FHIT (Fragile Histidine Triad)

Identity

HGNC	FHIT
Location	3p14.2
Location_base_pair	Starts at 59710076 and ends at 61212173 bp from pter ( according to hg18-Mar_2006).

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.

External links

	Nomenclature
HGNC	FHIT   3701
Entrez_Gene	FHIT  2272  fragile histidine triad gene
	Cards
Atlas	FHITID192ch3p14
GeneCards	FHIT
Ensembl	FHIT [Search_View]   ENSG00000189283 [Gene_View]  FHIT [Vega]
Genatlas	FHIT
GeneLynx	FHIT
eGenome	FHIT
euGene	2272
	Genomic and cartography
GoldenPath	FHIT  -  3p14.2   chr3:59710076-61212173 -  3p14.2   [Description]    (hg18-Mar_2006)
Ensembl	FHIT - 3p14.2 [CytoView]
NCBI	Mapview
OMIM	Disease map [OMIM]
HomoloGene	FHIT
	Gene and transcription
Genbank	AK127931 [ ENTREZ ]
Genbank	AK289824 [ ENTREZ ]
Genbank	BC032336 [ ENTREZ ]
Genbank	BC057223 [ ENTREZ ]
Genbank	DA239143 [ ENTREZ ]
RefSeq	NM_002012 [ SRS ]    NM_002012 [ ENTREZ ]
RefSeq	AC_000046 [ SRS ]    AC_000046 [ ENTREZ ]
RefSeq	AC_000135 [ SRS ]    AC_000135 [ ENTREZ ]
RefSeq	NC_000003 [ SRS ]    NC_000003 [ ENTREZ ]
RefSeq	NG_007551 [ SRS ]    NG_007551 [ ENTREZ ]
RefSeq	NT_022517 [ SRS ]    NT_022517 [ ENTREZ ]
RefSeq	NW_001838877 [ SRS ]    NW_001838877 [ ENTREZ ]
RefSeq	NW_921651 [ SRS ]    NW_921651 [ ENTREZ ]
CCDS	FHIT CCDS - NCBI
AceView	FHIT AceView - NCBI
Unigene	Hs.709558 [ SRS ]    Hs.709558 [ NCBI ]     HS709558 [ spliceNest ]
	Protein : pattern, domain, 3D structure
SwissProt	O00298 [ SRS]    O00298 [ EXPASY ]     O00298 [ INTERPRO ]     O00298 [ UNIPROT ] O00298 [ VarSplice ]
Prosite	PS51084 HIT_2 [ SRS ]    PS51084 HIT_2 [ Expasy ]
Interpro	IPR001310 HIT [ SRS ]    IPR001310 HIT [ EBI ]
CluSTr	O00298
Pfam	PF01230 HIT [ SRS ]    PF01230 HIT [ Sanger ]    pfam01230 [ NCBI-CDD ]
Blocks	O00298
HPRD	03096
	Protein Interaction databases
DIP	O00298
IntAct	O00298
	Polymorphism : SNP, mutations, diseases
OMIM	601153    [ map ]
GENECLINICS	601153
SNP	FHIT [dbSNP-NCBI]
SNP	NM_002012 [SNP-NCI]
SNP	FHIT [GeneSNPs - Utah]  FHIT] [HGBASE - SRS]
HAPMAP	FHIT [HAPMAP]
TICdb	FHIT [Translocation breakpoints In Cancer]
HGMD	FHIT
Genetic Association	FHIT
CDC HuGE	FHIT
	General knowledge
Family Browser	FHIT [UCSC Family Browser]
SOURCE	NM_002012
SMD	Hs.709558
SAGE	Hs.709558
GO	magnesium ion binding [Amigo]  magnesium ion binding
GO	protein binding [Amigo]  protein binding
GO	cytoplasm [Amigo]  cytoplasm
GO	nucleotide metabolic process [Amigo]  nucleotide metabolic process
GO	hydrolase activity [Amigo]  hydrolase activity
GO	manganese ion binding [Amigo]  manganese ion binding
GO	negative regulation of cell cycle [Amigo]  negative regulation of cell cycle
GO	bis(5'-adenosyl)-triphosphatase activity [Amigo]  bis(5'-adenosyl)-triphosphatase activity
KEGG	Purine metabolism
PubGene	FHIT
TreeFam	FHIT
CTD	2272 [Comparative ToxicoGenomics Database]
	Other databases
	Probes
Probe	FHIT Related clones (RZPD - Berlin)
	PubMed
PubMed	137 Pubmed reference(s) in Entrez

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)

Written	12-2006	Teresa Druck, Kay Huebner

Citation

This paper should be referenced as such :

Druck T, Huebner K . FHIT (Fragile Histidine Triad). Atlas Genet Cytogenet Oncol Haematol. December 2006 . URL : http://AtlasGeneticsOncology.org/Genes/FHITID192ch3p14.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

indexed on : Sun Nov 9 19:40:50 2008