* 601153

FRAGILE HISTIDINE TRIAD DIADENOSINE TRIPHOSPHATASE; FHIT


Alternative titles; symbols

FRAGILE HISTIDINE TRIAD GENE
AP3A HYDROLASE


Other entities represented in this entry:

FRAGILE SITE 3p14.2, INCLUDED; FRA3B, INCLUDED

HGNC Approved Gene Symbol: FHIT

Cytogenetic location: 3p14.2     Genomic coordinates (GRCh38): 3:59,747,277-61,251,452 (from NCBI)


TEXT

Cloning and Expression

A 200- to 300-kb region of 3p14.2, including the fragile site locus FRA3B (see CYTOGENETICS), is homozygously deleted in multiple tumor-derived cell lines. By exon amplification from cosmids covering this deleted region, Ohta et al. (1996) identified a gene that they designated fragile histidine triad (FHIT). The FHIT gene, a member of the histidine triad gene family, encodes a protein similar to the aph1 gene in S. pombe.

Barnes et al. (1996) found that the FHIT protein is a 147-amino acid AP3A hydrolase (EC 3.6.1.29).


Gene Structure

Ohta et al. (1996) determined that the FHIT gene contains 10 exons distributed over at least 500 kb.


Mapping

By sequence analysis, Ohta et al. (1996) mapped the FHIT gene to chromosome 3p14.2.


Gene Function

Barnes et al. (1996) identified FHIT as an AP3A hydrolase. They stated that the FHIT preferred substrate, AP3A (diadenosine 5-prime,5-triple prime-P(1),P(3)-triphosphate), and AP4A (see 602852) have been proposed to have various intracellular functions, including regulation of DNA replication and signaling stress responses. The conserved residues of the histidine triad are required for enzymatic activity.

Using a yeast 2-hybrid screen to search for proteins that interact with the FHIT protein in vivo, Shi et al. (2000) found that UBC9 (601661) is specifically associated with FHIT. The last 21 amino acids at the C terminus of UBC9 appear to be unimportant for its biologic activity, since a UBC9 mutant harboring a deletion of these amino acids could still restore normal growth of yeast containing a temperature-sensitive mutation in the homolog UBC9 gene. Mutational analysis indicated that UBC9 was associated with the C-terminal portion of FHIT. The interaction between FHIT and UBC9 appeared to be independent of the enzymatic activity of FHIT. Given that yeast UBC9 is involved in the degradation of S- and M-phase cyclins, Shi et al. (2000) concluded that FHIT may be involved in cell cycle control through its interaction with UBC9.

Pekarsky et al. (2004) noted that a considerable amount of data describing inactivation of FHIT in a variety of human malignancies and demonstrating the tumor suppressor potential of FHIT had been reported, and sought to determine the pathway through which FHIT induces apoptosis and inhibits growth of cancer cells. They demonstrated that FHIT is a target of tyrosine phosphorylation by the SRC protein kinase (190090). They showed that SRC phosphorylates tyrosine-114 of FHIT in vitro and in vivo, providing insight into a biochemical pathway involved in FHIT signaling.

Weiske et al. (2007) showed that FHIT associated with a complex of lymphoid enhancer-binding factor-1 (LEF1; 153245), T-cell factor (see TCF7; 189908), and beta-catenin (CTNNB1; 116806) in human embryonic kidney cells. FHIT bound directly to the C-terminal domain of beta-catenin, a major component of the canonical Wnt (see 164820) signaling pathway, and repressed transcription of target genes, including cyclin D1 (CCND1; 168461), AXIN2 (604025), MMP14 (600754), and survivin (BIRC5; 603352). Knockdown of FHIT reversed these effects, but this reversal was not detected with simultaneous knockdown of beta-catenin. Mutation of a residue critical for FHIT diadenosine-polyphosphate hydrolase activity (his96) showed that FHIT enzymatic activity was not required for downregulation of beta-catenin-mediated transcription. Chromatin immunoprecipitation analysis revealed recruitment of FHIT/beta-catenin complexes to target gene promoters. In soft agar assays, FHIT and beta-catenin regulated anchorage-independent growth in a human breast cancer cell line. Weiske et al. (2007) concluded that FHIT has a major role in regulating beta-catenin-mediated gene transcription.

Role of FHIT in Carcinoma

Ohta et al. (1996) identified aberrant FHIT transcripts in approximately 50% of esophageal, stomach, and colon carcinomas.

Sozzi et al. (1996) analyzed the FHIT gene structure and transcription in a large series of lung cancers of the small cell (SCLC) and nonsmall cell (NSCLC) type. FHIT transcripts from tumors and normal tissues were studied by RT-PCR. In 11 of 14 SCLC tumors, abnormal-sized transcripts were found. Both normal- and abnormal-sized transcripts were present in 9 of these cases. In 18 of 25 NSCLC tumors, abnormal transcripts were found; in these tumors, there were 1 or 2 abnormal-sized bands which were always accompanied by a normal-sized transcript. The authors postulated that the normal-sized transcripts reflected the presence of normal cells within the tumors. Sozzi et al. (1996) reported loss of heterozygosity for microsatellite markers internal to and flanking the FHIT locus. Eleven of 12 informative tumors that exhibited abnormal FHIT transcripts showed allelic loss at 1 or more of the loci tested. The authors postulated that in these tumors inactivation of the FHIT gene occurred by a mechanism of loss of 1 allele and altered expression of the remaining allele. They further postulated that loss of function of the FHIT gene could result in the constitutive accumulation of high levels of intracellular diadenosine tetraphosphate and the stimulation of DNA synthesis and proliferation. Sozzi et al. (1996) proposed that breakage in a fragile site-containing gene may occur as a consequence of physical, chemical, and biologic agents.

Virgilio et al. (1996) noted that head and neck cancers (HNSCC; 275355) represent 3% of all cancer in Western countries. In some geographic areas such as India, the proportion of cancer represented by these cancers is as high as 45%; 90 to 95% of head and neck cancers are of the squamous cell type. Tobacco and alcohol have been recognized as etiologic factors in these carcinomas. Several regions of loss of heterozygosity (LOH) have been identified in HNSCC. The 9p region presents the highest rate of genetic alteration (75%) and LOH has been related to the CDKN2 (600160) tumor suppressor gene. The second most frequent alteration involves 3p (45 to 55%). Virgilio et al. (1996) examined 26 HNSCC cell lines for deletions within the FHIT locus by Southern analysis, for allelic loss of specific exons of FHIT by fluorescence in situ hybridization, and for integrity of FHIT transcripts. Three of the 26 cell lines exhibited homozygous deletions within the FHIT gene, 55% (15 of 25) showed aberrant transcripts, and 65% (13 of 20) showed multiple cell populations with losses of different portions of the FHIT alleles. When the data were combined, 22 of 26 cell lines showed alterations of at least 1 allele of the FHIT gene. Thus, Virgilio et al. (1996) concluded that loss of FHIT function may be important in the development and/or progression of head and neck cancers.

Using Western blot analysis, Morikawa et al. (2000) found that 47% of colorectal adenomas showed altered expression of the FHIT protein, a higher frequency than that for KRAS2 (190070). The amount of FHIT protein was inversely correlated with the degree of dysplasia. Twenty-seven percent of low-grade dysplastic adenomas showed altered expression of FHIT protein. Additionally, expression of FHIT protein in colon carcinoma cell line SW480 exhibited a marked inhibition of growth and rendered SW480 cells highly susceptible to undergo apoptosis compared to control cells. These findings suggested that altered expression of the FHIT gene is an early aberration in the development of colorectal tumors and that FHIT protein may act as a tumor suppressor.

Lee et al. (2001) examined genomic alterations and abnormal expression of the FHIT gene in gastric carcinomas to determine whether it is a frequent target for alterations during gastric carcinogenesis. They concluded that a high frequency of aberrant FHIT transcripts, a significant rate of LOH at D3S1300, and altered expression of the FHIT protein indicate that alterations of the FHIT gene can play an important role in gastric carcinogenesis.

Holbach et al. (2002) examined biopsy specimens of periocular sebaceous gland carcinoma from 6 patients with Muir-Torre syndrome (158320). They found that the FHIT protein was detectable in just 1 sebaceous gland carcinoma from 1 patient with microsatellite instability. FHIT was undetectable in the remaining 5 sebaceous gland carcinomas, which showed no evidence of microsatellite instability. The authors concluded that inactivation of the FHIT tumor suppressor gene or inactivation of the mismatch-repair system resulting in microsatellite instability might contribute to the development of periocular sebaceous gland carcinoma in Muir-Torre syndrome.

Huebner and Croce (2003) reviewed the mutations in FHIT in primary tumors and the associated clinical features. They pointed out that since the FHIT gene was discovered in 1996 more than 350 reports of studies had been published. The data they summarized indicated that FHIT is altered in many human tumors, particularly in those caused by environmental carcinogens, such as those present in tobacco smoke. In many of these tumors, particularly in those induced by tobacco or other environmental carcinogens, alterations of FHIT occur very early during the multistep process of carcinogenesis. Huebner and Croce (2001) showed that FHIT-negative cancer cells are very sensitive to the expression of FHIT; for example, infection with FHIT recombinant viruses can cause regression and prevention of tumors in experimental animals. Thus, it is logical to predict the development of a gene therapy approach for the treatment and prevention of FHIT-negative human cancers.


Cytogenetics

Translocations Involving FHIT

Cohen et al. (1979) observed a constitutional reciprocal t(3;8) translocation associated with early onset, bilateral, and multifocal clear cell renal carcinoma (144700). Wang and Perkins (1984) demonstrated that the site of the break on chromosome 3 is at 3p14.2. Another cytogenetic landmark in the 3p14.2 region is the FRA3B fragile site (Markkanen et al., 1982). A 200- to 300-kb region of 3p14.2, including FRA3B, is homozygously deleted in multiple tumor-derived cell lines. Ohta et al. (1996) determined that three 5-prime untranslated exons of FHIT are centromeric to the renal carcinoma-associated 3p14.2 breakpoint, the remaining exons are telomeric to this translocation breakpoint, and exon 5 is within the homozygously deleted fragile region.

Gemmill et al. (1998) studied the family of Cohen et al. (1979) in which the constitutional reciprocal t(3;8) translocation was associated with early-onset, bilateral, and multifocal clear cell renal carcinoma. Previous studies had demonstrated that the 3p14.2 breakpoint interrupts the FHIT gene in its 5-prime noncoding region; however, that FHIT was causally related to renal or other malignancies was controversial. Gemmill et al. (1998) showed that the 8q24.1 breakpoint region encodes a 664-amino acid multiple membrane-spanning protein, TRC8 (603046), with similarity to the hereditary basal cell carcinoma/segment polarity gene 'Patched' (PTCH; 601309). In the 3;8 translocation, TRC8 is fused to FHIT and is disrupted within the sterol-sensing domain. In contrast, the FHIT coding region is maintained and expressed.

Geurts et al. (1997) found that FHIT was involved in a translocation-derived fusion with HMGIC (600698), the causative gene in a variety of benign tumors.

Fragile Site FRA3B

FRA3B at chromosome 3p14.2 is the most common of the constitutive aphidicolin (APH)-inducible fragile sites (Markkanen et al., 1982).

Rassool et al. (1996) investigated the structure of the fragile site FRA3B and compared it to the structures of other fragile sites, such as FRAXA (see 309550) and FRAXE (309548). They constructed a partial contig of genomic clones spanning 85 kb of genomic DNA in the 3p14.2 region using a recombinogenic pSV2neo plasmid as a means to select for common fragile sites. This contig lies approximately 350 kb from the t(3;8) constitutional rearrangement. Rare fragile sites are often associated with (CGG)n repeats. However, by sequencing and Southern analysis Rassool et al. (1996) found neither (CGG)n repeats nor other sequences associated with rare fragile sites within the 85-kb contig. Fluorescence in situ hybridization of genomic clones from this contig to metaphase chromosomes induced to express breaks showed hybridization adjoining the chromosome breaks, and occasionally the hybridization signal spanned the break. Rassool et al. (1996) concluded that (1) breakage at the common fragile site FRA3B may differ from breakage at rare fragile sites and (2) breakage at common fragile sites may occur at variable positions within a large region.

The hypothesis that chromosomal fragile sites may be 'weak links' that result in hotspots for cancer-specific chromosome rearrangements was supported by the discovery that numerous cancer cell homozygous deletions and familial translocations map within the FHIT gene, which encompasses the common fragile site FRA3B. By sequence analysis of 276 kb of the FRA3B/FHIT locus and 22 associated cancer cell deletion endpoints, Inoue et al. (1997) demonstrated that this locus is a frequent target of homologous recombination between long interspersed nuclear element (LINE) sequences resulting in FHIT gene internal deletions, probably as a result of carcinogen-induced damage at FRA3B fragile sites.

To determine whether some individuals have increased fragility of FRA3B that might increase the risk for breakage or deletion in 3p14.2, Stein et al. (2002) examined fragile site expression in smokers, nonsmokers, and SCLC patients. They found that active smokers exhibited a significantly higher frequency of fragile site expression, including FRA3B, compared to that of nonsmokers and patients diagnosed with SCLC who had stopped smoking. These results suggested that active tobacco exposure increases chromosome fragile site expression, and that this fragility is transient and reversible.

FRA3B is deleted in many different cancers, including cervical cancers. Becker et al. (2002) presented evidence indicating that fragility extends over a 4-Mb region containing 5 genes, including FHIT. FRA3B gene expression analysis on a panel of cervical tumor-derived cell lines revealed that 3 of the 5 genes within FRA3B were aberrantly regulated. A similar analysis of genes outside of FRA3B indicated that the surrounding genes were not aberrantly expressed.

Jiang et al. (2009) analyzed chromatin modification patterns within the 6 human common fragile sites (CFSs) with the highest levels of breakage, including FRA3B and FRA16D (see 605131), and their surrounding non-fragile regions. Chromatin at most of the CFSs analyzed had significantly less histone acetylation than that of their surrounding non-fragile regions. Trichostatin A and/or 5-azadeoxycytidine treatment reduced chromosome breakage at CFSs. Chromatin at the most commonly expressed CFS, FRA3B, was more resistant to micrococcal nuclease than that of the flanking non-fragile sequences. The authors concluded that histone hypoacetylation is a characteristic epigenetic pattern of CFSs, and chromatin within CFSs may be relatively more compact than that of the non-fragile regions, indicating a role for chromatin conformation in genomic instability at CFSs. Jiang et al. (2009) hypothesized that lack of histone acetylation at CFSs may contribute to the defective response to replication stress characteristic of CFSs, leading to the genetic instability characteristic of these regions.

To investigate the unusual sensitivity of chromosomal common fragile sites to APH-induced replication stress, Palakodeti et al. (2010) examined replication dynamics within a 50-kb region of FRA3B, which is the most frequently expressed CFS. In untreated cells, there was significantly less newly replicated DNA at FRA3B origins of replication 1 to 3 (among a total of 4), as compared with 3 control origins located within nonfragile regions. In APH-treated cells, all 4 FRA3B origins and 3 control origins tested were active; however, there was a significant increase of nascent strand DNA at the control origins and, to a lesser extent, at FRA3B origins 1 to 3. Palakodeti et al. (2010) hypothesized that CFS origins may be less efficient, and that aphidicolin treatment may slow replication fork movement near these origins to a greater extent, resulting in impaired DNA replication and, ultimately, leading to the genetic instability characteristic of CFSs.

Letessier et al. (2011) showed that the fragility of FRA3B--the most active common fragile site in human lymphocytes--does not rely on fork slowing or stalling but on a paucity of initiation events. Indeed, in lymphoblastoid cells, but not in fibroblasts, initiation events are excluded from a FRA3B core extending approximately 700 kb, which forces forks coming from flanking regions to cover long distances in order to complete replication. Letessier et al. (2011) also showed that origins of the flanking regions fire in mid-S phase, leaving the site incompletely replicated upon fork slowing. Notably, FRA3B instability is specific to cells showing this particular initiation pattern. The fact that both origin setting and replication timing are highly plastic in mammalian cells explains the tissue specificity of common fragile site instability that they observed. Thus, Letessier et al. (2011) proposed that common fragile sites correspond to the latest initiation-poor regions to complete replication in a given cell type. For historical reasons, common fragile sites have been essentially mapped in lymphocytes. Therefore, common fragile site contribution to chromosomal rearrangements in tumors should be reassessed after mapping fragile sites in the cell type from which each tumor originates.


Animal Model

To investigate the role of the Fhit gene in carcinogen induction of neoplasia, Fong et al. (2000) inactivated 1 Fhit allele in mouse embryonic stem cells to produce F1 mice with an inactivated Fhit allele (+/-). Fhit +/+ and +/- mice were treated intragastrically with nitrosomethylbenzylamine and observed for 10 weeks posttreatment. In 25% of the +/+ mice, adenoma or papilloma of the forestomach developed, whereas 100% of the +/- mice developed multiple tumors that were a mixture of adenomas, squamous papillomas, and invasive carcinomas of the forestomach, as well as tumors of sebaceous glands. The visceral and sebaceous tumors, which lacked Fhit protein, were similar to those characteristic of the Muir-Torre familial cancer syndrome.

Zanesi et al. (2001) demonstrated that the tumor spectra for spontaneous and induced tumors observed in mice with 1 or both Fhit alleles inactivated was similar, suggesting that Fhit may be a one-hit tumor suppressor gene in some tissues.

Dumon et al. (2001) inhibited tumor development by oral gene transfer using adenoviral or adeno-associated viral vectors expressing the human FHIT gene in Fhit +/- mice, which are prone to tumor development after carcinogen exposure. They suggested that FHIT gene therapy could be a novel clinical approach not only in treatment of early stages of cancer, but also in prevention of human cancer.

Shiraishi et al. (2001) compared orthologous fragile regions, within the human FRA3B/FHIT and the murine Fra14a2/Fhit loci. They sequenced over 600 kb of the mouse locus, covering the region orthologous to the fragile epicenter of the FRA3B gene, and determined the Fhit deletion breakpoints in a mouse kidney cancer cell line. The murine locus, like the human FRA3B, was characterized by a high AT content. Alignment of the 2 sequences showed that this fragile region was stable in evolution despite its susceptibility to mitotic recombination on inhibition of DNA replication. There were also several unusual highly conserved regions (HCRs). The mouse Fhit locus, near the centromere of mouse chromosome 14, is an aphidicolin-inducible common fragile site.


REFERENCES

  1. Barnes, L. D., Garrison, P. N., Siprashvili, Z., Guranowski, A., Robinson, A. K., Ingram, S. W., Croce, C. M., Ohta, M., Huebner, K. Fhit, a putative tumor suppressor in humans, is a dinucleoside 5-prime,5-triple prime-P(1),P(3)-triphosphate hydrolase. Biochemistry 35: 11529-11535, 1996. [PubMed: 8794732, related citations] [Full Text]

  2. Becker, N. A., Thorland, E. C., Denison, S. R., Phillips, L. A., Smith, D. I. Evidence that instability within the FRA3B region extends four megabases. Oncogene 21: 8713-8722, 2002. [PubMed: 12483524, related citations] [Full Text]

  3. Bernar, J., Funderburk, S. J., Sparkes, R. S. The inducible fragile site on chromosome 3. (Letter) Hum. Genet. 66: 373 only, 1984. [PubMed: 6724590, related citations] [Full Text]

  4. Cohen, A. J., Li, F. P., Berg, S., Marchetto, D. J., Tsai, S., Jacobs, S. C., Brown, R. S. Hereditary renal-cell carcinoma associated with chromosomal translocation. New Eng. J. Med. 301: 592-595, 1979. [PubMed: 470981, related citations] [Full Text]

  5. Dumon, K. R., Ishii, H., Fong, L. Y. Y., Zanesi, N., Fidanza, V., Mancini, R., Vecchione, A., Baffa, R., Trapasso, F., During, M. J., Huebner, K., Croce, C. M. FHIT gene therapy prevents tumor development in Fhit-deficient mice. Proc. Nat. Acad. Sci. 98: 3346-3351, 2001. [PubMed: 11248081, images, related citations] [Full Text]

  6. Fong, L. Y. 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. Muir-Torre-like syndrome in Fhit-deficient mice. Proc. Nat. Acad. Sci. 97: 4742-4747, 2000. [PubMed: 10758156, images, related citations] [Full Text]

  7. Gemmill, R. M., West, J. D., Boldog, F., Tanaka, N., Robinson, L. J., Smith, D. I., Li, F., Drabkin, H. A. The hereditary renal cell carcinoma 3;8 translocation fuses FHIT to a patched-related gene, TRC8. Proc. Nat. Acad. Sci. 95: 9572-9577, 1998. [PubMed: 9689122, images, related citations] [Full Text]

  8. Geurts, J. M., Schoenmakers, E. F., Roijer, E., Stenman, G., Van de Ven, W. J. M. Expression of reciprocal hybrid transcripts of HMGIC and FHIT in a pleomorphic adenoma of the parotid gland. Cancer Res. 57: 13-17, 1997. [PubMed: 8988031, related citations]

  9. Holbach, L. M., von Moller, A., Decker, C., Junemann, A. G. M., Rummelt-Hofmann, C., Ballhausen, W. G. Loss of fragile histidine triad (FHIT) expression and microsatellite instability in periocular sebaceous gland carcinoma in patients with Muir-Torre syndrome. Am. J. Ophthal. 134: 147-148, 2002. [PubMed: 12095833, related citations] [Full Text]

  10. Huebner, K., Croce, C. M. FRA3B and other common fragile sites: the weakest links. Nature Rev. Cancer 1: 214-221, 2001. [PubMed: 11902576, related citations] [Full Text]

  11. Huebner, K., Croce, C. M. Cancer and the FRA3B/FHIT fragile locus: it's a HIT. Brit. J. Cancer 88: 1501-1506, 2003. [PubMed: 12771912, related citations] [Full Text]

  12. Inoue, H., Ishii, H., Alder, H., Snyder, E., Druck, T., Huebner, K., Croce, C. M. Sequence of the FRA3B common fragile region: implications for the mechanism of FHIT deletion. Proc. Nat. Acad. Sci. 94: 14584-14589, 1997. [PubMed: 9405656, images, related citations] [Full Text]

  13. Jiang, Y., Lucas, I., Young, D. J., Davis, E. M., Karrison, T., Rest, J. S., Le Beau, M. M. Common fragile sites are characterized by histone hypoacetylation. Hum. Molec. Genet. 18: 4501-4512, 2009. [PubMed: 19717471, images, related citations] [Full Text]

  14. Lee, S.-H., Kim, W.-H., Kim, H.-K., Woo, K.-M., Nam, H.-S., Kim, H.-S., Kim, J.-G., Cho, M.-H. Altered expression of the fragile histidine triad gene in primary gastric adenocarcinomas. Biochem. Biophys. Res. Commun. 284: 850-855, 2001. [PubMed: 11396980, related citations] [Full Text]

  15. Letessier, A., Millot, G. A., Koundrioukoff, S., Lachages, A.-M., Vogt, N., Hansen, R. S., Malfoy, B., Brison, O., Debatisse, M. Cell-type-specific replication initiation programs set fragility of the FRA3B fragile site. Nature 470: 120-123, 2011. [PubMed: 21258320, related citations] [Full Text]

  16. Markkanen, A., Heinonen, K., Knuutila, S., de la Chapelle, A. Methotrexate-induced increase in gap formation in human chromosome band 3p14. Hereditas 96: 317-319, 1982. [PubMed: 6985468, related citations] [Full Text]

  17. Markkanen, A., Knuutila, S., de la Chapelle, A. Inducible fragile site on chromosome 3. (Letter) Hum. Genet. 65: 217 only, 1983. [PubMed: 6654339, related citations] [Full Text]

  18. Morikawa, H., Nakagawa, Y., Hashimoto, K., Niki, M., Egashira, Y., Hirata, I., Katsu, K., Akao, Y. Frequent altered expression of fragile histidine triad protein in human colorectal adenomas. Biochem. Biophys. Res. Commun. 278: 205-210, 2000. [PubMed: 11071873, related citations] [Full Text]

  19. Ohta, M., Inoue, H., Cotticelli, M. G., Kastury, K., Baffa, R., Palazzo, J., Siprashvili, Z., Mori, M., McCue, P., Druck, T., Croce, C. M., Huebner, K. The FHIT gene, spanning the chromosome 3p14.2 fragile site and renal carcinoma-associated t(3;8) breakpoint, is abnormal in digestive tract cancers. Cell 84: 587-597, 1996. [PubMed: 8598045, related citations] [Full Text]

  20. Palakodeti, A., Lucas, I., Jiang, Y., Young, D. J., Fernald, A. A., Karrison, T., Le Beau, M. M. Impaired replication dynamics at the FRA3B common fragile site. Hum. Molec. Genet. 19: 99-110, 2010. [PubMed: 19815620, images, related citations] [Full Text]

  21. Pekarsky, Y., Garrison, P. N., Palamarchuk, A., Zanesi, N., Aqeilan, R. I., Huebner, K., Barnes, L. D., Croce, C. M. Fhit is a physiological target of the protein kinase Src. Proc. Nat. Acad. Sci. 101: 3775-3779, 2004. [PubMed: 15007172, images, related citations] [Full Text]

  22. Rassool, F. V., Le Beau, M. M., Shen, M.-L., Neilly, M. E., Espinosa, R., III, Ong, S. T., Boldog, F., Drabkin, H., McCarroll, R., McKeithan, T. W. Direct cloning of DNA sequences from the common fragile site region at chromosome band 3p14.2. Genomics 35: 109-117, 1996. [PubMed: 8661111, related citations] [Full Text]

  23. Rudduck, C., Franzen, G. A new heritable fragile site on human chromosome 3. Hereditas 98: 297-299, 1983. [PubMed: 6874402, related citations] [Full Text]

  24. Shi, Y., Zou, M., Farid, N. R., Paterson, M. C. Association of FHIT (fragile histidine triad), a candidate tumour suppressor gene, with the ubiquitin-conjugating enzyme hUBC9. Biochem. J. 352: 443-448, 2000. [PubMed: 11085938, related citations]

  25. Shiraishi, T., Druck, T., Mimori, K., Flomenberg, J., Berk, L., Alder, H., Miller, W., Huebner, K., Croce, C. M. Sequence conservation at human and mouse orthologous common fragile regions, FRA3B/FHIT and Fra14A2/Fhit. Proc. Nat. Acad. Sci. 98: 5722-5727, 2001. [PubMed: 11320209, images, related citations] [Full Text]

  26. Sozzi, G., Veronese, M. L., Negrini, M., Baffa, R., Cotticelli, M. G., Inoue, H., Tornielli, S., Pilotti, S., De Gregorio, L., Pastorino, U., Pierotti, M. A., Ohta, M., Huebner, K., Croce, C. M. The FHIT gene at 3p14.2 is abnormal in lung cancer. Cell 85: 17-26, 1996. [PubMed: 8620533, related citations] [Full Text]

  27. Stein, C. K., Glover, T. W., Palmer, J. L., Glisson, B. S. Direct correlation between FRA3B expression and cigarette smoking. Genes Chromosomes Cancer 34: 333-340, 2002. [PubMed: 12007194, related citations] [Full Text]

  28. Virgilio, L., Shuster, M., Gollin, S. M., Veronese, M. L., Ohta, M., Huebner, K., Croce, C. M. FHIT gene alterations in head and neck squamous cell carcinomas. Proc. Nat. Acad. Sci. 93: 9770-9775, 1996. [PubMed: 8790406, related citations] [Full Text]

  29. Wang, N., Perkins, K. L. Involvement of band 3p14 in t(3;8) hereditary renal carcinoma. Cancer Genet. Cytogenet. 11: 479-481, 1984. [PubMed: 6704944, related citations] [Full Text]

  30. Wegner, R.-D. A new inducible fragile site on chromosome 3 (p14.2) in human lymphocytes. Hum. Genet. 63: 297-298, 1983. [PubMed: 6852828, related citations] [Full Text]

  31. Wegner, R.-D. Reply to the letter of A. Markkanen, S. Knuutila, and A. de la Chapelle. (Letter) Hum. Genet. 65: 218 only, 1983.

  32. Weiske, J., Albring, K. F., Huber, O. The tumor suppressor Fhit acts as a repressor of beta-catenin transcriptional activity. Proc. Nat. Acad. Sci. 104: 20344-20349, 2007. [PubMed: 18077326, images, related citations] [Full Text]

  33. Zanesi, N., Fidanza, V., Fong, L. Y., Mancini, R., Druck, T., Valtieri, M., Rudiger, T., McCue, P. A., Croce, C. M., Huebner, K. The tumor spectrum in FHIT-deficient mice. Proc. Nat. Acad. Sci. 98: 10250-10255, 2001. [PubMed: 11517343, images, related citations] [Full Text]


Ada Hamosh - updated : 6/10/2011
George E. Tiller - updated : 11/12/2010
George E. Tiller - updated : 10/28/2010
Patricia A. Hartz - updated : 4/16/2008
Victor A. McKusick - updated : 4/9/2004
Victor A. McKusick - updated : 9/16/2003
Victor A. McKusick - updated : 2/12/2003
Jane Kelly - updated : 11/5/2002
Victor A. McKusick - updated : 8/23/2002
Victor A. McKusick - updated : 12/6/2001
Victor A. McKusick - updated : 6/1/2001
Victor A. McKusick - updated : 4/11/2001
Victor A. McKusick - updated : 6/15/2000
Victor A. McKusick - updated : 8/31/1998
Jennifer P. Macke - updated : 7/15/1998
Victor A. McKusick - updated : 2/6/1998
Jennifer P. Macke - updated : 7/25/1996
Moyra Smith - updated : 4/22/1996
Creation Date:
Victor A. McKusick : 3/22/1996
alopez : 05/04/2022
carol : 03/04/2021
alopez : 06/22/2011
terry : 6/10/2011
wwang : 11/19/2010
terry : 11/12/2010
wwang : 11/8/2010
terry : 10/28/2010
terry : 10/8/2008
mgross : 4/16/2008
carol : 11/27/2006
mgross : 1/21/2005
tkritzer : 4/14/2004
terry : 4/9/2004
tkritzer : 9/30/2003
cwells : 9/16/2003
carol : 2/27/2003
tkritzer : 2/24/2003
terry : 2/12/2003
cwells : 11/5/2002
tkritzer : 9/9/2002
tkritzer : 9/9/2002
tkritzer : 8/28/2002
terry : 8/23/2002
terry : 8/23/2002
carol : 7/1/2002
carol : 12/11/2001
mcapotos : 12/6/2001
mcapotos : 6/7/2001
mcapotos : 6/4/2001
terry : 6/1/2001
mcapotos : 4/23/2001
mcapotos : 4/18/2001
mcapotos : 4/16/2001
terry : 4/11/2001
mcapotos : 7/17/2000
mcapotos : 7/11/2000
mcapotos : 7/11/2000
terry : 6/15/2000
carol : 9/18/1998
dkim : 9/9/1998
terry : 8/31/1998
alopez : 7/15/1998
alopez : 5/21/1998
mark : 2/15/1998
terry : 2/6/1998
mark : 11/18/1996
terry : 10/23/1996
mark : 10/16/1996
mark : 7/25/1996
terry : 5/24/1996
carol : 5/22/1996
carol : 4/22/1996
mark : 3/25/1996

* 601153

FRAGILE HISTIDINE TRIAD DIADENOSINE TRIPHOSPHATASE; FHIT


Alternative titles; symbols

FRAGILE HISTIDINE TRIAD GENE
AP3A HYDROLASE


Other entities represented in this entry:

FRAGILE SITE 3p14.2, INCLUDED; FRA3B, INCLUDED

HGNC Approved Gene Symbol: FHIT

Cytogenetic location: 3p14.2     Genomic coordinates (GRCh38): 3:59,747,277-61,251,452 (from NCBI)


TEXT

Cloning and Expression

A 200- to 300-kb region of 3p14.2, including the fragile site locus FRA3B (see CYTOGENETICS), is homozygously deleted in multiple tumor-derived cell lines. By exon amplification from cosmids covering this deleted region, Ohta et al. (1996) identified a gene that they designated fragile histidine triad (FHIT). The FHIT gene, a member of the histidine triad gene family, encodes a protein similar to the aph1 gene in S. pombe.

Barnes et al. (1996) found that the FHIT protein is a 147-amino acid AP3A hydrolase (EC 3.6.1.29).


Gene Structure

Ohta et al. (1996) determined that the FHIT gene contains 10 exons distributed over at least 500 kb.


Mapping

By sequence analysis, Ohta et al. (1996) mapped the FHIT gene to chromosome 3p14.2.


Gene Function

Barnes et al. (1996) identified FHIT as an AP3A hydrolase. They stated that the FHIT preferred substrate, AP3A (diadenosine 5-prime,5-triple prime-P(1),P(3)-triphosphate), and AP4A (see 602852) have been proposed to have various intracellular functions, including regulation of DNA replication and signaling stress responses. The conserved residues of the histidine triad are required for enzymatic activity.

Using a yeast 2-hybrid screen to search for proteins that interact with the FHIT protein in vivo, Shi et al. (2000) found that UBC9 (601661) is specifically associated with FHIT. The last 21 amino acids at the C terminus of UBC9 appear to be unimportant for its biologic activity, since a UBC9 mutant harboring a deletion of these amino acids could still restore normal growth of yeast containing a temperature-sensitive mutation in the homolog UBC9 gene. Mutational analysis indicated that UBC9 was associated with the C-terminal portion of FHIT. The interaction between FHIT and UBC9 appeared to be independent of the enzymatic activity of FHIT. Given that yeast UBC9 is involved in the degradation of S- and M-phase cyclins, Shi et al. (2000) concluded that FHIT may be involved in cell cycle control through its interaction with UBC9.

Pekarsky et al. (2004) noted that a considerable amount of data describing inactivation of FHIT in a variety of human malignancies and demonstrating the tumor suppressor potential of FHIT had been reported, and sought to determine the pathway through which FHIT induces apoptosis and inhibits growth of cancer cells. They demonstrated that FHIT is a target of tyrosine phosphorylation by the SRC protein kinase (190090). They showed that SRC phosphorylates tyrosine-114 of FHIT in vitro and in vivo, providing insight into a biochemical pathway involved in FHIT signaling.

Weiske et al. (2007) showed that FHIT associated with a complex of lymphoid enhancer-binding factor-1 (LEF1; 153245), T-cell factor (see TCF7; 189908), and beta-catenin (CTNNB1; 116806) in human embryonic kidney cells. FHIT bound directly to the C-terminal domain of beta-catenin, a major component of the canonical Wnt (see 164820) signaling pathway, and repressed transcription of target genes, including cyclin D1 (CCND1; 168461), AXIN2 (604025), MMP14 (600754), and survivin (BIRC5; 603352). Knockdown of FHIT reversed these effects, but this reversal was not detected with simultaneous knockdown of beta-catenin. Mutation of a residue critical for FHIT diadenosine-polyphosphate hydrolase activity (his96) showed that FHIT enzymatic activity was not required for downregulation of beta-catenin-mediated transcription. Chromatin immunoprecipitation analysis revealed recruitment of FHIT/beta-catenin complexes to target gene promoters. In soft agar assays, FHIT and beta-catenin regulated anchorage-independent growth in a human breast cancer cell line. Weiske et al. (2007) concluded that FHIT has a major role in regulating beta-catenin-mediated gene transcription.

Role of FHIT in Carcinoma

Ohta et al. (1996) identified aberrant FHIT transcripts in approximately 50% of esophageal, stomach, and colon carcinomas.

Sozzi et al. (1996) analyzed the FHIT gene structure and transcription in a large series of lung cancers of the small cell (SCLC) and nonsmall cell (NSCLC) type. FHIT transcripts from tumors and normal tissues were studied by RT-PCR. In 11 of 14 SCLC tumors, abnormal-sized transcripts were found. Both normal- and abnormal-sized transcripts were present in 9 of these cases. In 18 of 25 NSCLC tumors, abnormal transcripts were found; in these tumors, there were 1 or 2 abnormal-sized bands which were always accompanied by a normal-sized transcript. The authors postulated that the normal-sized transcripts reflected the presence of normal cells within the tumors. Sozzi et al. (1996) reported loss of heterozygosity for microsatellite markers internal to and flanking the FHIT locus. Eleven of 12 informative tumors that exhibited abnormal FHIT transcripts showed allelic loss at 1 or more of the loci tested. The authors postulated that in these tumors inactivation of the FHIT gene occurred by a mechanism of loss of 1 allele and altered expression of the remaining allele. They further postulated that loss of function of the FHIT gene could result in the constitutive accumulation of high levels of intracellular diadenosine tetraphosphate and the stimulation of DNA synthesis and proliferation. Sozzi et al. (1996) proposed that breakage in a fragile site-containing gene may occur as a consequence of physical, chemical, and biologic agents.

Virgilio et al. (1996) noted that head and neck cancers (HNSCC; 275355) represent 3% of all cancer in Western countries. In some geographic areas such as India, the proportion of cancer represented by these cancers is as high as 45%; 90 to 95% of head and neck cancers are of the squamous cell type. Tobacco and alcohol have been recognized as etiologic factors in these carcinomas. Several regions of loss of heterozygosity (LOH) have been identified in HNSCC. The 9p region presents the highest rate of genetic alteration (75%) and LOH has been related to the CDKN2 (600160) tumor suppressor gene. The second most frequent alteration involves 3p (45 to 55%). Virgilio et al. (1996) examined 26 HNSCC cell lines for deletions within the FHIT locus by Southern analysis, for allelic loss of specific exons of FHIT by fluorescence in situ hybridization, and for integrity of FHIT transcripts. Three of the 26 cell lines exhibited homozygous deletions within the FHIT gene, 55% (15 of 25) showed aberrant transcripts, and 65% (13 of 20) showed multiple cell populations with losses of different portions of the FHIT alleles. When the data were combined, 22 of 26 cell lines showed alterations of at least 1 allele of the FHIT gene. Thus, Virgilio et al. (1996) concluded that loss of FHIT function may be important in the development and/or progression of head and neck cancers.

Using Western blot analysis, Morikawa et al. (2000) found that 47% of colorectal adenomas showed altered expression of the FHIT protein, a higher frequency than that for KRAS2 (190070). The amount of FHIT protein was inversely correlated with the degree of dysplasia. Twenty-seven percent of low-grade dysplastic adenomas showed altered expression of FHIT protein. Additionally, expression of FHIT protein in colon carcinoma cell line SW480 exhibited a marked inhibition of growth and rendered SW480 cells highly susceptible to undergo apoptosis compared to control cells. These findings suggested that altered expression of the FHIT gene is an early aberration in the development of colorectal tumors and that FHIT protein may act as a tumor suppressor.

Lee et al. (2001) examined genomic alterations and abnormal expression of the FHIT gene in gastric carcinomas to determine whether it is a frequent target for alterations during gastric carcinogenesis. They concluded that a high frequency of aberrant FHIT transcripts, a significant rate of LOH at D3S1300, and altered expression of the FHIT protein indicate that alterations of the FHIT gene can play an important role in gastric carcinogenesis.

Holbach et al. (2002) examined biopsy specimens of periocular sebaceous gland carcinoma from 6 patients with Muir-Torre syndrome (158320). They found that the FHIT protein was detectable in just 1 sebaceous gland carcinoma from 1 patient with microsatellite instability. FHIT was undetectable in the remaining 5 sebaceous gland carcinomas, which showed no evidence of microsatellite instability. The authors concluded that inactivation of the FHIT tumor suppressor gene or inactivation of the mismatch-repair system resulting in microsatellite instability might contribute to the development of periocular sebaceous gland carcinoma in Muir-Torre syndrome.

Huebner and Croce (2003) reviewed the mutations in FHIT in primary tumors and the associated clinical features. They pointed out that since the FHIT gene was discovered in 1996 more than 350 reports of studies had been published. The data they summarized indicated that FHIT is altered in many human tumors, particularly in those caused by environmental carcinogens, such as those present in tobacco smoke. In many of these tumors, particularly in those induced by tobacco or other environmental carcinogens, alterations of FHIT occur very early during the multistep process of carcinogenesis. Huebner and Croce (2001) showed that FHIT-negative cancer cells are very sensitive to the expression of FHIT; for example, infection with FHIT recombinant viruses can cause regression and prevention of tumors in experimental animals. Thus, it is logical to predict the development of a gene therapy approach for the treatment and prevention of FHIT-negative human cancers.


Cytogenetics

Translocations Involving FHIT

Cohen et al. (1979) observed a constitutional reciprocal t(3;8) translocation associated with early onset, bilateral, and multifocal clear cell renal carcinoma (144700). Wang and Perkins (1984) demonstrated that the site of the break on chromosome 3 is at 3p14.2. Another cytogenetic landmark in the 3p14.2 region is the FRA3B fragile site (Markkanen et al., 1982). A 200- to 300-kb region of 3p14.2, including FRA3B, is homozygously deleted in multiple tumor-derived cell lines. Ohta et al. (1996) determined that three 5-prime untranslated exons of FHIT are centromeric to the renal carcinoma-associated 3p14.2 breakpoint, the remaining exons are telomeric to this translocation breakpoint, and exon 5 is within the homozygously deleted fragile region.

Gemmill et al. (1998) studied the family of Cohen et al. (1979) in which the constitutional reciprocal t(3;8) translocation was associated with early-onset, bilateral, and multifocal clear cell renal carcinoma. Previous studies had demonstrated that the 3p14.2 breakpoint interrupts the FHIT gene in its 5-prime noncoding region; however, that FHIT was causally related to renal or other malignancies was controversial. Gemmill et al. (1998) showed that the 8q24.1 breakpoint region encodes a 664-amino acid multiple membrane-spanning protein, TRC8 (603046), with similarity to the hereditary basal cell carcinoma/segment polarity gene 'Patched' (PTCH; 601309). In the 3;8 translocation, TRC8 is fused to FHIT and is disrupted within the sterol-sensing domain. In contrast, the FHIT coding region is maintained and expressed.

Geurts et al. (1997) found that FHIT was involved in a translocation-derived fusion with HMGIC (600698), the causative gene in a variety of benign tumors.

Fragile Site FRA3B

FRA3B at chromosome 3p14.2 is the most common of the constitutive aphidicolin (APH)-inducible fragile sites (Markkanen et al., 1982).

Rassool et al. (1996) investigated the structure of the fragile site FRA3B and compared it to the structures of other fragile sites, such as FRAXA (see 309550) and FRAXE (309548). They constructed a partial contig of genomic clones spanning 85 kb of genomic DNA in the 3p14.2 region using a recombinogenic pSV2neo plasmid as a means to select for common fragile sites. This contig lies approximately 350 kb from the t(3;8) constitutional rearrangement. Rare fragile sites are often associated with (CGG)n repeats. However, by sequencing and Southern analysis Rassool et al. (1996) found neither (CGG)n repeats nor other sequences associated with rare fragile sites within the 85-kb contig. Fluorescence in situ hybridization of genomic clones from this contig to metaphase chromosomes induced to express breaks showed hybridization adjoining the chromosome breaks, and occasionally the hybridization signal spanned the break. Rassool et al. (1996) concluded that (1) breakage at the common fragile site FRA3B may differ from breakage at rare fragile sites and (2) breakage at common fragile sites may occur at variable positions within a large region.

The hypothesis that chromosomal fragile sites may be 'weak links' that result in hotspots for cancer-specific chromosome rearrangements was supported by the discovery that numerous cancer cell homozygous deletions and familial translocations map within the FHIT gene, which encompasses the common fragile site FRA3B. By sequence analysis of 276 kb of the FRA3B/FHIT locus and 22 associated cancer cell deletion endpoints, Inoue et al. (1997) demonstrated that this locus is a frequent target of homologous recombination between long interspersed nuclear element (LINE) sequences resulting in FHIT gene internal deletions, probably as a result of carcinogen-induced damage at FRA3B fragile sites.

To determine whether some individuals have increased fragility of FRA3B that might increase the risk for breakage or deletion in 3p14.2, Stein et al. (2002) examined fragile site expression in smokers, nonsmokers, and SCLC patients. They found that active smokers exhibited a significantly higher frequency of fragile site expression, including FRA3B, compared to that of nonsmokers and patients diagnosed with SCLC who had stopped smoking. These results suggested that active tobacco exposure increases chromosome fragile site expression, and that this fragility is transient and reversible.

FRA3B is deleted in many different cancers, including cervical cancers. Becker et al. (2002) presented evidence indicating that fragility extends over a 4-Mb region containing 5 genes, including FHIT. FRA3B gene expression analysis on a panel of cervical tumor-derived cell lines revealed that 3 of the 5 genes within FRA3B were aberrantly regulated. A similar analysis of genes outside of FRA3B indicated that the surrounding genes were not aberrantly expressed.

Jiang et al. (2009) analyzed chromatin modification patterns within the 6 human common fragile sites (CFSs) with the highest levels of breakage, including FRA3B and FRA16D (see 605131), and their surrounding non-fragile regions. Chromatin at most of the CFSs analyzed had significantly less histone acetylation than that of their surrounding non-fragile regions. Trichostatin A and/or 5-azadeoxycytidine treatment reduced chromosome breakage at CFSs. Chromatin at the most commonly expressed CFS, FRA3B, was more resistant to micrococcal nuclease than that of the flanking non-fragile sequences. The authors concluded that histone hypoacetylation is a characteristic epigenetic pattern of CFSs, and chromatin within CFSs may be relatively more compact than that of the non-fragile regions, indicating a role for chromatin conformation in genomic instability at CFSs. Jiang et al. (2009) hypothesized that lack of histone acetylation at CFSs may contribute to the defective response to replication stress characteristic of CFSs, leading to the genetic instability characteristic of these regions.

To investigate the unusual sensitivity of chromosomal common fragile sites to APH-induced replication stress, Palakodeti et al. (2010) examined replication dynamics within a 50-kb region of FRA3B, which is the most frequently expressed CFS. In untreated cells, there was significantly less newly replicated DNA at FRA3B origins of replication 1 to 3 (among a total of 4), as compared with 3 control origins located within nonfragile regions. In APH-treated cells, all 4 FRA3B origins and 3 control origins tested were active; however, there was a significant increase of nascent strand DNA at the control origins and, to a lesser extent, at FRA3B origins 1 to 3. Palakodeti et al. (2010) hypothesized that CFS origins may be less efficient, and that aphidicolin treatment may slow replication fork movement near these origins to a greater extent, resulting in impaired DNA replication and, ultimately, leading to the genetic instability characteristic of CFSs.

Letessier et al. (2011) showed that the fragility of FRA3B--the most active common fragile site in human lymphocytes--does not rely on fork slowing or stalling but on a paucity of initiation events. Indeed, in lymphoblastoid cells, but not in fibroblasts, initiation events are excluded from a FRA3B core extending approximately 700 kb, which forces forks coming from flanking regions to cover long distances in order to complete replication. Letessier et al. (2011) also showed that origins of the flanking regions fire in mid-S phase, leaving the site incompletely replicated upon fork slowing. Notably, FRA3B instability is specific to cells showing this particular initiation pattern. The fact that both origin setting and replication timing are highly plastic in mammalian cells explains the tissue specificity of common fragile site instability that they observed. Thus, Letessier et al. (2011) proposed that common fragile sites correspond to the latest initiation-poor regions to complete replication in a given cell type. For historical reasons, common fragile sites have been essentially mapped in lymphocytes. Therefore, common fragile site contribution to chromosomal rearrangements in tumors should be reassessed after mapping fragile sites in the cell type from which each tumor originates.


Animal Model

To investigate the role of the Fhit gene in carcinogen induction of neoplasia, Fong et al. (2000) inactivated 1 Fhit allele in mouse embryonic stem cells to produce F1 mice with an inactivated Fhit allele (+/-). Fhit +/+ and +/- mice were treated intragastrically with nitrosomethylbenzylamine and observed for 10 weeks posttreatment. In 25% of the +/+ mice, adenoma or papilloma of the forestomach developed, whereas 100% of the +/- mice developed multiple tumors that were a mixture of adenomas, squamous papillomas, and invasive carcinomas of the forestomach, as well as tumors of sebaceous glands. The visceral and sebaceous tumors, which lacked Fhit protein, were similar to those characteristic of the Muir-Torre familial cancer syndrome.

Zanesi et al. (2001) demonstrated that the tumor spectra for spontaneous and induced tumors observed in mice with 1 or both Fhit alleles inactivated was similar, suggesting that Fhit may be a one-hit tumor suppressor gene in some tissues.

Dumon et al. (2001) inhibited tumor development by oral gene transfer using adenoviral or adeno-associated viral vectors expressing the human FHIT gene in Fhit +/- mice, which are prone to tumor development after carcinogen exposure. They suggested that FHIT gene therapy could be a novel clinical approach not only in treatment of early stages of cancer, but also in prevention of human cancer.

Shiraishi et al. (2001) compared orthologous fragile regions, within the human FRA3B/FHIT and the murine Fra14a2/Fhit loci. They sequenced over 600 kb of the mouse locus, covering the region orthologous to the fragile epicenter of the FRA3B gene, and determined the Fhit deletion breakpoints in a mouse kidney cancer cell line. The murine locus, like the human FRA3B, was characterized by a high AT content. Alignment of the 2 sequences showed that this fragile region was stable in evolution despite its susceptibility to mitotic recombination on inhibition of DNA replication. There were also several unusual highly conserved regions (HCRs). The mouse Fhit locus, near the centromere of mouse chromosome 14, is an aphidicolin-inducible common fragile site.


See Also:

Bernar et al. (1984); Markkanen et al. (1983); Rudduck and Franzen (1983); Wegner (1983); Wegner (1983)

REFERENCES

  1. Barnes, L. D., Garrison, P. N., Siprashvili, Z., Guranowski, A., Robinson, A. K., Ingram, S. W., Croce, C. M., Ohta, M., Huebner, K. Fhit, a putative tumor suppressor in humans, is a dinucleoside 5-prime,5-triple prime-P(1),P(3)-triphosphate hydrolase. Biochemistry 35: 11529-11535, 1996. [PubMed: 8794732] [Full Text: https://doi.org/10.1021/bi961415t]

  2. Becker, N. A., Thorland, E. C., Denison, S. R., Phillips, L. A., Smith, D. I. Evidence that instability within the FRA3B region extends four megabases. Oncogene 21: 8713-8722, 2002. [PubMed: 12483524] [Full Text: https://doi.org/10.1038/sj.onc.1205950]

  3. Bernar, J., Funderburk, S. J., Sparkes, R. S. The inducible fragile site on chromosome 3. (Letter) Hum. Genet. 66: 373 only, 1984. [PubMed: 6724590] [Full Text: https://doi.org/10.1007/BF00287648]

  4. Cohen, A. J., Li, F. P., Berg, S., Marchetto, D. J., Tsai, S., Jacobs, S. C., Brown, R. S. Hereditary renal-cell carcinoma associated with chromosomal translocation. New Eng. J. Med. 301: 592-595, 1979. [PubMed: 470981] [Full Text: https://doi.org/10.1056/NEJM197909133011107]

  5. Dumon, K. R., Ishii, H., Fong, L. Y. Y., Zanesi, N., Fidanza, V., Mancini, R., Vecchione, A., Baffa, R., Trapasso, F., During, M. J., Huebner, K., Croce, C. M. FHIT gene therapy prevents tumor development in Fhit-deficient mice. Proc. Nat. Acad. Sci. 98: 3346-3351, 2001. [PubMed: 11248081] [Full Text: https://doi.org/10.1073/pnas.061020098]

  6. Fong, L. Y. 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. Muir-Torre-like syndrome in Fhit-deficient mice. Proc. Nat. Acad. Sci. 97: 4742-4747, 2000. [PubMed: 10758156] [Full Text: https://doi.org/10.1073/pnas.080063497]

  7. Gemmill, R. M., West, J. D., Boldog, F., Tanaka, N., Robinson, L. J., Smith, D. I., Li, F., Drabkin, H. A. The hereditary renal cell carcinoma 3;8 translocation fuses FHIT to a patched-related gene, TRC8. Proc. Nat. Acad. Sci. 95: 9572-9577, 1998. [PubMed: 9689122] [Full Text: https://doi.org/10.1073/pnas.95.16.9572]

  8. Geurts, J. M., Schoenmakers, E. F., Roijer, E., Stenman, G., Van de Ven, W. J. M. Expression of reciprocal hybrid transcripts of HMGIC and FHIT in a pleomorphic adenoma of the parotid gland. Cancer Res. 57: 13-17, 1997. [PubMed: 8988031]

  9. Holbach, L. M., von Moller, A., Decker, C., Junemann, A. G. M., Rummelt-Hofmann, C., Ballhausen, W. G. Loss of fragile histidine triad (FHIT) expression and microsatellite instability in periocular sebaceous gland carcinoma in patients with Muir-Torre syndrome. Am. J. Ophthal. 134: 147-148, 2002. [PubMed: 12095833] [Full Text: https://doi.org/10.1016/s0002-9394(02)01434-4]

  10. Huebner, K., Croce, C. M. FRA3B and other common fragile sites: the weakest links. Nature Rev. Cancer 1: 214-221, 2001. [PubMed: 11902576] [Full Text: https://doi.org/10.1038/35106058]

  11. Huebner, K., Croce, C. M. Cancer and the FRA3B/FHIT fragile locus: it's a HIT. Brit. J. Cancer 88: 1501-1506, 2003. [PubMed: 12771912] [Full Text: https://doi.org/10.1038/sj.bjc.6600937]

  12. Inoue, H., Ishii, H., Alder, H., Snyder, E., Druck, T., Huebner, K., Croce, C. M. Sequence of the FRA3B common fragile region: implications for the mechanism of FHIT deletion. Proc. Nat. Acad. Sci. 94: 14584-14589, 1997. [PubMed: 9405656] [Full Text: https://doi.org/10.1073/pnas.94.26.14584]

  13. Jiang, Y., Lucas, I., Young, D. J., Davis, E. M., Karrison, T., Rest, J. S., Le Beau, M. M. Common fragile sites are characterized by histone hypoacetylation. Hum. Molec. Genet. 18: 4501-4512, 2009. [PubMed: 19717471] [Full Text: https://doi.org/10.1093/hmg/ddp410]

  14. Lee, S.-H., Kim, W.-H., Kim, H.-K., Woo, K.-M., Nam, H.-S., Kim, H.-S., Kim, J.-G., Cho, M.-H. Altered expression of the fragile histidine triad gene in primary gastric adenocarcinomas. Biochem. Biophys. Res. Commun. 284: 850-855, 2001. [PubMed: 11396980] [Full Text: https://doi.org/10.1006/bbrc.2001.5038]

  15. Letessier, A., Millot, G. A., Koundrioukoff, S., Lachages, A.-M., Vogt, N., Hansen, R. S., Malfoy, B., Brison, O., Debatisse, M. Cell-type-specific replication initiation programs set fragility of the FRA3B fragile site. Nature 470: 120-123, 2011. [PubMed: 21258320] [Full Text: https://doi.org/10.1038/nature09745]

  16. Markkanen, A., Heinonen, K., Knuutila, S., de la Chapelle, A. Methotrexate-induced increase in gap formation in human chromosome band 3p14. Hereditas 96: 317-319, 1982. [PubMed: 6985468] [Full Text: https://doi.org/10.1111/j.1601-5223.1982.tb00866.x]

  17. Markkanen, A., Knuutila, S., de la Chapelle, A. Inducible fragile site on chromosome 3. (Letter) Hum. Genet. 65: 217 only, 1983. [PubMed: 6654339] [Full Text: https://doi.org/10.1007/BF00286671]

  18. Morikawa, H., Nakagawa, Y., Hashimoto, K., Niki, M., Egashira, Y., Hirata, I., Katsu, K., Akao, Y. Frequent altered expression of fragile histidine triad protein in human colorectal adenomas. Biochem. Biophys. Res. Commun. 278: 205-210, 2000. [PubMed: 11071873] [Full Text: https://doi.org/10.1006/bbrc.2000.3771]

  19. Ohta, M., Inoue, H., Cotticelli, M. G., Kastury, K., Baffa, R., Palazzo, J., Siprashvili, Z., Mori, M., McCue, P., Druck, T., Croce, C. M., Huebner, K. The FHIT gene, spanning the chromosome 3p14.2 fragile site and renal carcinoma-associated t(3;8) breakpoint, is abnormal in digestive tract cancers. Cell 84: 587-597, 1996. [PubMed: 8598045] [Full Text: https://doi.org/10.1016/s0092-8674(00)81034-x]

  20. Palakodeti, A., Lucas, I., Jiang, Y., Young, D. J., Fernald, A. A., Karrison, T., Le Beau, M. M. Impaired replication dynamics at the FRA3B common fragile site. Hum. Molec. Genet. 19: 99-110, 2010. [PubMed: 19815620] [Full Text: https://doi.org/10.1093/hmg/ddp470]

  21. Pekarsky, Y., Garrison, P. N., Palamarchuk, A., Zanesi, N., Aqeilan, R. I., Huebner, K., Barnes, L. D., Croce, C. M. Fhit is a physiological target of the protein kinase Src. Proc. Nat. Acad. Sci. 101: 3775-3779, 2004. [PubMed: 15007172] [Full Text: https://doi.org/10.1073/pnas.0400481101]

  22. Rassool, F. V., Le Beau, M. M., Shen, M.-L., Neilly, M. E., Espinosa, R., III, Ong, S. T., Boldog, F., Drabkin, H., McCarroll, R., McKeithan, T. W. Direct cloning of DNA sequences from the common fragile site region at chromosome band 3p14.2. Genomics 35: 109-117, 1996. [PubMed: 8661111] [Full Text: https://doi.org/10.1006/geno.1996.0329]

  23. Rudduck, C., Franzen, G. A new heritable fragile site on human chromosome 3. Hereditas 98: 297-299, 1983. [PubMed: 6874402] [Full Text: https://doi.org/10.1111/j.1601-5223.1983.tb00608.x]

  24. Shi, Y., Zou, M., Farid, N. R., Paterson, M. C. Association of FHIT (fragile histidine triad), a candidate tumour suppressor gene, with the ubiquitin-conjugating enzyme hUBC9. Biochem. J. 352: 443-448, 2000. [PubMed: 11085938]

  25. Shiraishi, T., Druck, T., Mimori, K., Flomenberg, J., Berk, L., Alder, H., Miller, W., Huebner, K., Croce, C. M. Sequence conservation at human and mouse orthologous common fragile regions, FRA3B/FHIT and Fra14A2/Fhit. Proc. Nat. Acad. Sci. 98: 5722-5727, 2001. [PubMed: 11320209] [Full Text: https://doi.org/10.1073/pnas.091095898]

  26. Sozzi, G., Veronese, M. L., Negrini, M., Baffa, R., Cotticelli, M. G., Inoue, H., Tornielli, S., Pilotti, S., De Gregorio, L., Pastorino, U., Pierotti, M. A., Ohta, M., Huebner, K., Croce, C. M. The FHIT gene at 3p14.2 is abnormal in lung cancer. Cell 85: 17-26, 1996. [PubMed: 8620533] [Full Text: https://doi.org/10.1016/s0092-8674(00)81078-8]

  27. Stein, C. K., Glover, T. W., Palmer, J. L., Glisson, B. S. Direct correlation between FRA3B expression and cigarette smoking. Genes Chromosomes Cancer 34: 333-340, 2002. [PubMed: 12007194] [Full Text: https://doi.org/10.1002/gcc.10061]

  28. Virgilio, L., Shuster, M., Gollin, S. M., Veronese, M. L., Ohta, M., Huebner, K., Croce, C. M. FHIT gene alterations in head and neck squamous cell carcinomas. Proc. Nat. Acad. Sci. 93: 9770-9775, 1996. [PubMed: 8790406] [Full Text: https://doi.org/10.1073/pnas.93.18.9770]

  29. Wang, N., Perkins, K. L. Involvement of band 3p14 in t(3;8) hereditary renal carcinoma. Cancer Genet. Cytogenet. 11: 479-481, 1984. [PubMed: 6704944] [Full Text: https://doi.org/10.1016/0165-4608(84)90028-1]

  30. Wegner, R.-D. A new inducible fragile site on chromosome 3 (p14.2) in human lymphocytes. Hum. Genet. 63: 297-298, 1983. [PubMed: 6852828] [Full Text: https://doi.org/10.1007/BF00284670]

  31. Wegner, R.-D. Reply to the letter of A. Markkanen, S. Knuutila, and A. de la Chapelle. (Letter) Hum. Genet. 65: 218 only, 1983.

  32. Weiske, J., Albring, K. F., Huber, O. The tumor suppressor Fhit acts as a repressor of beta-catenin transcriptional activity. Proc. Nat. Acad. Sci. 104: 20344-20349, 2007. [PubMed: 18077326] [Full Text: https://doi.org/10.1073/pnas.0703664105]

  33. Zanesi, N., Fidanza, V., Fong, L. Y., Mancini, R., Druck, T., Valtieri, M., Rudiger, T., McCue, P. A., Croce, C. M., Huebner, K. The tumor spectrum in FHIT-deficient mice. Proc. Nat. Acad. Sci. 98: 10250-10255, 2001. [PubMed: 11517343] [Full Text: https://doi.org/10.1073/pnas.191345898]


Contributors:
Ada Hamosh - updated : 6/10/2011
George E. Tiller - updated : 11/12/2010
George E. Tiller - updated : 10/28/2010
Patricia A. Hartz - updated : 4/16/2008
Victor A. McKusick - updated : 4/9/2004
Victor A. McKusick - updated : 9/16/2003
Victor A. McKusick - updated : 2/12/2003
Jane Kelly - updated : 11/5/2002
Victor A. McKusick - updated : 8/23/2002
Victor A. McKusick - updated : 12/6/2001
Victor A. McKusick - updated : 6/1/2001
Victor A. McKusick - updated : 4/11/2001
Victor A. McKusick - updated : 6/15/2000
Victor A. McKusick - updated : 8/31/1998
Jennifer P. Macke - updated : 7/15/1998
Victor A. McKusick - updated : 2/6/1998
Jennifer P. Macke - updated : 7/25/1996
Moyra Smith - updated : 4/22/1996

Creation Date:
Victor A. McKusick : 3/22/1996

Edit History:
alopez : 05/04/2022
carol : 03/04/2021
alopez : 06/22/2011
terry : 6/10/2011
wwang : 11/19/2010
terry : 11/12/2010
wwang : 11/8/2010
terry : 10/28/2010
terry : 10/8/2008
mgross : 4/16/2008
carol : 11/27/2006
mgross : 1/21/2005
tkritzer : 4/14/2004
terry : 4/9/2004
tkritzer : 9/30/2003
cwells : 9/16/2003
carol : 2/27/2003
tkritzer : 2/24/2003
terry : 2/12/2003
cwells : 11/5/2002
tkritzer : 9/9/2002
tkritzer : 9/9/2002
tkritzer : 8/28/2002
terry : 8/23/2002
terry : 8/23/2002
carol : 7/1/2002
carol : 12/11/2001
mcapotos : 12/6/2001
mcapotos : 6/7/2001
mcapotos : 6/4/2001
terry : 6/1/2001
mcapotos : 4/23/2001
mcapotos : 4/18/2001
mcapotos : 4/16/2001
terry : 4/11/2001
mcapotos : 7/17/2000
mcapotos : 7/11/2000
mcapotos : 7/11/2000
terry : 6/15/2000
carol : 9/18/1998
dkim : 9/9/1998
terry : 8/31/1998
alopez : 7/15/1998
alopez : 5/21/1998
mark : 2/15/1998
terry : 2/6/1998
mark : 11/18/1996
terry : 10/23/1996
mark : 10/16/1996
mark : 7/25/1996
terry : 5/24/1996
carol : 5/22/1996
carol : 4/22/1996
mark : 3/25/1996