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Gene Review

Fhit  -  fragile histidine triad gene

Mus musculus

Synonyms: AP3A hydrolase, AP3Aase, AW045638, Bis(5'-adenosyl)-triphosphatase, Diadenosine 5',5'''-P1,P3-triphosphate hydrolase, ...
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Disease relevance of Fhit

  • Most normal mouse tissues expressed wild-type Fhit mRNA, whereas approximately 40% of murine lung carcinomas expressed wild-type and aberrant Fhit RT-PCR products that lacked various exons [1].
  • We sequenced over 600 kbp of the mouse Fra14A2, covering the region orthologous to the fragile epicenter of FRA3B, and determined the Fhit deletion break points in a mouse kidney cancer cell line (RENCA) [2].
  • To determine if Fhit-deficient mice exhibit increased susceptibility to carcinogen-induced lung cancer, mice were treated with the pulmonary carcinogen 4-methylnitrosamino-1-3-pyridyl-1-butanone [3].
  • Whereas no spontaneous lung tumors were observed in Fhit-/- or Vhl+/- mice, 44% of Fhit-/-Vhl+/- mice developed adenocarcinomas by 2 years of age [3].
  • Dimethylnitrosamine (6 mg/kg body weight) induced lung tumors (adenomas and carcinomas) in 100% of Fhit-/-Vhl+/- mice and adenomas in 40% of Fhit-/- mice by 20 months of age [3].

High impact information on Fhit


Chemical compound and disease context of Fhit

  • Because substitution of Tyr(114) (Y114) with phenylalanine (Y114F) diminishes Fhit functions, we did protein expression profiling to identify proteins differentially expressed in Fhit-negative H1299 lung cancer cells infected with wild-type (Ad-FHIT-wt) and Y114 mutant FHIT-expressing (Ad-FHIT-Y114F) adenoviruses [8].
  • A decrease of up to > 90% in Fhit protein levels was also observed in 22 local sarcomas (mostly fibrosarcomas) induced by i.m. injection of nickel subsulfide in C57BL/6 and MT+ (C57BL/6 overexpressing metallothionein) mice, as compared with normal muscles [9].

Biological context of Fhit

  • The murine Fhit locus maps near the centromere nu proximal Ptprg locus on mouse chromosome 14 [1].
  • Specific Fhit signal pathways have not been identified [10].
  • Several tumorigenic mouse cell lines exhibited homozygous deletions of Fhit exons [1].
  • These results also illustrate the importance of balanced checkpoint activation in genomic stability and suggest a connection between the radioresistance and mutagenesis, carcinogenesis, as well as tumor progression in Fhit-deficient cells or tissue [10].
  • Insights into Fhit mouse genetics that have emerged in the last 7 years, and are reviewed in the present article, allowed for development of new tools in carcinogenesis and gene delivery studies [11].

Anatomical context of Fhit

  • Most murine cell lines tested, including lines established from normal mouse embryos and tumors, expressed very low or undetectable levels of Fhit mRNA [1].
  • To investigate the role of the Fhit gene in carcinogen induction of neoplasia, we have inactivated one Fhit allele in mouse embryonic stem cells and produced (129/SvJ x C57BL/6J) F(1) mice with a Fhit allele inactivated (+/-) [12].
  • As one test of this hypothesis, we isolated the murine Fhit gene and asked whether it also contains a common fragile site and if it is unstable in mouse tumors or tumor cell lines [13].
  • Here we demonstrate that Fhit gene knockout mice develop tumours in the lymphoid tissue, liver, uterus, testis, forestomach and small intestine, together with structural abnormalities in the small intestinal mucosa [14].
  • Normal renal tubule epithelial cells express Fhit uniformly and strongly, whereas 51% of the tumors are completely negative, 34% of tumors show a mixture of positive and negative cells, and 14% are uniformly positive, although usually less strongly positive than the normal epithelial cells [15].

Associations of Fhit with chemical compounds

  • Both genes code for fusion proteins in which the Fhit domain is fused with a novel domain showing homology to bacterial and plant nitrilases; the D. melanogaster fusion protein exhibited diadenosine triphosphate (ApppA) hydrolase activity expected of an authentic Fhit homolog [16].
  • In the current study a single N-nitrosomethylbenzylamine dose was administered to Fhit +/+, +/-, and -/- mice to compare carcinogen susceptibility in +/- and -/- Fhit-deficient mice [17].
  • To determine if Fhit absence, in combination with deficiency of an additional 3p tumor suppressor, would affect the frequency of tumor induction, we examined the spontaneous and dimethylnitrosamine-induced tumor phenotype of Fhit-/-Vhl+/- mice [3].
  • Results showed that 8 of 28 (28%) and 6 of 13 (46%) of the Fhit -/- and +/-, respectively, versus 2 of 25 (8%) Fhit +/+ mice developed invasive carcinoma after treatment with N-butyl-N-(4-hydroxybutyl) nitrosamine [18].
  • Fhit hydrolyzes dinucleotide 5',5"'-P1,P3-triphosphate in vitro and mutation of a central histidine abolishes hydrolase activity [19].

Other interactions of Fhit


Analytical, diagnostic and therapeutic context of Fhit


  1. The murine Fhit locus: isolation, characterization, and expression in normal and tumor cells. Pekarsky, Y., Druck, T., Cotticelli, M.G., Ohta, M., Shou, J., Mendrola, J., Montgomery, J.C., Buchberg, A.M., Siracusa, L.D., Manenti, G., Fong, L.Y., Dragani, T.A., Croce, C.M., Huebner, K. Cancer Res. (1998) [Pubmed]
  2. Sequence conservation at human and mouse orthologous common fragile regions, FRA3B/FHIT and Fra14A2/Fhit. Shiraishi, T., Druck, T., Mimori, K., Flomenberg, J., Berk, L., Alder, H., Miller, W., Huebner, K., Croce, C.M. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  3. Lung cancer susceptibility in Fhit-deficient mice is increased by Vhl haploinsufficiency. Zanesi, N., Mancini, R., Sevignani, C., Vecchione, A., Kaou, M., Valtieri, M., Calin, G.A., Pekarsky, Y., Gnarra, J.R., Croce, C.M., Huebner, K. Cancer Res. (2005) [Pubmed]
  4. Restored expression of fragile histidine triad protein and tumorigenicity of cervical carcinoma cells. Wu, R., Connolly, D.C., Dunn, R.L., Cho, K.R. J. Natl. Cancer Inst. (2000) [Pubmed]
  5. Novel tumor suppressor locus in human chromosome region 3p14.2. Jülicher, K., Marquitan, G., Werner, N., Bardenheuer, W., Vieten, L., Bröcker, F., Topal, H., Seeber, S., Opalka, B., Schütte, J. J. Natl. Cancer Inst. (1999) [Pubmed]
  6. Fhit is a physiological target of the protein kinase Src. Pekarsky, Y., Garrison, P.N., Palamarchuk, A., Zanesi, N., Aqeilan, R.I., Huebner, K., Barnes, L.D., Croce, C.M. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  7. 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, H.C., Huebner, K., Croce, C.M., Brenner, C. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  8. Protein expression profiling identifies cyclophilin A as a molecular target in Fhit-mediated tumor suppression. Semba, S., Huebner, K. Mol. Cancer Res. (2006) [Pubmed]
  9. Reduced Fhit protein expression in nickel-transformed mouse cells and in nickel-induced murine sarcomas. Kowara, R., Salnikow, K., Diwan, B.A., Bare, R.M., Waalkes, M.P., Kasprzak, K.S. Mol. Cell. Biochem. (2004) [Pubmed]
  10. Fhit and CHK1 have opposing effects on homologous recombination repair. Hu, B., Wang, H., Wang, X., Lu, H.R., Huang, C., Powell, S.N., Huebner, K., Wang, Y. Cancer Res. (2005) [Pubmed]
  11. A mouse model of the fragile gene FHIT: From carcinogenesis to gene therapy and cancer prevention. Zanesi, N., Pekarsky, Y., Croce, C.M. Mutat. Res. (2005) [Pubmed]
  12. Muir-Torre-like syndrome in Fhit-deficient mice. Fong, L.Y., Fidanza, V., Zanesi, N., Lock, L.F., Siracusa, L.D., Mancini, R., Siprashvili, Z., Ottey, M., Martin, S.E., Druck, T., McCue, P.A., Croce, C.M., Huebner, K. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  13. The murine Fhit gene is highly similar to its human orthologue and maps to a common fragile site region. Glover, T.W., Hoge, A.W., Miller, D.E., Ascara-Wilke, J.E., Adam, A.N., Dagenais, S.L., Wilke, C.M., Dierick, H.A., Beer, D.G. Cancer Res. (1998) [Pubmed]
  14. Development of spontaneous tumours and intestinal lesions in Fhit gene knockout mice. Fujishita, T., Doi, Y., Sonoshita, M., Hiai, H., Oshima, M., Huebner, K., Croce, C.M., Taketo, M.M. Br. J. Cancer (2004) [Pubmed]
  15. Absence or reduction of Fhit expression in most clear cell renal carcinomas. Hadaczek, P., Siprashvili, Z., Markiewski, M., Domagala, W., Druck, T., McCue, P.A., Pekarsky, Y., Ohta, M., Huebner, K., Lubinski, J. Cancer Res. (1998) [Pubmed]
  16. Nitrilase and Fhit homologs are encoded as fusion proteins in Drosophila melanogaster and Caenorhabditis elegans. Pekarsky, Y., Campiglio, M., Siprashvili, Z., Druck, T., Sedkov, Y., Tillib, S., Draganescu, A., Wermuth, P., Rothman, J.H., Huebner, K., Buchberg, A.M., Mazo, A., Brenner, C., Croce, C.M. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  17. The tumor spectrum in FHIT-deficient mice. Zanesi, N., Fidanza, V., Fong, L.Y., Mancini, R., Druck, T., Valtieri, M., Rüdiger, T., McCue, P.A., Croce, C.M., Huebner, K. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  18. Inactivation of the FHIT gene favors bladder cancer development. Vecchione, A., Sevignani, C., Giarnieri, E., Zanesi, N., Ishii, H., Cesari, R., Fong, L.Y., Gomella, L.G., Croce, C.M., Baffa, R. Clin. Cancer Res. (2004) [Pubmed]
  19. Replacement of Fhit in cancer cells suppresses tumorigenicity. Siprashvili, Z., Sozzi, G., Barnes, L.D., McCue, P., Robinson, A.K., Eryomin, V., Sard, L., Tagliabue, E., Greco, A., Fusetti, L., Schwartz, G., Pierotti, M.A., Croce, C.M., Huebner, K. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  20. Crystal structure of the worm NitFhit Rosetta Stone protein reveals a Nit tetramer binding two Fhit dimers. Pace, H.C., Hodawadekar, S.C., Draganescu, A., Huang, J., Bieganowski, P., Pekarsky, Y., Croce, C.M., Brenner, C. Curr. Biol. (2000) [Pubmed]
  21. Effect of adenoviral transduction of the fragile histidine triad gene into esophageal cancer cells. Ishii, H., Dumon, K.R., Vecchione, A., Trapasso, F., Mimori, K., Alder, H., Mori, M., Sozzi, G., Baffa, R., Huebner, K., Croce, C.M. Cancer Res. (2001) [Pubmed]
  22. FHIT gene therapy prevents tumor development in Fhit-deficient mice. Dumon, K.R., Ishii, H., Fong, L.Y., Zanesi, N., Fidanza, V., Mancini, R., Vecchione, A., Baffa, R., Trapasso, F., During, M.J., Huebner, K., Croce, C.M. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  23. CpG methylation in the Fhit regulatory region: relation to Fhit expression in murine tumors. Han, S.Y., Iliopoulos, D., Druck, T., Guler, G., Grubbs, C.J., Pereira, M., Zhang, Z., You, M., Lubet, R.A., Fong, L.Y., Huebner, K. Oncogene (2004) [Pubmed]
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