Affinage

PHIP

PH-interacting protein · UniProt Q8WWQ0

Round 2 corrected
Length
1821 aa
Mass
206.7 kDa
Annotated
2026-04-28
130 papers in source corpus 13 papers cited in narrative 13 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PHIP (PH-interacting protein/BRWD2/DCAF14/RepID) is a chromatin-associated substrate receptor for the CRL4 (CUL4–DDB1–ROC1) ubiquitin E3 ligase complex that couples multivalent histone mark recognition to diverse downstream processes including DNA replication origin licensing, mitotic checkpoint termination, transcriptional regulation, and cell motility (PMID:16964240, PMID:29089422, PMID:34819353). PHIP engages chromatin through a trivalent reader module—a CryptoTudor domain binding H3K4 methylation, bromodomain 1 reading H3K14ac, and bromodomain 2 reading H4K12ac—and recruits CRL4 to chromatin to facilitate replication licensing at a subset of origins that are non-redundant with SCF-SKP2–dependent origins; during mitosis, CRL4 dissociates from PHIP and partners with RBBP7 to ubiquitinate BUB3, enabling spindle assembly checkpoint silencing and mitotic exit (PMID:30018425, PMID:31911655, PMID:34819353). Beyond ubiquitin ligase functions, PHIP directly enhances POMC transcription to regulate energy homeostasis, promotes pancreatic beta-cell proliferation through cyclin D2 upregulation and PKB/AKT activation, and drives cancer cell invasion by physically interacting with vinculin at the force transduction layer of focal adhesions (PMID:17636024, PMID:32492392, PMID:32273388). De novo heterozygous loss-of-function PHIP variants cause a neurodevelopmental syndrome featuring intellectual disability, obesity, and dysmorphic features that phenotypically overlaps with CUL4B deficiency (PMID:27900362).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2006 High

    Identifying PHIP/DCAF14 as a WD40-repeat substrate receptor of the CRL4 ubiquitin ligase established the molecular framework through which PHIP connects to the ubiquitin–proteasome system.

    Evidence Tandem affinity purification of DDB1/CUL4A complexes followed by mass spectrometry in human cells

    PMID:16964240

    Open questions at the time
    • Substrates recruited by PHIP/DCAF14 to CRL4 were unknown
    • How PHIP engages chromatin was uncharacterized
    • Physiological functions of PHIP-CRL4 were not addressed
  2. 2007 High

    Demonstrating that the full-length PHIP1 isoform transcriptionally upregulates cyclin D2 and activates PKB/AKT to promote beta-cell proliferation and survival revealed a first physiological role for PHIP in cell growth control.

    Evidence RNAi knockdown, overexpression, cyclin D2 promoter-reporter assays, dominant-negative PKB epistasis, and apoptosis assays in pancreatic beta cells

    PMID:17636024

    Open questions at the time
    • Whether the proliferative function depends on CRL4 association was not tested
    • Mechanism of cyclin D2 transcriptional activation was not resolved
    • In vivo beta-cell phenotype was not assessed
  3. 2010 High

    PHIP1-knockout mice revealed an essential, IGF-1/AKT-independent role for PHIP in postnatal growth, separating its in vivo growth function from the AKT pathway previously implicated in beta cells.

    Evidence Conditional knockout mouse model with MEF proliferation assays, AKT phosphorylation, and IGF-1 stimulation

    PMID:20816727

    Open questions at the time
    • The AKT-independent mechanism driving postnatal growth remained unknown
    • Tissue-specific contributions to the growth phenotype were not dissected
  4. 2012 High

    PHIP was shown to contain functional bromodomains recognizing acetylated histones, and its suppression inhibited melanoma metastasis in vivo, linking its chromatin-reading capacity to cancer progression.

    Evidence X-ray crystallography of bromodomain family, histone peptide arrays, shRNA knockdown in melanoma cell lines, mouse xenograft survival studies, copy number analysis

    PMID:22464331 PMID:22511720

    Open questions at the time
    • Specific acetyl-histone marks read by PHIP bromodomains were not fully defined
    • Whether the metastatic role depended on CRL4 recruitment was untested
  5. 2016 Low

    Identification of de novo loss-of-function PHIP variants in patients with intellectual disability, obesity, and dysmorphic features established PHIP haploinsufficiency as the basis of a neurodevelopmental syndrome overlapping CUL4B deficiency.

    Evidence Whole-exome sequencing and clinical phenotyping of affected individuals

    PMID:27900362

    Open questions at the time
    • Causal mechanism linking PHIP haploinsufficiency to neurodevelopmental phenotypes was not established beyond genotype–phenotype correlation
    • Functional impact of individual patient variants on CRL4 pathway was not tested
    • Independent replication cohort was limited
  6. 2017 High

    Genome-wide colocalization of PHIP with H3K4 methylation and identification of the CryptoTudor domain as a direct H3K4me reader revealed how PHIP is targeted to chromatin, connecting its CRL4 substrate receptor function to a specific epigenetic mark.

    Evidence ChIP-seq across human cells, mouse ES cells, and Drosophila; direct peptide-binding assays; CRISPR-Cas9 COMPASS knockouts; Drosophila dBRWD3 depletion with H3K27ac profiling

    PMID:29089422

    Open questions at the time
    • Contributions of bromodomains to chromatin targeting were not resolved
    • Functional consequences of CRL4 recruitment at H3K4me-marked sites were unknown
  7. 2018 High

    Characterization of PHIP's bromodomain 2 as an H4K91ac reader and demonstration that PHIP recruits CRL4 to replication origins—where its loss forces reliance on the alternative SCF-SKP2 pathway—revealed PHIP's essential role in DNA replication licensing and a synthetic-lethal vulnerability.

    Evidence Bromodomain-histone peptide array binding, siRNA/knockout replication assays, origin mapping, SKP2 inhibitor sensitivity and re-replication assays

    PMID:29866840 PMID:30018425

    Open questions at the time
    • Direct CRL4 substrates at replication origins were not identified
    • Structural basis for origin-specific vs. SKP2-origin targeting was unresolved
  8. 2020 High

    Three concurrent advances resolved PHIP's roles in mitotic checkpoint control (via CRL4-RBBP7–mediated BUB3 ubiquitination), POMC transcription for energy homeostasis, and focal adhesion force transduction (via vinculin interaction), greatly expanding the functional repertoire beyond replication licensing.

    Evidence Co-IP and ubiquitination assays for BUB3 substrate identification; mitotic exit timing and paclitaxel sensitivity assays; POMC transcription reporter assays with disease-associated variants; confocal microscopy, Co-IP of PHIP–VCL, shRNA with TLN1/ZYX rescue, and intracranial xenograft

    PMID:31911655 PMID:32273388 PMID:32492392

    Open questions at the time
    • How CRL4 switches from RepID-dependent chromatin tethering to RBBP7-dependent mitotic activity is mechanistically unclear
    • Direct transcriptional mechanism of POMC activation by PHIP is unresolved
    • Whether the focal adhesion function requires CRL4 activity or is CRL4-independent is unknown
  9. 2021 High

    Reconstitution with semisynthetic nucleosomes defined PHIP's trivalent chromatin-reading module (CryptoTudor for H3K4me, BD1 for H3K14ac, BD2 for H4K12ac) and showed that neurodevelopmental and cancer-associated mutations disrupt these interactions, unifying the chromatin-targeting mechanism with human disease.

    Evidence Semisynthetic nucleosome binding assays with defined histone PTMs, disease-variant mutagenesis, CRL4 chromatin recruitment assays

    PMID:34819353

    Open questions at the time
    • No high-resolution structure of full-length PHIP on a nucleosome exists
    • Quantitative contribution of each reader domain to in vivo chromatin occupancy is not established
    • Whether all three marks must co-occur on the same nucleosome or can be read in trans is unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • The direct CRL4 substrates at replication origins, the structural basis for PHIP's chromatin-to-focal-adhesion shuttling, and the mechanism by which PHIP activates POMC transcription remain major open questions.
  • CRL4 substrates at replication origins have not been identified
  • No structural model of full-length PHIP exists
  • Mechanism of POMC transcriptional activation is undefined
  • Relationship between CRL4-dependent and CRL4-independent PHIP functions is unexplored

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0042393 histone binding 4 GO:0060090 molecular adaptor activity 3 GO:0140110 transcription regulator activity 2
Localization
GO:0005694 chromosome 3 GO:0005634 nucleus 2 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 2 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
Partners
BUB3CUL4ADDB1RBBP7TLN1VCL
Complex memberships
CRL4 (CUL4-DDB1-ROC1)

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 A larger 1,821-aa WD40 repeat-containing isoform of PHIP (PHIP1) is expressed in pancreatic beta-cell nuclei. PHIP1 overexpression stimulates IGF-1-dependent and -independent beta-cell proliferation by transcriptionally upregulating cyclin D2. RNAi knockdown of PHIP1 abrogates IRS2-mediated DNA synthesis. PHIP1 overexpression also blocks free fatty acid-induced apoptosis via activation of PKB/AKT and inhibition of caspase-9/-3 cleavage; dominant-negative PKB attenuates this cytoprotection. Cloning/immunoblotting, RNAi knockdown, cyclin D2 promoter-reporter assay, overexpression with dominant-negative PKB, apoptosis assays (caspase cleavage) Molecular and cellular biology High 17636024
2010 Mice lacking PHIP1 (the full-length isoform) are born at normal size but develop a ~40% postnatal growth deficit by weaning, hypoglycemia, and die at 4–5 weeks. PHIP1-deficient mouse embryonic fibroblasts proliferate markedly slower than wild-type but show normal AKT phosphorylation and increased cell proliferation in response to IGF-1, indicating PHIP1 regulates postnatal growth in an IGF-1/AKT pathway-independent manner. Conditional knockout mouse model, MEF proliferation assays, AKT phosphorylation western blot, IGF-1 stimulation FEBS letters High 20816727
2012 PHIP promotes melanoma metastasis; systemic shRNA targeting of Phip inhibited metastatic progression in vivo. Stable suppression of Phip in melanoma cell lines suppressed metastatic potential and prolonged survival of tumor-bearing mice. PHIP locus is preserved (not deleted) and overexpressed in melanoma, and elevated PHIP copy number was found in a high proportion of PHIP-overexpressing melanomas. Plasmid-based shRNA in vivo, stable shRNA knockdown in melanoma cell lines, mouse xenograft survival studies, copy number analysis Proceedings of the National Academy of Sciences of the United States of America High 22511720
2017 BRWD2/PHIP colocalizes with histone H3K4 methylation genome-wide in human cells, mouse embryonic stem cells, and Drosophila. PHIP biochemically associates with the CRL4 (Cullin-4-RING ubiquitin E3 ligase) complex, nucleosomes, and chromatin remodelers. PHIP binds directly to H3K4 methylation through a previously unidentified chromatin-binding module related to Royal Family Tudor domains, named the CryptoTudor domain. COMPASS H3K4 methyltransferase family members differentially regulate BRWD2/PHIP chromatin occupancy. Depletion of the Drosophila homolog dBRWD3 results in altered gene expression and aberrant H3K27 acetylation at enhancers and promoters. ChIP-seq (genome-wide colocalization), biochemical pulldown/Co-IP (CRL4 complex, nucleosomes), direct binding assay with H3K4me peptides, CRISPR-Cas9 knockouts, Drosophila dBRWD3 depletion with gene expression and H3K27ac profiling Genes & development High 29089422
2018 PHIP's bromodomain is functional and specifically binds the histone modification H4K91ac. Suppression of PHIP significantly inhibited tumor cell proliferation and invasion in melanoma, triple-negative/basal-like breast cancer, and bronchioid NSCLC cell lines, coordinately suppressing phosphorylated AKT, cyclin D1, and talin1. Bromodomain binding assay (histone peptide array), shRNA suppression with proliferation and invasion assays, western blot for downstream effectors Proceedings of the National Academy of Sciences of the United States of America High 29866840
2018 RepID/DCAF14/PHIP recruits the CRL4 ubiquitin ligase complex to chromatin prior to DNA synthesis, playing a crucial architectural role in licensing chromosomes for replication. In the absence of RepID, cells rely on the alternative ubiquitin ligase SKP2-containing SCF complex 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 (siRNA/knockout), chromatin fractionation, origin-firing assays, SKP2 inhibitor sensitivity, re-replication assays, origin mapping Nature communications High 30018425
2020 PHIP drives glioblastoma motility and invasion through effects on the force transduction layer of the focal adhesion complex. PHIP localizes to the leading edge of glioblastoma cells and to the force transduction layer specifically, co-localizing with talin 1 (TLN1), vinculin (VCL), integrin beta 1, paxillin (pPXN), and focal adhesion kinase (pFAK). Co-immunoprecipitation revealed a physical interaction between PHIP and VCL. PHIP silencing down-regulated these focal adhesion proteins and zyxin (ZYX), and produced disorganized stress fibers. PHIP knockdown suppressed tumor growth in intracranial implantation and reduced microvessel density and secreted VEGF levels. Migratory/invasive capacity was partially restored by TLN1 or ZYX cDNA overexpression. Immunofluorescence and confocal microscopy (localization), co-immunoprecipitation (PHIP–VCL interaction), shRNA knockdown, live-cell imaging (ZYX-GFP focal adhesion dynamics), rescue by cDNA overexpression, intracranial xenograft Proceedings of the National Academy of Sciences of the United States of America High 32273388
2020 Nuclear PHIP directly enhances transcription of pro-opiomelanocortin (POMC), a neuropeptide that suppresses appetite. Obesity-associated PHIP variants (identified by exome sequencing) repressed POMC transcription in cell-based assays, linking PHIP haploinsufficiency to disrupted central melanocortin signaling and human energy homeostasis. Exome sequencing (variant identification), cell-based POMC transcription assays with wild-type and variant PHIP constructs Cell metabolism Medium 32492392
2020 RepID/PHIP is required for CRL4 recruitment to chromatin. During mitosis, CRL4 dissociates from RepID and associates with RBBP7, which ubiquitinates the spindle assembly checkpoint (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-IP (RepID–CRL4–RBBP7 interactions), ubiquitination assay (BUB3 as substrate), RNAi/KO depletion, mitotic exit timing assays, genomic instability and drug sensitivity assays Nature communications High 31911655
2021 PHIP is a chromatin-associated CRL4 ubiquitin ligase substrate receptor required for CRL4 recruitment to chromatin. PHIP binds chromatin through a trivalent reader module: a CryptoTudor domain (H3K4-methyl binding), bromodomain 1 (BD1, reader of H3K14ac), and bromodomain 2 (BD2, reader of H4K12ac). These interactions were characterized using semisynthetic nucleosomes with defined histone post-translational modifications. Human disease-associated (neurodevelopmental disorder/cancer) mutations map to each domain and the intervening linker region and likely disrupt chromatin binding. Semisynthetic nucleosome binding assays with defined PTMs, bromodomain binding characterization, disease-variant mutagenesis, CRL4 chromatin recruitment assays Genes & development High 34819353
2016 PHIP haploinsufficiency (via de novo heterozygous frameshift, nonsense, and missense variants) causes a syndrome of developmental delay, intellectual disability, obesity, anxiety, hypotonia, and dysmorphic features. The phenotype overlaps with CUL4B deficiency, suggesting PHIP mutations cause disease through disruption of the ubiquitin ligase pathway. PHIP produces multiple protein products including PHIP1/DCAF14 (a CUL4-DDB1 substrate receptor) and NDRP. Whole-exome sequencing, clinical phenotyping, genotype-phenotype correlation Cold Spring Harbor molecular case studies Low 27900362
2006 The DDB1-CUL4A-ROC1 ubiquitin ligase complex uses a novel family of WD40-repeat proteins as substrate-recruiting modules; PHIP/DCAF14 is among the DCAFs (DDB1- and CUL4-associated factors) identified by tandem-affinity purification of human DDB1 and CUL4A complexes followed by mass spectrometry, establishing PHIP as a substrate receptor of the CRL4 E3 ligase. Tandem affinity purification of DDB1/CUL4A complexes, mass spectrometry identification of WD40-repeat DCAFs, crystallographic analysis of DDB1 complex Nature High 16964240
2012 Large-scale structural analysis of the human bromodomain family identified PHIP as containing bromodomains. Crystal structures were determined for BRD family members and cross-family screening against histone-peptide arrays revealed acetylation-dependent substrate recognition; flanking PTMs influence bromodomain binding, suggesting BRDs recognize combinations of marks. X-ray crystallography (29 BRD structures), histone peptide array screening Cell Medium 22464331

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2012 Histone recognition and large-scale structural analysis of the human bromodomain family. Cell 1328 22464331
2012 Diagnostic exome sequencing in persons with severe intellectual disability. The New England journal of medicine 1245 23033978
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2006 Molecular architecture and assembly of the DDB1-CUL4A ubiquitin ligase machinery. Nature 585 16964240
2006 A family of diverse Cul4-Ddb1-interacting proteins includes Cdt2, which is required for S phase destruction of the replication factor Cdt1. Molecular cell 538 16949367
2015 A Dynamic Protein Interaction Landscape of the Human Centrosome-Cilium Interface. Cell 433 26638075
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
1997 The prostate: a target for carcinogenicity of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) derived from cooked foods. Cancer research 323 9000552
2010 Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. Cell 318 21145461
2013 The functional interactome landscape of the human histone deacetylase family. Molecular systems biology 235 23752268
2014 Proximity biotinylation and affinity purification are complementary approaches for the interactome mapping of chromatin-associated protein complexes. Journal of proteomics 215 25281560
2015 Screen identifies bromodomain protein ZMYND8 in chromatin recognition of transcription-associated DNA damage that promotes homologous recombination. Genes & development 203 25593309
2011 Identification and characterization of a set of conserved and new regulators of cytoskeletal organization, cell morphology and migration. BMC biology 164 21834987
2020 Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders. Nature communications 161 33004838
2004 Proteomics analysis of the centromere complex from HeLa interphase cells: UV-damaged DNA binding protein 1 (DDB-1) is a component of the CEN-complex, while BMI-1 is transiently co-localized with the centromeric region in interphase. Genes to cells : devoted to molecular & cellular mechanisms 151 15009096
2020 A High-Density Human Mitochondrial Proximity Interaction Network. Cell metabolism 148 32877691
2018 PhIP-Seq characterization of serum antibodies using oligonucleotide-encoded peptidomes. Nature protocols 147 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
2012 Functional proteomics establishes the interaction of SIRT7 with chromatin remodeling complexes and expands its role in regulation of RNA polymerase I transcription. Molecular & cellular proteomics : MCP 145 22586326
2019 Mapping the proximity interaction network of the Rho-family GTPases reveals signalling pathways and regulatory mechanisms. Nature cell biology 137 31871319
2018 Interactome Rewiring Following Pharmacological Targeting of BET Bromodomains. Molecular cell 136 30554943
2000 Shotgun sequencing of the human transcriptome with ORF expressed sequence tags. Proceedings of the National Academy of Sciences of the United States of America 135 10737800
2014 The central role of EED in the orchestration of polycomb group complexes. Nature communications 131 24457600
2013 Proteomic analysis of podocyte exosome-enriched fraction from normal human urine. Journal of proteomics 126 23376485
1989 Genotoxicity of the food mutagen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP): formation of 2-hydroxamino-PhIP, a directly acting genotoxic metabolite. Carcinogenesis 121 2665964
2019 Systematic bromodomain protein screens identify homologous recombination and R-loop suppression pathways involved in genome integrity. Genes & development 110 31753913
2011 Parahydrogen-induced polarization (PHIP) hyperpolarized MR receptor imaging in vivo: a pilot study of 13C imaging of atheroma in mice. NMR in biomedicine 98 21538638
1992 Formation of DNA adducts of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in male Fischer-344 rats. Cancer letters 87 1483260
1997 Chemoprotection against the formation of colon DNA adducts from the food-borne carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in the rat. Mutation research 85 9202746
1993 Enzymatic phase II activation of the N-hydroxylamines of IQ, MeIQx and PhIP by various organs of monkeys and rats. Carcinogenesis 82 8222059
2001 The role of human glutathione S-transferases (hGSTs) in the detoxification of the food-derived carcinogen metabolite N-acetoxy-PhIP, and the effect of a polymorphism in hGSTA1 on colorectal cancer risk. Mutation research 79 11535243
1990 Activation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) to mutagenic metabolites. Carcinogenesis 78 2197012
2005 Differential metabolism of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in mice humanized for CYP1A1 and CYP1A2. Chemical research in toxicology 76 16167840
1997 Carcinogenicity of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in the rat. Mutation research 75 9202745
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
1996 Mutational spectra of the dietary carcinogen 2-amino-1-methyl-6- phenylimidazo[4,5-b]pyridine(PhIP) at the Chinese hamsters hprt locus. Carcinogenesis 65 8625468
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 Exome Sequencing Identifies Genes and Gene Sets Contributing to Severe Childhood Obesity, Linking PHIP Variants to Repressed POMC Transcription. Cell metabolism 62 32492392
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
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
2020 Identification of novel, clinically correlated autoantigens in the monogenic autoimmune syndrome APS1 by proteome-wide PhIP-Seq. eLife 55 32410729
2016 De novo PHIP-predicted deleterious variants are associated with developmental delay, intellectual disability, obesity, and dysmorphic features. Cold Spring Harbor molecular case studies 55 27900362
2008 ABCG2/BCRP decreases the transfer of a food-born chemical carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in perfused term human placenta. Toxicology and applied pharmacology 55 18680760
2005 Coffee diterpenes prevent the genotoxic effects of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and N-nitrosodimethylamine in a human derived liver cell line (HepG2). Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 55 15680679
2002 Molecular and genetic toxicology of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Mutation research 54 12351148
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 54 12438004
2007 A comprehensive investigation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) metabolism in the mouse using a multivariate data analysis approach. Chemical research in toxicology 51 17279779
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
2018 Metabolic Studies of Tumor Cells Using [1-13 C] Pyruvate Hyperpolarized by Means of PHIP-Side Arm Hydrogenation. Chemphyschem : a European journal of chemical physics and physical chemistry 46 30248218
2017 A genotype-first approach identifies an intellectual disability-overweight syndrome caused by PHIP haploinsufficiency. European journal of human genetics : EJHG 44 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
2004 Human UDP-glucuronosyltransferase 1A1 is the primary enzyme responsible for the N-glucuronidation of N-hydroxy-PhIP in vitro. Chemical research in toxicology 44 15310245
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
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
2000 Effect of diet on serum albumin and hemoglobin adducts of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in humans. International journal of cancer 42 10962432
2013 Combined genotoxic effects of a polycyclic aromatic hydrocarbon (B(a)P) and an heterocyclic amine (PhIP) in relation to colorectal carcinogenesis. PloS one 41 23484039
2018 The replication initiation determinant protein (RepID) modulates replication by recruiting CUL4 to chromatin. Nature communications 40 30018425
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 40 22511720
2002 Mammary gland carcinogenesis by food-derived heterocyclic amines and studies on the mechanisms of carcinogenesis of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Mutation research 40 12351154
2022 Autoantibody discovery across monogenic, acquired, and COVID-19-associated autoimmunity with scalable PhIP-seq. eLife 39 36300623
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
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
2016 DNA damage response curtails detrimental replication stress and chromosomal instability induced by the dietary carcinogen PhIP. Nucleic acids research 33 27599846
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 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
1994 Removal of DNA adducts of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in the male Fischer-344 rat. Carcinogenesis 32 7955116
2020 The RepID-CRL4 ubiquitin ligase complex regulates metaphase to anaphase transition via BUB3 degradation. Nature communications 31 31911655
1992 Metabolism of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in mice. Carcinogenesis 31 1576715
2021 A trivalent nucleosome interaction by PHIP/BRWD2 is disrupted in neurodevelopmental disorders and cancer. Genes & development 30 34819353
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
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 29 12856103
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
2019 Ultrafast Single-Scan 2D NMR Spectroscopic Detection of a PHIP-Hyperpolarized Protease Inhibitor. Chemistry (Weinheim an der Bergstrasse, Germany) 26 30698310
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
1997 Reduction in formation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced aberrant crypt foci in the rat colon by docosahexaenoic acid (DHA). Carcinogenesis 26 9364003
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 25 29866840
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
2002 2-Amino-1-methyl-6-(5-hydroxy-)phenylimidazo[4,5-b]pyridine (5-OH-PhIP), a biomarker for the genotoxic dose of the heterocyclic amine, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 25 12067574
2020 In-vitro NMR Studies of Prostate Tumor Cell Metabolism by Means of Hyperpolarized [1-13C]Pyruvate Obtained Using the PHIP-SAH Method. Frontiers in oncology 24 32363160
1996 Short-term carcinogenicity testing of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) in E(mu)-pim-1 transgenic mice. Carcinogenesis 24 8895492
1993 Metabolism of the food-derived mutagen/carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in nonhuman primates. Carcinogenesis 24 8269621
2000 More frequent beta-catenin gene mutations in adenomas than in aberrant crypt foci or adenocarcinomas in the large intestines of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-treated rats. Japanese journal of cancer research : Gann 23 10965019
2019 Clinical and genetic characterization of individuals with predicted deleterious PHIP variants. Cold Spring Harbor molecular case studies 22 31167805
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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 21 34582963
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
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
2010 The full-length isoform of the mouse pleckstrin homology domain-interacting protein (PHIP) is required for postnatal growth. FEBS letters 20 20816727
2004 Inhibitory effects of beer on heterocyclic amine-induced mutagenesis and PhIP-induced aberrant crypt foci in rat colon. Mutation research 20 15066585
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
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2005 Induction of colon tumors in C57BL/6J mice fed MeIQx, IQ, or PhIP followed by dextran sulfate sodium treatment. Toxicological sciences : an official journal of the Society of Toxicology 19 15635146
1998 Bioactivation of the proximal food mutagen 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine (N-OH-PhIP) to DNA-binding species by human mammary gland enzymes. Nutrition (Burbank, Los Angeles County, Calif.) 19 9760588
1995 DNA-binding and disposition of 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine (PhIP) in the rat. Carcinogenesis 19 7586200
2015 Protective activity of probiotic bacteria against 2-amino-3-methyl-3H-imidazo[4,5-f]quinoline (IQ) and 2-amino-1-methyl-6-phenyl-1H-imidazo[4,5-b]pyridine (PhIP) - an in vitro study. Food additives & contaminants. Part A, Chemistry, analysis, control, exposure & risk assessment 18 26295367
2007 Racial differences in clinical and pathological associations with PhIP-DNA adducts in prostate. International journal of cancer 18 17487839
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1999 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) retards mammary gland involution in lactating Sprague-Dawley rats. Carcinogenesis 18 10383905
1998 Inhibition of DNA adduct formation of PhIP in female F344 rats by dietary conjugated linoleic acid. Nutrition and cancer 18 10050262
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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
2007 New insights in the formation of deoxynucleoside adducts with the heterocyclic aromatic amines PhIP and IQ by means of ion trap MSn and accurate mass measurement of fragment ions. Journal of the American Society for Mass Spectrometry 17 17936011
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