4, 5-b] pyridine (PhIP) on histopathology, oxidative stress, and expression of c-fos, c-jun and p16 in rat stomachs. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 14 23313794
2003 Direct reduction of N-acetoxy-PhIP by tea polyphenols: a possible mechanism for chemoprevention against PhIP-DNA adduct formation. Mutation research 14 12628517
1999 Mutant yields and mutational spectra of the heterocyclic amines MeIQ and PhIP at the S1 locus of human-hamster AL cells with activation by chick embryo liver (CELC) co-cultures. Mutation research 14 10082914

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