FHIT gene and cancer
【Key Words】 FHIT
Abstract: Based on the FHIT gene molecular biology, new discoveries, the FHIT gene structure, function and relationship with tumor are reviewed.
Key words: FHIT gene; tumor
Since 1996, Ohta  such as the use of exon trapping method showed that positioning of the FHIT gene at 3p14.2 has been through years of research that the FHIT gene is an important tumor suppressor genes and have accumulated some evidence. In further understand the nature of FHIT gene on the basis of this study will incorporate a number of FHIT gene on the newly discovered molecular biology of FHIT gene structure, function and its relationship with the tumor are summarized below.
1 FHIT gene discovery and structure of
Since 1979, from an Italian early-onset, bilateral,
multiple foci of renal cell carcinoma pedigrees that there are chromosomal translocation observed in t (3; 8) (p14.2; q24) after . The study found a variety of tumor tissues in
different short arm of chromosome 3 in (3p) the phenomenon of frequent deletion in 1996, Ohta  such as the use of positional cloning and exon trapping method in chromosome 3p14.2 within the region to find a new genes. This gene encodes a protein belonging to three acid family, but this
gene are susceptible to breakage, so named after the FHIT gene (fragile histidine triad gene, that is fragile histidine triad gene). FHIT gene in the chromosome occupies 1Mb size of the location, covering FRA3B fragile sites, renal cell carcinoma
associated breakpoint t (3; 8), tumor suppressor gene protein
tyrosine phosphatase γ gene (proteintyrosine phosphataseγ
gene, PTPRG) The 5 'end and HPV16 integration sites, and contain encoding histidine triad (HIT) functions . FHIT
gene cDNA length 1095bp, from 10 exons and the composition and distribution of the total length of 1Mb locus; its 5 'end with a period of about 350bp of non-coding region, followed by exon
5 ~ 9 the composition of length of 500bp encoding 147 amino
acids open reading frame (openreadingframe, ORF), 3 'end of multiple polyadenylation consensus sequences
(polyAconsensussequence), and a polyA tail; three initial exon 1 ~ 3 at t ( 3; 8) breaking the centromere side in front of exon 5 containing the methionine start codon, HPV16
integration of exon 5 'side of the centromere; exon 6 contains an ORF within the Met password, exon 5 deletion cases, can not complete his translation of FHIT protein; exon 8 containing the encoding histidine triad (HIT) of the core modules .
FRA3B is located in FHIT intron 4 and 5, between the FHIT gene encodes the first exon (exon 5) on both sides, across 200 ~ 300kb region.
The genetic characteristics: first, in the brittle-side
detection area there are many Alu sequences, rich in AT, may
be starting point for DNA replication; second, almost all exons to AC sequence. In higher organisms where, Alu repeats are considered to be related to the duplication of DNA . Thus, when exposed to certain organs of some carcinogenic
effect of factors will result in disruption of DNA replication, which led to fracture this fragile sites, leading to gene deletion.
2 FHIT protein structure and function of
Ohta et al  found that FHIT gene encoding FHIT protein, 147 amino acids, and its homology analysis carried out, because of its sequence and HIT (histidine triad, FHIT) protein was similar, so that the FHIT protein is in the HIT protein family members. The core of its 109 amino acids and yeast Schizosaccharomyces pombe the Ap4A hydrolase (5 ', 5 "'
P1, Ptetraphosphat hydrolase 2 adenosine phosphate hydrolase 4) 57 identical (52%), 76 amino acid similarity (69% ). Ap4A hydrolase can Ap4A substrate asymmetrically broken down into ATP and AMP. FHIT protein and Ap4A hydrolase prompted the
similarity between the FHIT protein may also be an enzyme. Barnes et al  found that FHIT protein is a typical The two
adenosine triphosphate hydrolases (5 ', 5 "' P1, P3triphosphate hydrolase, Ap3A), can be hydrolyzed ApnA (n = 3-6) into ADP and AMP, the optimum substrate Ap3A; FHIT protein in the sequences associated with the HIT protein, while the HIT protein family structural features from the four conserved histidine (H35, H94, H96, H98), of which three histidine to form a histidine triad (HIT) sequence HXHXH: X
often as valine. Through the site direct mutagenesis showed that the full functionality of FHIT protein required four conserved histidine, as histidine mutation into asparagine, Ap3A hydrolytic activity has also been gradually declining,
its central body is the three histidine Ap3A hydrolase activity is absolutely essential, Mn2 and Mg2 can stimulate its activity, while Zn2 inhibit its activity.
FHIT protein in all the body's tissues are expressed, but its specific functions in the body is unclear. The study found APnA in animal cells, the concentration of environmental change and stress response was very sensitive in the regulation of cell proliferation, differentiation, apoptosis may be the signal system or alarm system to external stimuli
. Now known: ? FHIT gene mutations will lead to the loss of Ap3A hydrolytic activity caused elevated levels of Ap3A. Ap3A is the ATP analogues, can inhibit the protein kinase activity, its elevated levels may enhance the growth signal
transduction pathway, block apoptosis suppressor pathway or channel leading to tumor generation . ? mRNA hat features:
FHIT protein can function in mRNA cap analogues, affecting important gene mRNA translation . ? FHIT substrate complex
role: FHIT protein can also be combined with its substrate APnA generated by ApnAFHIT tumor suppressor role of the complex. Siprashvili, etc.  to wild-type and mutant FHIT
genes were transfected into the lack of FHIT tumor cell lines and found that mutant FHIT (H96 ? Asn) encoding a protein-
free Ap3A hydrolytic activity, but also can inhibit tumor cells in the The tumorigenic effect in nude mice. Therefore considered that FHIT protein and its substrate-binding inhibit
tumor production of hydrolytic enzyme activity than their more
important. Based on the above study, Brenner et al  put forward the hypothesis that apoptosis signal: that under normal circumstances tRNA transferase can be transferred to the tRNA on the amino acids to complete the cell proliferation, and when cells in a state of stress and so on with ADP, ATP binding to form APnA, which combined with the
FHIT protein conformation changes occurring activation, hydrolysis of nitriles into acids, ammonia and other products, which this product also induce apoptosis through a variety of
ways. Ishii  and other studies found that FHIT-induced
apoptosis need to activate the Caspases8 and Caspases9, also need to Bid activation, that FHIT also participates in apoptosis of mitochondria and Caspases8 two ways. ? cell
cycle arrest, can play a tumor suppressor role. Some studies [10,11] showed that, FHIT gene in apoptosis and cell cycle regulation plays an important role in the FHIT gene deletion of the tumor cells were FHITcDNA lead to re-expression of FHIT
protein may cause arrested at S phase and G0 / G1 phase of the cell number increased number of apoptotic cells increased, decreased carcinogenicity. Shi et al  study found that C-
terminal part of the FHIT protein and hUBC9 related, and this relationship has nothing to do with the FHIT of activity are known to yeast UBC9 is involved in cell cycle S phase and M phase of the degradation process, suggesting that FHIT may be through it with hUBC9 interaction involved in cell cycle regulation.
Chaudhuri et al  The study found that wild-type and
mutant (H96N) FHIT protein (non-hydrolytic activity but
suppressor activity) on tubulin have a strong binding force, both of which greatly enhance the microtubule-associated
protein poly-nuclear role of microtubule dynamics by limiting
or interfering with microtubule fragmentation of the process of preventing cell mitosis, inhibit excessive cell proliferation, and thus play a tumor suppressor function.
Thus, FHIT protein, possibly through a variety of ways to play these or other tumor suppressor function.
3 FHIT gene and cancer
FHIT gene abnormalities found in a variety of tumors and tumor cell lines, especially common in carcinogen exposure-
related tumors, such as lung cancer, cervical cancer, head and neck cancer, esophageal cancer, stomach cancer, colorectal cancer and so on.
31 lung cancer
Common in lung cancer FHIT gene abnormalities including: abnormal transcripts, LOH and protein expression of allele
reduced or missing and so on. Sozzi  for applications such as RTPCR, DNA sequencing, LOH Southern Blot and
immunohistochemical staining of the more than 100 cases of primary lung cancer tissues were analyzed FHIT gene abnormalities, 80% of small cell lung cancer (small cell lung cancer, SCLC) and 40% of non-small cell lung cancer (nonsmall
cell lung cancer, NSCLC) there is abnormal FHIT gene transcription. DNA sequencing analysis showed that the most common abnormal transcription of exon 4 or 5 to 8 missing.
There are two types of SCLC missing: the first type is missing exon 4 ~ 6, or 4 to 8, both missing exon 5; the second type is missing exon 8, resulting in histidine 3 conjoined domain exception. The abnormal transcription of NSCLC are also
divided into two types, namely loss of exon 8 and exon 4 downstream of insertion-218bp fragment. E5 is the FHIT gene
coding first exon, while the E8 coding HIT domain, so these two types of loss all contribute to the loss of FHIT gene
functions. Through the clinical data analyzed, Geradts et al  found that, FHIT gene loss of heterozygosity indicates a poor prognosis. Of lung cancer in Chinese organizations also exist a high frequency of FHIT gene loss of heterozygosity, Li et al  studies have shown that the gene is located within the three microsatellite loci D3S1234, D3S1300 and D3S4103 were the frequency of LOH around 60%. Reduction or absence of FHIT protein expression in lung cancer and pulmonary bronchial precancerous lesions are very common in 1998 Sozzi  were also carried out on NSCLC Immunohistochemistry results showed that 73% NSCLC and 93% of the precancerous lesions are FHIT reduced protein expression, and the FHIT protein in lung squamous cell carcinoma to reduce the incidence (87%) was
significantly higher than adenocarcinoma (57%) (P