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FHIT (Fragile Histidine Triad)

Identity

HGNC (Hugo) FHIT
LocusID (NCBI) 2272
Location 3p14.2
Location_base_pair Starts at 59735036 and ends at 61237133 bp from pter ( according to hg19-Feb_2009)  [Mapping]

DNA/RNA

 
  Depiction of the more than 1.67 Mb FHIT gene genomic locus with coding exons 5 through 9 (dark purple) and untranslated exons 1-4 and 10 (light purple). The position of the familial kidney cancer associated chromosome translocation is also shown.
Description The FHIT gene spans more than 1.6 Mb of genomic DNA and is composed of 10 exons.
Transcription The FHIT gene encodes a 1.1 kb mRNA which is expressed at low levels in most tissue types. FHIT encompasses the common fragile site FRA3B, where carcinogen-induced damage can lead to deletions, translocations and subsequent aberrant transcripts. Aberrant transcripts from this gene have been found in about half of all esophageal carcinomas, stomach carcinomas, and other carcinomas.
Pseudogene A pseudogene, with sequences nearly identical to the 5¹UTR of FHIT, is located on chromosome 1.

Protein

Description FHIT encodes a 147 amino acid (16.8 kDa) protein that can be phosphorylated at tyrosine 114 by Src family proteins.
Expression Fhit is expressed at low to moderate levels in most tissue types, with kidney and liver expressing the highest steady state levels
Localisation Fhit is primarily located in the cytosol, but is also found in the mitochondria.
Function Fhit protein is a tumor suppressor with reduced or no expression in many types of cancer. Fhit expression is more frequently lost in cancers of individuals with familial mutations causing deficiency in DNA repair genes such as BRCA1 and BRCA2 and MSH2. In vitro Fhit acts as a hydrolase that cleaves diadenosine triphosphate (Ap3A) to ADP and AMP. The Fhit-Ap3A enzyme-substrate complex appears to be the tumor suppressor signal. Restoration of Fhit expression in Fhit-deficient cancer cells causes death by apoptosis, involving the intrinsic caspase pathway, in cancer-derived cells and in tumor xenografts.
Homology Fhit is similar to a yeast enzyme, diadenosine tetraphosphate (Ap4A) hydrolase and is a member of the large HIT family of proteins characterized by the histidine triad motif, HxHxHxx (where x is a hydrophobic residue).

Mutations

Note The following FHIT polymorphisms have been described:
524 A/G (exon 6) silent
545 G/A (exon 6) silent
626 C/T (exon 7) silent
651 G/T (exon 8) valine to phenylalanine
656 T/C (exon 8) silent
several intronic splice regions
Somatic No bona fide somatic point mutations thus far confirmed.

Implicated in

Entity Various types of cancer
Disease Loss of expression occurs in more than 60% of human cancers; loss is very early in some cancers such as lung cancer. In a large, 4 generation family, a balanced translocation between FHIT (in intron 3) at 3p14.2 and TRC8, a patched related gene, at chromosome 8q24 is associated with bilateral, multifocal clear cell kidney carcinoma. Also, microsatellite loci within the FHIT gene, were shown to be closely linked to a gene that contributes to susceptibility to familial prostate cancer.
Prognosis There are numerous reports of association of Fhit loss with specific prognostic or other clinical features of specific types of cancer.
Cytogenetics The FHIT locus is involved in translocations and deletions in some fraction of many types of cancer, likely due to the recombinogenicity of the fragile region within FHIT and subsequent selective growth or survival advantage of cells with reduced Fhit protein expression.
  

Other Solid tumors implicated (Data extracted from papers in the Atlas)

Solid Tumors AmeloblastomID5945 MedulloblastomaID5065 rhab5004 rhabID5004 blad5001
bladID5001 colon5006

External links

Nomenclature
HGNC (Hugo)FHIT   3701
Cards
AtlasFHITID192ch3p14
Entrez_Gene (NCBI)FHIT  2272  fragile histidine triad
GeneCards (Weizmann)FHIT
Ensembl (Hinxton)ENSG00000189283 [Gene_View]  chr3:59735036-61237133 [Contig_View]  FHIT [Vega]
ICGC DataPortalENSG00000189283
cBioPortalFHIT
AceView (NCBI)FHIT
Genatlas (Paris)FHIT
WikiGenes2272
SOURCE (Princeton)NM_001166243 NM_002012
Genomic and cartography
GoldenPath (UCSC)FHIT  -  3p14.2   chr3:59735036-61237133 -  3p14.2   [Description]    (hg19-Feb_2009)
EnsemblFHIT - 3p14.2 [CytoView]
Mapping of homologs : NCBIFHIT [Mapview]
OMIM601153   
Gene and transcription
Genbank (Entrez)AK127931 AK289824 BC032336 BC057223 DA239143
RefSeq transcript (Entrez)NM_001166243 NM_002012
RefSeq genomic (Entrez)AC_000135 NC_000003 NC_018914 NG_007551 NT_022517 NW_001838877 NW_004929309
Consensus coding sequences : CCDS (NCBI)FHIT
Cluster EST : UnigeneHs.655995 [ NCBI ]
CGAP (NCI)Hs.655995
Alternative Splicing : Fast-db (Paris)GSHG0041911
Alternative Splicing GalleryENSG00000189283
Gene ExpressionFHIT [ NCBI-GEO ]     FHIT [ SEEK ]   FHIT [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP49789 (Uniprot)
NextProtP49789  [Medical]
With graphics : InterProP49789
Splice isoforms : SwissVarP49789 (Swissvar)
Catalytic activity : Enzyme3.6.1.29 [ Enzyme-Expasy ]   3.6.1.293.6.1.29 [ IntEnz-EBI ]   3.6.1.29 [ BRENDA ]   3.6.1.29 [ KEGG ]   
Domaine pattern : Prosite (Expaxy)HIT_1 (PS00892)    HIT_2 (PS51084)   
Domains : Interpro (EBI)Histidine_triad_CS [organisation]   Histidine_triad_HIT [organisation]   HIT-like [organisation]  
Related proteins : CluSTrP49789
Domain families : Pfam (Sanger)HIT (PF01230)   
Domain families : Pfam (NCBI)pfam01230   
DMDM Disease mutations2272
Blocks (Seattle)P49789
PDB (SRS)1FHI    1FIT    2FHI    2FIT    3FIT    4FIT    5FIT    6FIT   
PDB (PDBSum)1FHI    1FIT    2FHI    2FIT    3FIT    4FIT    5FIT    6FIT   
PDB (IMB)1FHI    1FIT    2FHI    2FIT    3FIT    4FIT    5FIT    6FIT   
PDB (RSDB)1FHI    1FIT    2FHI    2FIT    3FIT    4FIT    5FIT    6FIT   
Human Protein AtlasENSG00000189283 [gene] [tissue] [antibody] [cell] [cancer]
Peptide AtlasP49789
HPRD03096
IPIIPI00028095   IPI00930501   IPI00946848   
Protein Interaction databases
DIP (DOE-UCLA)P49789
IntAct (EBI)P49789
FunCoupENSG00000189283
BioGRIDFHIT
InParanoidP49789
Interologous Interaction database P49789
IntegromeDBFHIT
STRING (EMBL)FHIT
Ontologies - Pathways
Ontology : AmiGOnucleotide binding  catalytic activity  protein binding  nucleus  cytoplasm  mitochondrion  cytosol  purine nucleotide metabolic process  DNA replication  transcription, DNA-templated  regulation of transcription, DNA-templated  nucleotide metabolic process  hydrolase activity  ubiquitin protein ligase binding  negative regulation of proteasomal ubiquitin-dependent protein catabolic process  identical protein binding  bis(5'-adenosyl)-triphosphatase activity  extracellular vesicular exosome  intrinsic apoptotic signaling pathway by p53 class mediator  
Ontology : EGO-EBInucleotide binding  catalytic activity  protein binding  nucleus  cytoplasm  mitochondrion  cytosol  purine nucleotide metabolic process  DNA replication  transcription, DNA-templated  regulation of transcription, DNA-templated  nucleotide metabolic process  hydrolase activity  ubiquitin protein ligase binding  negative regulation of proteasomal ubiquitin-dependent protein catabolic process  identical protein binding  bis(5'-adenosyl)-triphosphatase activity  extracellular vesicular exosome  intrinsic apoptotic signaling pathway by p53 class mediator  
Pathways : KEGGPurine metabolism    Small cell lung cancer    Non-small cell lung cancer   
Protein Interaction DatabaseFHIT
Wikipedia pathwaysFHIT
Gene fusion - rearrangments
Rearrangement : COSMICFHIT [3p14.2]  -  HMGA2 [12q14.3]  
  [COSF1024] [COSF1025] 
Rearrangement : COSMICHMGA2 [12q14.3]  -  FHIT [3p14.2]  
  [COSF1022] [COSF1023] 
Rearrangement : TICdbHMGA2 [12q14.3]  -  FHIT [6p21.1]
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)FHIT
snp3D : Map Gene to Disease2272
SNP (GeneSNP Utah)FHIT
SNP : HGBaseFHIT
Genetic variants : HAPMAPFHIT
Exome VariantFHIT
1000_GenomesFHIT 
ICGC programENSG00000189283 
Cancer Gene: CensusFHIT 
Somatic Mutations in Cancer : COSMICFHIT 
CONAN: Copy Number AnalysisFHIT 
Mutations and Diseases : HGMDFHIT
Mutations and Diseases : intOGenFHIT
Genomic VariantsFHIT  FHIT [DGVbeta]
dbVarFHIT
ClinVarFHIT
Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
Diseases
OMIM601153   
MedgenFHIT
GENETestsFHIT
Disease Genetic AssociationFHIT
Huge Navigator FHIT [HugePedia]  FHIT [HugeCancerGEM]
General knowledge
Homologs : HomoloGeneFHIT
Homology/Alignments : Family Browser (UCSC)FHIT
Phylogenetic Trees/Animal Genes : TreeFamFHIT
Chemical/Protein Interactions : CTD2272
Chemical/Pharm GKB GenePA28140
Clinical trialFHIT
Cancer Resource (Charite)ENSG00000189283
Other databases
Probes
Litterature
PubMed256 Pubmed reference(s) in Entrez
CoreMineFHIT
iHOPFHIT
OncoSearchFHIT

Bibliography

Fhit, a putative tumor suppressor in humans, is a dinucleoside 5',5'-P1,P3-triphosphate hydrolase.
Barnes LD, Garrison PN, Siprashvili Z, Guranowski A, Robinson AK, Ingram SW, Croce CM, Ohta M, Huebner K
Biochemistry. 1996 ; 35 (36) : 11529-11535.
PMID 8794732
 
The FHIT gene, spanning the chromosome 3p14.2 fragile site and renal carcinoma-associated t(3;8) breakpoint, is abnormal in digestive tract cancers.
Ohta M, Inoue H, Cotticelli MG, Kastury K, Baffa R, Palazzo J, Siprashvili Z, Mori M, McCue P, Druck T, Croce CM, Huebner K
Cell. 1996 ; 84 (4) : 587-597.
PMID 8598045
 
Analysis of the FHIT gene and FRA3B region in sporadic breast cancer, preneoplastic lesions, and familial breast cancer probands.
Ahmadian M, Wistuba II, Fong KM, Behrens C, Kodagoda DR, Saboorian MH, Shay J, Tomlinson GE, Blum J, Minna JD, Gazdar AF
Cancer research. 1997 ; 57 (17) : 3664-3668.
PMID 9288768
 
Purification and crystallization of complexes modeling the active state of the fragile histidine triad protein.
Brenner C, Pace HC, Garrison PN, Robinson AK, Rosler A, Liu XH, Blackburn GM, Croce CM, Huebner K, Barnes LD
Protein engineering. 1997 ; 10 (12) : 1461-1463.
PMID 9543008
 
Structure and expression of the human FHIT gene in normal and tumor cells.
Druck T, Hadaczek P, Fu TB, Ohta M, Siprashvili Z, Baffa R, Negrini M, Kastury K, Veronese ML, Rosen D, Rothstein J, McCue P, Cotticelli MG, Inoue H, Croce CM, Huebner K
Cancer research. 1997 ; 57 (3) : 504-512.
PMID 9012482
 
Replacement of Fhit in cancer cells suppresses tumorigenicity.
Siprashvili Z, Sozzi G, Barnes LD, McCue P, Robinson AK, Eryomin V, Sard L, Tagliabue E, Greco A, Fusetti L, Schwartz G, Pierotti MA, Croce CM, Huebner K
Proceedings of the National Academy of Sciences of the United States of America. 1997 ; 94 (25) : 13771-13776.
PMID 9391102
 
FHITness and cancer.
Druck T, Berk L, Huebner K
Oncology research. 1998 ; 10 (7) : 341-345.
PMID 10063967
 
The hereditary renal cell carcinoma 3;8 translocation fuses FHIT to a patched-related gene, TRC8.
Gemmill RM, West JD, Boldog F, Tanaka N, Robinson LJ, Smith DI, Li F, Drabkin HA
Proceedings of the National Academy of Sciences of the United States of America. 1998 ; 95 (16) : 9572-9577.
PMID 9689122
 
Instability at chromosomal fragile sites.
Glover TW
Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer. 1998 ; 154 : 185-199.
PMID 10027000
 
The role of the FHIT/FRA3B locus in cancer.
Huebner K, Garrison PN, Barnes LD, Croce CM
Annual review of genetics. 1998 ; 32 : 7-31.
PMID 9928473
 
Genetic, biochemical, and crystallographic characterization of Fhit-substrate complexes as the active signaling form of Fhit.
Pace HC, Garrison PN, Robinson AK, Barnes LD, Draganescu A, Rˆsler A, Blackburn GM, Siprashvili Z, Croce CM, Huebner K, Brenner C
Proceedings of the National Academy of Sciences of the United States of America. 1998 ; 95 (10) : 5484-5489.
PMID 9576908
 
The histidine triad superfamily of nucleotide-binding proteins.
Brenner C, Bieganowski P, Pace HC, Huebner K
Journal of cellular physiology. 1999 ; 181 (2) : 179-187.
PMID 10497298
 
Induction of apoptosis and inhibition of tumorigenicity and tumor growth by adenovirus vector-mediated fragile histidine triad (FHIT) gene overexpression.
Ji L, Fang B, Yen N, Fong K, Minna JD, Roth JA
Cancer research. 1999 ; 59 (14) : 3333-3339.
PMID 10416589
 
Muir-Torre-like syndrome in Fhit-deficient mice.
Fong LY, Fidanza V, Zanesi N, Lock LF, Siracusa LD, Mancini R, Siprashvili Z, Ottey M, Martin SE, Druck T, McCue PA, Croce CM, Huebner K
Proceedings of the National Academy of Sciences of the United States of America. 2000 ; 97 (9) : 4742-4747.
PMID 10758156
 
FHIT gene therapy prevents tumor development in Fhit-deficient mice.
Dumon KR, Ishii H, Fong LY, Zanesi N, Fidanza V, Mancini R, Vecchione A, Baffa R, Trapasso F, During MJ, Huebner K, Croce CM
Proceedings of the National Academy of Sciences of the United States of America. 2001 ; 98 (6) : 3346-3351.
PMID 11248081
 
Fragile histidine triad expression delays tumor development and induces apoptosis in human pancreatic cancer.
Dumon KR, Ishii H, Vecchione A, Trapasso F, Baldassarre G, Chakrani F, Druck T, Rosato EF, Williams NN, Baffa R, During MJ, Huebner K, Croce CM
Cancer research. 2001 ; 61 (12) : 4827-4836.
PMID 11406559
 
Translocation breakpoints in FHIT and FRA3B in both homologs of chromosome 3 in an esophageal adenocarcinoma.
Fang JM, Arlt MF, Burgess AC, Dagenais SL, Beer DG, Glover TW
Genes, chromosomes & cancer. 2001 ; 30 (3) : 292-298.
PMID 11170287
 
FRA3B and other common fragile sites: the weakest links.
Huebner K, Croce CM
Nature reviews. Cancer. 2001 ; 1 (3) : 214-221.
PMID 11902576
 
Potential cancer therapy with the fragile histidine triad gene: review of the preclinical studies.
Ishii H, Dumon KR, Vecchione A, Fong LY, Baffa R, Huebner K, Croce CM
JAMA : the journal of the American Medical Association. 2001 ; 286 (19) : 2441-2449.
PMID 11712940
 
Effect of adenoviral transduction of the fragile histidine triad gene into esophageal cancer cells.
Ishii H, Dumon KR, Vecchione A, Trapasso F, Mimori K, Alder H, Mori M, Sozzi G, Baffa R, Huebner K, Croce CM
Cancer research. 2001 ; 61 (4) : 1578-1584.
PMID 11245468
 
The tumor spectrum in FHIT-deficient mice.
Zanesi N, Fidanza V, Fong LY, Mancini R, Druck T, Valtieri M, Rˆºdiger T, McCue PA, Croce CM, Huebner K
Proceedings of the National Academy of Sciences of the United States of America. 2001 ; 98 (18) : 10250-10255.
PMID 11517343
 
5' CpG island methylation of the FHIT gene is correlated with loss of gene expression in lung and breast cancer.
Zˆchbauer-Mˆºller S, Fong KM, Maitra A, Lam S, Geradts J, Ashfaq R, Virmani AK, Milchgrub S, Gazdar AF, Minna JD
Cancer research. 2001 ; 61 (9) : 3581-3585.
PMID 11325823
 
Hint, Fhit, and GalT: function, structure, evolution, and mechanism of three branches of the histidine triad superfamily of nucleotide hydrolases and transferases.
Brenner C
Biochemistry. 2002 ; 41 (29) : 9003-9014.
PMID 12119013
 
Loss of fragile histidine triad (FHIT) expression and microsatellite instability in periocular sebaceous gland carcinoma in patients with Muir-Torre syndrome.
Holbach LM, von Moller A, Decker C, Jˆºnemann AG, Rummelt-Hofmann C, Ballhausen WG
American journal of ophthalmology. 2002 ; 134 (1) : 147-148.
PMID 12095833
 
FHIT: from gene discovery to cancer treatment and prevention.
Pekarsky Y, Zanesi N, Palamarchuk A, Huebner K, Croce CM
The lancet oncology. 2002 ; 3 (12) : 748-754.
PMID 12473516
 
Loss of heterozygosity at the FHIT gene in different solid human tumours and its association with survival in colorectal cancer patients.
Petursdottir TE, Hafsteinsdottir SH, Jonasson JG, Moller PH, Thorsteinsdottir U, Huiping C, Egilsson V, Ingvarsson S
Anticancer research. 2002 ; 22 (6A) : 3205-3212.
PMID 12530066
 
The fragile histidine triad/common chromosome fragile site 3B locus and repair-deficient cancers.
Turner BC, Ottey M, Zimonjic DB, Potoczek M, Hauck WW, Pequignot E, Keck-Waggoner CL, Sevignani C, Aldaz CM, McCue PA, Palazzo J, Huebner K, Popescu NC
Cancer research. 2002 ; 62 (14) : 4054-4060.
PMID 12124341
 
Two-hit inactivation of FHIT by loss of heterozygosity and hypermethylation in breast cancer.
Yang Q, Nakamura M, Nakamura Y, Yoshimura G, Suzuma T, Umemura T, Shimizu Y, Mori I, Sakurai T, Kakudo K
Clinical cancer research : an official journal of the American Association for Cancer Research. 2002 ; 8 (9) : 2890-2893.
PMID 12231533
 
Cancer and the FRA3B/FHIT fragile locus: it's a HIT.
Huebner K, Croce CM
British journal of cancer. 2003 ; 88 (10) : 1501-1506.
PMID 12771912
 
Designed FHIT alleles establish that Fhit-induced apoptosis in cancer cells is limited by substrate binding.
Trapasso F, Krakowiak A, Cesari R, Arkles J, Yendamuri S, Ishii H, Vecchione A, Kuroki T, Bieganowski P, Pace HC, Huebner K, Croce CM, Brenner C
Proceedings of the National Academy of Sciences of the United States of America. 2003 ; 100 (4) : 1592-1597.
PMID 12574506
 
The fragile genes FHIT and WWOX are inactivated coordinately in invasive breast carcinoma.
Guler G, Uner A, Guler N, Han SY, Iliopoulos D, Hauck WW, McCue P, Huebner K
Cancer. 2004 ; 100 (8) : 1605-1614.
PMID 15073846
 
Fhit is a physiological target of the protein kinase Src.
Pekarsky Y, Garrison PN, Palamarchuk A, Zanesi N, Aqeilan RI, Huebner K, Barnes LD, Croce CM
Proceedings of the National Academy of Sciences of the United States of America. 2004 ; 101 (11) : 3775-3779.
PMID 15007172
 
Genetic linkage of prostate cancer risk to the chromosome 3 region bearing FHIT.
Larson GP, Ding Y, Cheng LS, Lundberg C, Gagalang V, Rivas G, Geller L, Weitzel J, MacDonald D, Archambeau J, Slater J, Neuberg D, Daly MB, Angel I, Benson AB 3rd, Smith K, Kirkwood JM, O'Dwyer PJ, Raskay B, Sutphen R, Drew R, Stewart JA, Werndli J, Johnson D, Ruckdeschel JC, Elston RC, Krontiris TG
Cancer research. 2005 ; 65 (3) : 805-814.
PMID 15705877
 
Concordant loss of fragile gene expression early in breast cancer development.
Guler G, Uner A, Guler N, Han SY, Iliopoulos D, McCue P, Huebner K
Pathology international. 2005 ; 55 (8) : 471-478.
PMID 15998374
 
Fragile genes as biomarkers: epigenetic control of WWOX and FHIT in lung, breast and bladder cancer.
Iliopoulos D, Guler G, Han SY, Johnston D, Druck T, McCorkell KA, Palazzo J, McCue PA, Baffa R, Huebner K
Oncogene. 2005 ; 24 (9) : 1625-1633.
PMID 15674328
 
Fhit modulation of the Akt-survivin pathway in lung cancer cells: Fhit-tyrosine 114 (Y114) is essential.
Semba S, Trapasso F, Fabbri M, McCorkell KA, Volinia S, Druck T, Iliopoulos D, Pekarsky Y, Ishii H, Garrison PN, Barnes LD, Croce CM, Huebner K
Oncogene. 2006 ; 25 (20) : 2860-2872.
PMID 16407838
 
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Contributor(s)

Written12-2006Teresa Druck, Kay Huebner

Citation

This paper should be referenced as such :
Huebner, K ; Druck, T
FHIT (fragile histidine triad)
Atlas Genet Cytogenet Oncol Haematol. 2007;11(2):96-98.
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/FHITID192ch3p14.html

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