Affinage

FHIT

Bis(5'-adenosyl)-triphosphatase · UniProt P49789

Length
147 aa
Mass
16.9 kDa
Annotated
2026-06-09
100 papers in source corpus 24 papers cited in narrative 24 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/7 claims corpus-supported (86%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FHIT is a genome-caretaker tumor suppressor that protects against replication stress while operating in parallel as a signaling and pro-apoptotic factor, and its biochemical hydrolase activity is dispensable for its tumor-suppressive functions (PMID:9391102, PMID:23209436). Although recombinant FHIT is a homodimeric Ap3A hydrolase (PMID:10733886), both wild-type and active-site (His-mutant) FHIT suppress tumorigenicity, dissociating dinucleotide hydrolysis from growth suppression (PMID:9391102). Its principal caretaker role is preventing DNA replication stress: FHIT loss causes replication fork stalling and collapse and double-strand breaks driven by dysregulated Thymidine Kinase 1 expression and thymidine triphosphate pool imbalance, defects rescued by restoring nucleotide balance and dependent on Chk1 activity but independent of ATR/ATM (PMID:23209436, PMID:23102829). This replication stress generates single-stranded DNA that becomes a substrate for APOBEC3B-mediated mutagenesis, and nucleotide supplementation reduces APOBEC-directed mutations (PMID:25401976). FHIT activity converges on the conserved Y114 residue, which is phosphorylated by Src and required for caspase-dependent apoptosis through inhibition of the PI3K-Akt-survivin pathway and modulation of the mid-S-phase Hus1/Chk1 checkpoint (PMID:15007172, PMID:16407838, PMID:17145874). FHIT localizes to cytoplasm and mitochondria, where it interacts with Hsp60/Hsp10 and stabilizes ferredoxin reductase (Fdxr) to promote ROS production and apoptosis under oxidative stress (PMID:19004824, PMID:19486340). It also represses oncogenic transcription, binding the C-terminal domain of β-catenin to repress Wnt target genes independent of hydrolase activity (PMID:18077326), and suppresses EMT and metastasis through miR-30c upregulation and downregulation of the EGFR/Src/ERK/Slug axis (PMID:25340791, PMID:24464917).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1997 High

    Established that FHIT's enzymatic Ap3A hydrolase activity is separable from its tumor-suppressive function, redirecting the field away from a purely metabolic enzyme model.

    Evidence In vitro hydrolase assay with active-site mutagenesis plus nude mouse tumorigenicity assay of FHIT-transfected cells

    PMID:9391102

    Open questions at the time
    • Did not identify the non-catalytic effector function responsible for tumor suppression
    • Mechanism of growth suppression unresolved
  2. 2000 High

    Defined the biochemical parameters of FHIT as a homodimeric Ap3A asymmetric hydrolase, providing rigorous kinetic characterization of the purified enzyme.

    Evidence Recombinant E. coli expression, purification, and Ap3A hydrolysis kinetics

    PMID:10733886

    Open questions at the time
    • Does not connect enzymatic activity to any cellular function
    • In vivo substrate not established
  3. 2004 High

    Placed FHIT in a Src signaling pathway by identifying it as a Src substrate phosphorylated at Y114, a residue that became central to its regulatory functions.

    Evidence In vitro kinase assay, in vivo phosphorylation, and site-directed mutagenesis

    PMID:15007172

    Open questions at the time
    • Functional consequence of Y114 phosphorylation not defined in this study
    • Single kinase identified; broader regulatory network unknown
  4. 2004 Medium

    Demonstrated that FHIT loss produces a mutator phenotype with resistance to DNA-damaging agents, framing FHIT as a guardian of genome integrity.

    Evidence Matched Fhit-positive/negative cancer pairs and Fhit knockout mouse cells; clonogenic survival and mutation frequency assays

    PMID:15494723

    Open questions at the time
    • Molecular basis of the mutator phenotype not yet identified
    • Did not link to replication or checkpoint machinery
  5. 2006 High

    Connected FHIT's Y114-dependent apoptotic activity to suppression of the PI3K-Akt-survivin survival pathway and to mid-S-phase checkpoint modulation (Hus1/phospho-Chk1).

    Evidence Adenoviral wild-type vs. Y114 mutant FHIT, caspase and Akt activity assays, constitutively active Akt rescue, and Western blot for checkpoint proteins

    PMID:16407838 PMID:17145874

    Open questions at the time
    • Direct enzymatic or binding link between FHIT and Akt/Hus1 not established
    • Whether Y114 phosphorylation drives or merely permits these effects unclear
  6. 2006 Medium

    Extended FHIT signaling output to NF-κB inhibition and to enhancement of chemotherapy-induced apoptosis via Bcl-2 family modulation, broadening its pro-apoptotic repertoire.

    Evidence Gain- and loss-of-function FHIT in colon and other cancer cells; Western blot for p-IκB-α and Bcl-2 family; caspase assays

    PMID:16231322 PMID:16733051

    Open questions at the time
    • Direct molecular targets in NF-κB and apoptotic pathways not identified
    • Single-lab correlative readouts
  7. 2007 High

    Identified a direct transcriptional repression function: FHIT binds β-catenin to repress Wnt target genes independent of hydrolase activity, providing a non-enzymatic tumor-suppressive mechanism.

    Evidence Reciprocal Co-IP, ChIP, double knockdown, reporter and soft-agar assays with enzymatically inactive H96N mutant

    PMID:18077326

    Open questions at the time
    • How cytoplasmic/mitochondrial FHIT accesses promoter complexes unresolved
    • Structural basis of β-catenin binding not defined
  8. 2007 Medium

    Showed FHIT protects against HER2-driven tumors and that its protein levels are downregulated by EGFR/HER2-driven proteasomal degradation, establishing a feedback link between oncogenic signaling and FHIT loss.

    Evidence Fhit+/- x MMTV-HER2/neu mouse cross; proteasome inhibitor experiments; IHC of human breast carcinomas

    PMID:17374991

    Open questions at the time
    • E3 ligase mediating FHIT degradation not identified
    • Degradation signal/modification not mapped
  9. 2008 High

    Localized FHIT's pro-apoptotic, oxidative-stress function to mitochondria via Hsp60/Hsp10 chaperone interactions and stabilization of ferredoxin reductase (Fdxr), tying substrate-binding and Y114 competence to ROS-induced death.

    Evidence Chemical cross-linking, Co-IP, mutagenesis, subcellular fractionation, and ROS/apoptosis flow cytometry

    PMID:19004824 PMID:19486340

    Open questions at the time
    • Mechanism of Fdxr stabilization not biochemically defined
    • How chaperone interaction directs mitochondrial import unclear
  10. 2009 Medium

    Demonstrated through double-knockout mice that FHIT and Nit1, encoded together as a NitFhit fusion in invertebrates, act through distinct but additive tumor-suppressive pathways in mammals.

    Evidence Fhit-/-Nit1-/- double-knockout mouse tumor susceptibility; fractionation; hydroxyurea/H2O2 treatment

    PMID:19479888 PMID:9671749

    Open questions at the time
    • The distinct Nit1 pathway not molecularly defined
    • Whether the two ever physically cooperate in mammals unknown
  11. 2012 High

    Established the core caretaker mechanism: FHIT loss drives replication stress and double-strand breaks via TK1/dTTP pool imbalance, with damage prevention requiring the HIT domain, Y114, and Chk1 but not ATR/ATM.

    Evidence DNA combing, siRNA, TK1 and thymidine rescue, γH2AX, knockout mouse tissue, and Chk1/ATR/ATM inhibitor/knockdown

    PMID:23102829 PMID:23209436

    Open questions at the time
    • How FHIT regulates TK1 expression mechanistically not defined
    • Connection between hydrolase HIT domain and nucleotide pool control unresolved
  12. 2014 Medium

    Linked FHIT loss to EMT and metastasis through two pathways: failure to upregulate miR-30c (targeting MTDH/HMGA2/VIM/FN1) and de-repression of the EGFR/Src/ERK/Slug axis.

    Evidence In vivo/in vitro invasion and metastasis assays, miR-30c target validation, and pharmacologic/genetic pathway dissection

    PMID:24464917 PMID:25340791

    Open questions at the time
    • How FHIT controls miR-30c expression not established
    • Direct vs. indirect regulation of EGFR axis unclear
  13. 2015 Medium

    Showed FHIT-driven replication stress generates ssDNA exploited by APOBEC3B, mechanistically connecting FHIT loss to a defined mutational signature reversible by nucleotide supplementation.

    Evidence TCGA correlation with in vitro knockdown, APOBEC3B-directed TP53 mutation assay, and thymidine rescue

    PMID:25401976

    Open questions at the time
    • Correlative tumor data not causal in vivo
    • Generality across mutation signatures unknown
  14. 2015 Medium

    Revealed a context-dependent nuclear role in which EGF-induced nuclear FHIT promotes proliferation, contrasting with its cytoplasmic tumor-suppressive activity.

    Evidence Subcellular fractionation, NLS-fusion constructs, proteasome inhibitor and Y114F mutant analysis with proliferation marker Western blots

    PMID:25711523

    Open questions at the time
    • Reconciliation with earlier non-nuclear localization reports incomplete
    • Mechanism of nuclear FHIT's proliferative effect undefined
  15. 2017 Medium

    Connected FHIT to post-transcriptional regulation by showing FHIT status alters ribosome occupancy of hundreds of cancer-associated mRNAs.

    Evidence Ribosome profiling in matched Fhit-positive/negative cells with mRNA steady-state measurement

    PMID:29282095

    Open questions at the time
    • Direct molecular link between FHIT hydrolase activity and translation not shown
    • Causal targets driving phenotype not isolated
  16. 2019 Medium

    Identified FHIT as a genetic modifier of BMPR2 signaling relevant to pulmonary arterial hypertension, extending its role beyond cancer.

    Evidence Genome-scale siRNA screen, Fhit-/- mouse hypoxia model, and in vitro cell dysfunction assays

    PMID:30107138

    Open questions at the time
    • Molecular mechanism linking FHIT to BMPR2 signaling not defined
    • Direct interaction vs. indirect modifier role unresolved
  17. 2021 Medium

    Provided a pharmacological handle by showing tanshinone compounds bind FHIT and inhibit its hydrolase activity, with FHIT required for tanshinone-induced apoptosis.

    Evidence Surface plasmon resonance binding, in vitro hydrolase inhibition, FHIT siRNA, and apoptosis assay

    PMID:34108553

    Open questions at the time
    • How hydrolase inhibition triggers apoptosis given enzyme-independent tumor suppression unclear
    • On-target specificity in vivo not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • The unifying biochemical mechanism that links FHIT's catalytic HIT domain to its diverse non-enzymatic functions (TK1/nucleotide control, β-catenin repression, mitochondrial apoptosis, translation) remains unresolved.
  • No structural model explaining how Y114 phosphorylation gates effector interactions
  • Direct in vivo substrate and the molecular route from hydrolase activity to caretaker function undefined
  • Apparent localization conflicts (cytoplasm/mitochondria vs. nucleus/plasma membrane) not mechanistically reconciled

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 3 GO:0140098 catalytic activity, acting on RNA 2 GO:0140110 transcription regulator activity 1
Localization
GO:0005739 mitochondrion 3 GO:0005829 cytosol 2 GO:0005634 nucleus 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-73894 DNA Repair 3 R-HSA-1640170 Cell Cycle 2
Partners
CHEK1CTNNB1FDXRHSPD1HSPE1HUS1SRC
Complex memberships
LEF1/TCF/β-catenin complex

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 Fhit hydrolyzes dinucleotide 5',5'''-P1,P3-triphosphate (Ap3A) in vitro; mutation of the central histidine abolishes hydrolase activity. However, both wild-type and hydrolase-dead Fhit mutant proteins suppressed tumorigenicity in nude mice, indicating that Ap3A hydrolysis is not required for tumor suppression. In vitro enzymatic assay; active-site mutagenesis; nude mouse tumorigenicity assay with FHIT-transfected cancer cell lines Proceedings of the National Academy of Sciences of the United States of America High 9391102
2004 Fhit is a physiological substrate of the Src protein kinase; Src phosphorylates Fhit at tyrosine 114 (Y114) both in vitro and in vivo, placing Fhit in a Src-dependent signaling pathway. In vitro kinase assay; in vivo phosphorylation; site-directed mutagenesis identifying Y114 as the phosphorylation site Proceedings of the National Academy of Sciences of the United States of America High 15007172
2006 Fhit Y114 is essential for caspase-dependent apoptosis; wild-type Fhit (but not Y114 mutants) inhibits Akt activity and reduces survivin expression in lung cancer cells, placing Fhit upstream of the PI3K-Akt-survivin survival pathway. Adenoviral expression of wild-type vs. Y114 mutant FHIT in lung cancer cell lines; caspase activation assays; expression profiling; Akt activity measurement in vitro and in vivo; constitutively active Akt rescue experiment Oncogene High 16407838
2006 Fhit modulates expression of checkpoint proteins Hus1 and phospho-Chk1 at mid-S phase; exogenous Fhit introduction induces apoptosis in esophageal cancer cells through this checkpoint modulation, and Y114 mutation abolishes this function. Exogenous Fhit expression in cancer cell lines; Western blot for Hus1 and phospho-Chk1; Y114 mutagenesis; apoptosis assays Cancer research Medium 17145874
2007 Fhit associates with the LEF1/TCF/β-catenin complex by directly binding to the β-catenin C-terminal domain, repressing transcription of Wnt target genes (cyclin D1, axin2, MMP-14, survivin); this function does not require Fhit's hydrolase activity; Fhit/β-catenin complexes are recruited to target gene promoters. Co-immunoprecipitation; ChIP; Fhit knockdown and double knockdown with β-catenin; reporter assays; soft-agar anchorage-independent growth assay; enzymatically inactive Fhit-H96N mutant Proceedings of the National Academy of Sciences of the United States of America High 18077326
2008 Fhit interacts with Hsp60/Hsp10 chaperone machinery (identified by chemical cross-linking and immunoprecipitation), and with ferredoxin reductase (Fdxr) in mitochondria; Fhit binds and stabilizes Fdxr, and this interaction promotes reactive oxygen species production and apoptosis under oxidative stress. Substrate-binding and Y114 phosphorylation-competent Fhit mutants are required for Hsp60 and Fdxr interactions and for mitochondrial localization. Chemical cross-linking; co-immunoprecipitation; mutagenesis of substrate-binding and Y114 residues; subcellular fractionation; flow cytometry for ROS and apoptosis The Journal of biological chemistry High 19004824
2012 Loss of Fhit expression causes DNA replication stress-induced double-strand breaks; Fhit-deficient cells show defective replication fork progression (fork stalling and collapse by DNA combing); the mechanism involves Fhit regulation of Thymidine Kinase 1 (TK1) expression and thymidine triphosphate pool levels—restoration of nucleotide balance rescues replication defects and suppresses DNA breakage. DNA combing (single-molecule replication fork analysis); siRNA knockdown; TK1 expression measurement; thymidine supplementation rescue; γH2AX foci; Fhit knockout mouse tissue analysis PLoS genetics High 23209436
2012 Fhit's ability to prevent DNA damage requires a functional HIT domain and Y114 residue, and depends on Chk1 kinase activity but is independent of ATR or ATM kinases, suggesting Fhit and Chk1 cooperate to prevent replication stress-induced DNA damage. HIT domain mutants; Y114 mutant; Chk1, ATR, ATM inhibitors/knockdown; DNA damage markers in Fhit-deficient cells Advances in biological regulation Medium 23102829
2009 Fhit localizes to both cytoplasm and mitochondria (but not nuclei) in normal tissue; Fhit-positive cancer cells exposed to oxidative stress (H2O2) produce higher levels of apoptosis-inducing ROS than matched Fhit-negative cells, a function linked to Fhit stabilization of mitochondrial Fdxr. Subcellular fractionation of normal and cancer cells; H2O2 treatment; ROS measurement; apoptosis assays in matched Fhit-positive vs. Fhit-negative cancer cells Cancer science Medium 19486340
2001 Fhit protein is localized to the nucleus and plasma membrane in rat tissues (by differential and density-gradient centrifugation of subcellular fractions), with expression levels varying by tissue type (highest in spleen and brain). Differential and density-gradient centrifugation; immunoblot of subcellular fractions; RT-PCR Molecular and cellular biochemistry Low 11768238
2015 Fhit loss-induced replication stress creates single-stranded DNA substrates optimal for APOBEC3B-mediated mutagenesis; FHIT-low/APOBEC3B-high tumors show significantly more APOBEC-signature mutations, and thymidine supplementation (rescuing TK1-dependent nucleotide imbalance) reduces APOBEC-directed TP53 mutations in vitro. TCGA data analysis correlated with in vitro Fhit knockdown; APOBEC3B-directed mutation assay in TP53; thymidine supplementation rescue Oncotarget Medium 25401976
2014 FHIT suppresses EMT and metastasis in lung cancer by upregulating miR-30c, which directly targets metastasis genes MTDH, HMGA2, VIM, and FN1; enforced FHIT expression reduces invasiveness in vivo and in vitro. In vivo metastasis assay; in vitro invasion assay; miR-30c target validation; ectopic FHIT expression; FHIT/miR-30c/target expression correlation in human tumors PLoS genetics Medium 25340791
2014 Fhit silencing in bronchial cells induces overexpression of MMP-9 and vimentin (EMT markers) via an EGFR/Src/ERK/Slug signaling axis; ectopic Fhit expression in Fhit-deficient lung cancer cells downregulates this pathway. Fhit siRNA knockdown; pharmacologic inhibitors (PD98059, PP1, gefitinib); anti-EGFR antibody; Slug knockdown; ectopic Fhit expression; IHC of human tumor specimens for Fhit/phospho-EGFR correlation Molecular cancer research : MCR Medium 24464917
2006 Fhit expression inhibits NF-κB signaling in colon cancer cells by reducing phosphorylation of IκB-α; FHIT-expressing cells show reduced basal p-IκB-α and attenuated NF-κB p65 phosphorylation in response to TNF-α. Stable FHIT transfection; FHIT siRNA knockdown; Western blot for IKK complex and p-IκB-α; TNF-α stimulation; NF-κB inhibitor sensitivity assays Experimental cell research Medium 16733051
2006 Fhit expression enhances paclitaxel-induced apoptosis through activation of caspase-3 and caspase-7 (but not caspase-8) and modulation of Bcl-2 family proteins (downregulation of Bcl-2/Bcl-xL; upregulation of Bax/Bad); this effect is reversed by FHIT siRNA. Stable FHIT transfection; FHIT siRNA; caspase activity assays; Western blot for Bcl-2 family; pan-caspase inhibitor International journal of cancer Medium 16231322
2009 Fhit and Nit1 tumor suppressor activities are additive in vivo (double-knockout mice develop more tumors than single knockouts), but Fhit and Nit1 affect distinct signal pathways in mammals; both proteins localize to cytoplasm and mitochondria but not nuclei. Fhit(-/-)Nit1(-/-) double-knockout mouse tumor susceptibility study; subcellular localization by fractionation; hydroxyurea and H2O2 treatment of double-deficient cells Journal of cellular biochemistry Medium 19479888
2000 Recombinant human Fhit protein is a homodimeric Ap3A asymmetric hydrolase with Km = 0.9 µM and kcat = 7.2 s⁻¹ per monomer, as measured by in vitro enzymatic assay of E. coli-expressed purified protein. Recombinant protein expression in E. coli; His-tag purification; in vitro enzymatic assay (Ap3A hydrolysis kinetics) Protein expression and purification High 10733886
2019 FHIT acts as a modifier of BMPR2 signaling; FHIT reduction is associated with endothelial and smooth muscle cell dysfunction in pulmonary arterial hypertension, and Fhit-/- mice show exaggerated hypoxic pulmonary hypertension and failed recovery. siRNA high-throughput screen of >20,000 genes identifying FHIT as BMPR2 modifier; Fhit-/- mouse hypoxia model; in vitro cell dysfunction assays American journal of respiratory and critical care medicine Medium 30107138
2004 Fhit-deficient cells (human cancer and Fhit-/- mouse) are ~10-fold more resistant to UVC and mitomycin C-induced killing than matched Fhit-positive cells; Fhit-/- cells exhibit greater than 5-fold increased mutation frequency after UVC survival, indicating Fhit loss promotes a mutator phenotype. Matched Fhit-positive vs. Fhit-negative cancer cell pairs and Fhit-/- vs. Fhit+/+ mouse kidney cells; clonogenic survival assays; synchronization; DNA synthesis measurement; mutation frequency assays British journal of cancer Medium 15494723
2015 Fhit expression is present in the nucleus of breast cancer cells at low levels; mitogenic (EGF) stimulation increases nuclear Fhit; forced nuclear localization of Fhit (via nuclear localization sequence) increases proliferation rate and levels of cyclin D1, phospho-MAPK, and phospho-STAT3, suggesting a proliferation-promoting role for nuclear Fhit distinct from cytoplasmic tumor suppression. Subcellular fractionation; nuclear localization sequence fusion construct; proteasome inhibitor experiments; FhitY114F mutant analysis; Western blot for proliferation markers Journal of cellular physiology Medium 25711523
1998 Drosophila melanogaster and C. elegans encode Fhit as a fusion protein with a nitrilase domain (NitFhit); the Drosophila fusion protein retains Ap3A hydrolase activity expected of an authentic Fhit homolog; in mammals, the Fhit and Nit1 functions are encoded by separate genes on different chromosomes, suggesting they collaborate in a biochemical pathway. Cloning and sequencing of Drosophila and C. elegans FHIT orthologs; in vitro Ap3A hydrolase activity assay of Drosophila fusion protein; chromosomal mapping of human and mouse NIT1 genes Proceedings of the National Academy of Sciences of the United States of America Medium 9671749
2021 Tanshinone compounds (STS/TSA) directly bind FHIT protein (Kd ~268 nM) and inhibit its Ap3A hydrolase activity by competing for the substrate-binding site (IC50 ~2.2 µM); depletion of FHIT blocks tanshinone-induced apoptosis in colorectal cancer cells. Surface plasmon resonance/binding affinity measurement; in vitro Ap3A hydrolase inhibition assay; FHIT siRNA knockdown; apoptosis assay Scientific reports Medium 34108553
2017 FHIT loss alters translation of cancer-associated mRNAs; ribosome profiling identified several hundred mRNAs with changed coding-region ribosome occupancy as a function of Fhit expression, including changes in translation efficiency and 5'-UTR ribosome occupancy, linking Fhit's cap-degrading hydrolase activity to post-transcriptional gene regulation. Ribosome profiling (ribo-seq) in Fhit-positive vs. Fhit-negative cells; mRNA steady-state measurements Molecular cancer Medium 29282095
2007 Fhit expression protects against HER2-driven mammary tumor development; Fhit protein levels in cancer cell lines are reduced by EGF-dependent activation of EGFR family members (including HER2) via proteasomal degradation; heterozygous Fhit loss in HER2/neu transgenic mice increases tumor incidence. Fhit+/- x MMTV-HER2/neu mouse cross; tumor incidence assessment; proteasome inhibitor experiments in cancer cell lines; IHC of human breast carcinomas Cell cycle (Georgetown, Tex.) Medium 17374991

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 The FHIT gene 3p14.2 is abnormal in lung cancer. Cell 545 8620533
1997 Replacement of Fhit in cancer cells suppresses tumorigenicity. Proceedings of the National Academy of Sciences of the United States of America 343 9391102
1996 FHIT gene alterations in head and neck squamous cell carcinomas. Proceedings of the National Academy of Sciences of the United States of America 240 8790406
1997 Structure and expression of the human FHIT gene in normal and tumor cells. Cancer research 208 9012482
2000 Muir-Torre-like syndrome in Fhit-deficient mice. Proceedings of the National Academy of Sciences of the United States of America 181 10758156
1998 The role of the FHIT/FRA3B locus in cancer. Annual review of genetics 170 9928473
2001 FHIT gene therapy prevents tumor development in Fhit-deficient mice. Proceedings of the National Academy of Sciences of the United States of America 143 11248081
1997 Loss of FHIT expression in cervical carcinoma cell lines and primary tumors. Cancer research 132 9354423
1998 The hereditary renal cell carcinoma 3;8 translocation fuses FHIT to a patched-related gene, TRC8. Proceedings of the National Academy of Sciences of the United States of America 128 9689122
2004 The fragile genes FHIT and WWOX are inactivated coordinately in invasive breast carcinoma. Cancer 121 15073846
2000 Altered expression of Fhit in carcinoma and precarcinomatous lesions of the esophagus. Cancer research 121 10728669
2002 FHIT: from gene discovery to cancer treatment and prevention. The Lancet. Oncology 113 12473516
1997 Frequent deletions of FHIT and FRA3B in Barrett's metaplasia and esophageal adenocarcinomas. Oncogene 107 9349498
2014 The FHIT gene product: tumor suppressor and genome "caretaker". Cellular and molecular life sciences : CMLS 83 25283145
2012 Initiation of genome instability and preneoplastic processes through loss of Fhit expression. PLoS genetics 81 23209436
1998 Absence or reduction of Fhit expression in most clear cell renal carcinomas. Cancer research 81 9679951
1996 Aberrant FHIT transcripts in Merkel cell carcinoma. Cancer research 79 8653678
1998 An FHIT tumor suppressor gene? Genes, chromosomes & cancer 72 9559339
2007 The tumor suppressor Fhit acts as a repressor of beta-catenin transcriptional activity. Proceedings of the National Academy of Sciences of the United States of America 69 18077326
2005 Roles of FHIT and WWOX fragile genes in cancer. Cancer letters 69 16225988
1998 Nitrilase and Fhit homologs are encoded as fusion proteins in Drosophila melanogaster and Caenorhabditis elegans. Proceedings of the National Academy of Sciences of the United States of America 64 9671749
2004 Fhit is a physiological target of the protein kinase Src. Proceedings of the National Academy of Sciences of the United States of America 62 15007172
2003 Expression of FRA16D/WWOX and FRA3B/FHIT genes in hematopoietic malignancies. Molecular cancer research : MCR 62 14638866
2000 Loss of FHIT expression in transitional cell carcinoma of the urinary bladder. The American journal of pathology 62 10666370
1999 The FHIT gene is expressed in pancreatic ductular cells and is altered in pancreatic cancers. Cancer research 62 10096564
2014 FHIT suppresses epithelial-mesenchymal transition (EMT) and metastasis in lung cancer through modulation of microRNAs. PLoS genetics 61 25340791
2000 Loss of Fhit expression in non-small-cell lung cancer: correlation with molecular genetic abnormalities and clinicopathological features. British journal of cancer 61 10735505
2003 Deletion of chromosome 3p14.2-p25 involving the VHL and FHIT genes in conventional renal cell carcinoma. Cancer research 60 12543802
2000 The expression of Fhit protein is related inversely to disease progression in patients with breast carcinoma. Cancer 60 10717620
2006 Fhit modulation of the Akt-survivin pathway in lung cancer cells: Fhit-tyrosine 114 (Y114) is essential. Oncogene 59 16407838
2000 Fhit expression in gastric adenocarcinoma: correlation with disease stage and survival. Cancer 58 10618602
2015 Aberrant gene promoter methylation of p16, FHIT, CRBP1, WWOX, and DLC-1 in Epstein-Barr virus-associated gastric carcinomas. Medical oncology (Northwood, London, England) 56 25720522
2004 Fhit-deficient normal and cancer cells are mitomycin C and UVC resistant. British journal of cancer 50 15494723
2000 Loss of fhit expression in invasive cervical carcinomas and intraepithelial lesions associated with invasive disease. Clinical cancer research : an official journal of the American Association for Cancer Research 50 10999736
2005 Involvement of the Fhit gene in the ionizing radiation-activated ATR/CHK1 pathway. Journal of cellular physiology 48 15389587
2003 Fragile site orthologs FHIT/FRA3B and Fhit/Fra14A2: evolutionarily conserved but highly recombinogenic. Proceedings of the National Academy of Sciences of the United States of America 47 14630947
1999 Reduced Fhit expression in sporadic and BRCA2-linked breast carcinomas. Cancer research 47 10363992
2008 Fhit tumor suppressor: guardian of the preneoplastic genome. Future oncology (London, England) 43 19086848
2014 Fhit regulates EMT targets through an EGFR/Src/ERK/Slug signaling axis in human bronchial cells. Molecular cancer research : MCR 41 24464917
1997 FHIT gene alterations in esophageal cancer and ulcerative colitis (UC). Oncogene 41 9233782
2010 Pathology and biology associated with the fragile FHIT gene and gene product. Journal of cellular biochemistry 40 20082323
1998 FHIT and p53 gene abnormalities in bronchioloalveolar carcinomas. Correlations with clinicopathological data and K-ras mutations. The Journal of pathology 40 9614374
2020 RBP EIF2S2 Promotes Tumorigenesis and Progression by Regulating MYC-Mediated Inhibition via FHIT-Related Enhancers. Molecular therapy : the journal of the American Society of Gene Therapy 39 32059763
2007 A Fhit-ing role in the DNA damage checkpoint response. Cell cycle (Georgetown, Tex.) 39 17457056
2000 Abnormalities of the FHIT gene in human oral carcinogenesis. British journal of cancer 38 10732756
2009 Fhit regulates invasion of lung tumor cells. Oncogene 37 19935706
2006 Fhit modulates the DNA damage checkpoint response. Cancer research 36 17145874
2019 FHIT, a Novel Modifier Gene in Pulmonary Arterial Hypertension. American journal of respiratory and critical care medicine 35 30107138
2008 Alterations of FHIT and P53 genes in keratocystic odontogenic tumor, dentigerous and radicular cyst. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 35 18221322
2002 Multiple molecular alterations of FHIT in betel-associated oral carcinoma. The Journal of pathology 35 11857493
1997 FHIT gene and the FRA3B region are not involved in the genetics of renal cell carcinomas. Genes, chromosomes & cancer 35 9290948
2009 Fragile gene product, Fhit, in oxidative and replicative stress responses. Cancer science 34 19486340
1998 Analysis of the FHIT gene and its product in squamous cell carcinomas of the head and neck. Oncogene 32 9671317
1998 The murine Fhit locus: isolation, characterization, and expression in normal and tumor cells. Cancer research 32 9699672
2003 Expression of Fhit, Mlh1, and P53 protein in human gallbladder carcinoma. Cancer letters 30 12969785
2001 Translocation breakpoints in FHIT and FRA3B in both homologs of chromosome 3 in an esophageal adenocarcinoma. Genes, chromosomes & cancer 29 11170287
2010 FHIT: doubts are clear now. TheScientificWorldJournal 28 20563537
2004 Inactivation of the FHIT gene favors bladder cancer development. Clinical cancer research : an official journal of the American Association for Cancer Research 28 15569992
1998 Analysis of FHIT transcripts in cervical and endometrial cancers. International journal of cancer 28 9537583
2013 Fhit deficiency-induced global genome instability promotes mutation and clonal expansion. PloS one 27 24244712
2003 FHIT expression and hypermethylation in esophageal squamous cell carcinoma. International journal of molecular medicine 27 12632095
2014 Replicative Stress and the FHIT Gene: Roles in Tumor Suppression, Genome Stability and Prevention of Carcinogenesis. Cancers 26 24901304
2014 Folate deficiency and FHIT hypermethylation and HPV 16 infection promote cervical cancerization. Asian Pacific journal of cancer prevention : APJCP 26 25422218
2008 Correlation of fragile histidine triad (Fhit) protein structural features with effector interactions and biological functions. The Journal of biological chemistry 26 19004824
2008 Hypermethylation of the 5'CpG island of the FHIT gene in clear cell renal carcinomas. Cancer letters 25 18378390
1999 FHIT gene abnormalities in both benign and malignant thyroid tumours. European journal of cancer (Oxford, England : 1990) 25 10448301
2017 Impact of FHIT loss on the translation of cancer-associated mRNAs. Molecular cancer 24 29282095
2015 FHIT loss-induced DNA damage creates optimal APOBEC substrates: Insights into APOBEC-mediated mutagenesis. Oncotarget 24 25401976
2004 Expression of Fhit, cell adhesion molecules and matrix metalloproteinases in atypical adenomatous hyperplasia and pulmonary adenocarcinoma. The Journal of pathology 24 15141378
2001 FHIT alterations in breast cancer. Seminars in cancer biology 24 11562178
1997 The FHIT gene is alternatively spliced in normal kidney and renal cell carcinoma. Oncogene 24 9233780
2000 fhit Alterations in endometrial carcinoma and hyperplasia. International journal of cancer 23 10652418
2004 Altered p16INK4a and Fhit expression in carcinogenesis and progression of human oral cancer. International journal of oncology 22 14719099
1997 Decreased or altered expression of the FHIT gene in human leukemias. Stem cells (Dayton, Ohio) 22 9170214
2013 Expression of fragile histidine triad (FHIT) and WW-domain oxidoreductase gene (WWOX) in nasopharyngeal carcinoma. Asian Pacific journal of cancer prevention : APJCP 21 23534718
2009 Nit1 and Fhit tumor suppressor activities are additive. Journal of cellular biochemistry 21 19479888
2023 Acetylcholine promotes chronic stress-induced lung adenocarcinoma progression via α5-nAChR/FHIT pathway. Cellular and molecular life sciences : CMLS 20 37029227
2015 Effect of FHIT loss and p53 mutation on HPV-infected lung carcinoma development. Oncology letters 20 26171037
2006 FHIT protein enhances paclitaxel-induced apoptosis in lung cancer cells. International journal of cancer 20 16231322
2006 Fhit protein inhibits cell growth by attenuating the signaling mediated by nuclear factor-kappaB in colon cancer cell lines. Experimental cell research 19 16733051
2002 FHIT expression in clear cell renal carcinomas: versatility of protein levels and correlation with survival. The Journal of pathology 19 11920739
2012 Characterization of the role of Fhit in suppression of DNA damage. Advances in biological regulation 18 23102829
2008 Frequent epigenetic silencing of the FHIT gene in penile squamous cell carcinomas. Virchows Archiv : an international journal of pathology 17 18299890
2007 Fhit expression protects against HER2-driven breast tumor development: unraveling the molecular interconnections. Cell cycle (Georgetown, Tex.) 17 17374991
2011 microRNA-143 protects cells from DNA damage-induced killing by downregulating FHIT expression. Cancer biotherapy & radiopharmaceuticals 16 21711110
2006 Effect of inducible FHIT and p53 expression in the Calu-1 lung cancer cell line. Cancer letters 16 16616810
2005 A mouse model of the fragile gene FHIT: From carcinogenesis to gene therapy and cancer prevention. Mutation research 16 16085127
2001 Distribution of Fhit protein in rat tissues and its intracellular localization. Molecular and cellular biochemistry 16 11768238
1999 Loss or reduction of Fhit expression in renal neoplasias: correlation with histogenic class. Human pathology 16 10571505
2021 Tanshinones induce tumor cell apoptosis via directly targeting FHIT. Scientific reports 15 34108553
2016 Fhit and Wwox loss-associated genome instability: A genome caretaker one-two punch. Advances in biological regulation 15 27773744
2015 Fhit Nuclear Import Following EGF Stimulation Sustains Proliferation of Breast Cancer Cells. Journal of cellular physiology 15 25711523
2003 Immunohistochemical detection of cell cycle regulators, Fhit protein and apoptotic cells in parathyroid lesions. European journal of endocrinology 15 12534361
1998 FHIT gene transcript alterations occur frequently in myeloproliferative and myelodysplastic diseases. Cytogenetics and cell genetics 15 9730598
1998 Aberrant transcripts of the FHIT gene are expressed in normal and leukaemic haemopoietic cells. British journal of cancer 15 9744498
2009 Aberrations of the FHIT gene and Fhit protein in canine lymphoma cell lines. The Journal of veterinary medical science 14 19578286
2006 Diadenosines as FHIT-ness instructors. Journal of cellular physiology 14 16547961
2002 Preferential loss of Fhit expression in signet-ring cell and Krukenberg subtypes of gastric cancer. Laboratory investigation; a journal of technical methods and pathology 14 12218081
2000 Expression in Escherichia coli and simple purification of human Fhit protein. Protein expression and purification 14 10733886
1999 Expression of FHIT in primary cultures of human epithelial ovarian tumors and malignant ovarian ascites. Molecular carcinogenesis 14 10204806

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