Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The FHIT (fragile histidine triad) gene has been recently identified and cloned at chromosome 3p14.2 including FRA3B, the most common fragile site in the human genome. FHIT is suggested to be a candidate tumour suppressor gene in gastrointestinal tract tumours. To elucidate the role of the FHIT gene in gastric cancer, a total of 133 curatively R0-resected gastric carcinomas were investigated for loss of heterozygosity (LOH) at 3p14.2, using four polymorphic microsatellite loci (D3S1300, D3S1313, D3S1481, and D3S1234). LOH of the FHIT gene affecting at least one of the investigated loci was observed in 20 of 123 informative tumours (16.3 per cent). The presence of LOH was correlated neither with major prognostic factors such as pT category, pN category or vascular invasion, nor with histological type or grade of differentiation of the tumours. In addition, there were no differences in the prognosis between patients with gastric carcinomas showing LOH at the FHIT gene and patients with tumours lacking LOH at the FHIT gene. These findings suggest that LOH of the FHIT gene represents an event in the tumourigenesis of only a small subset of gastric carcinomas and does not correlate with tumour progression or prognosis.
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PMID:FHIT gene in gastric cancer: association with tumour progression and prognosis. 1044 Jul 47

To help define the location of tumour suppressor genes implicated in the pathogenesis of oral squamous cell carcinoma (SCC), we have used microsatellite assay and restriction fragment length polymorphism (RFLP) analysis to screen 48 primary SCC for allelic imbalance (AI) with 32 polymorphic markers at chromosome 3p, and prepared a detailed deletion map. The finding of a high frequency of AI at specific regions, together with the presence of multiple small interstitial deletions involving these loci, identifies 5 areas at this chromosome arm that may harbour tumour suppressor genes. No sequence aberrations affecting the von Hippel Lindau (VHL) and fragile histidine triad (FHIT) genes, which reside within the candidate tumour suppressor gene areas at this chromosome arm, were identified. A more limited analysis of polymorphic sequences at 8p and 9p supports the existence of at least 2 areas that harbour tumour suppressor genes at 8p and evidence that additional targets for deletion reside centromeric and telomeric to the p16 gene at 9p21.
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PMID:Location of candidate tumour suppressor gene loci at chromosomes 3p, 8p and 9p for oral squamous cell carcinomas. 1049 23

The FHIT (fragile histidine triad) gene at chromosome 3p14.2 spans the FRA3B fragile site and encodes for a diadenosine triphosphate hydrolase-type protein. FHIT is frequently abnormal in solid tumours including those of the upper aerodigestive tract (UAT) and has therefore been proposed as a tumour-suppressor gene. This proposition was evaluated here for oral squamous cell carcinoma (SCC) using microsatellite analysis, reverse transcription-polymerase chain reaction (RT-PCR), FHIT exon 5 PCR and direct sequencing. Fifty-eight primary oral SCCs were examined with two FHIT gene microsatellite markers (D3S4103 and D3S1300) and two markers flanking FHIT. Allelic imbalance (AI) occurred in 28 of 52 informative cases (54%) at one or both FHIT markers (D3S4103: 53%; D3S1300: 42%). A significant association was noted between frequency of AI and advanced stage tumours for D3S4103 but not between AI frequency and smoking. AI frequency at D3S1300 and at a flanking marker correlated with low survival. Of eight oral/UAT SCC cell lines examined, six produced abundant wild-type transcript and one yielded mostly truncated transcripts, the most abundant of which lacked exons 5-7. A double deletion was also detected in one of 11 primary oral SCCs. Our microsatellite assay results show that the FHIT gene is frequently disrupted in oral SCC. However, as FHIT was shown to be expressed normally in the great majority of oral/UAT SCCs studied, its likely involvement in the molecular pathogenesis of the disease as a tumour suppressor remains doubtful.
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PMID:The FHIT gene in oral squamous cell carcinoma: allelic imbalance is frequent but cDNA aberrations are uncommon. 1074 70

The fragile histidine triad (FHIT) gene is a candidate tumour suppressor gene in breast and other cancers. We investigated deletions within the FHIT gene in lobular breast cancer and found that 16% of cases showed loss of heterozygosity (LOH) within the gene. We compared LOH within FHIT in lobular and ductal breast tumours and found a significant association between LOH at FHIT and the ductal histological type (P<0.001). To determine whether genomic alteration of the FHIT gene in lobular breast cancer leads to Fhit inactivation we have assessed the level of Fhit expression by immunohistochemical detection and determined that 27% (15 of 55) consecutive sporadic lobular tumours showed negative or reduced Fhit expression. A significant association was found between LOH at the FHIT gene and reduced Fhit expression in lobular and ductal tumours (P=0.025 and P=0.001, respectively). Thus, genetic alterations within the FHIT gene, leading to loss of Fhit protein, may play an important role in the carcinogenesis of a significant number of sporadic lobular breast cancers, even though the apparent frequency of genomic alterations within the gene is lower than in ductal breast cancer.
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PMID:Analysis of the fragile histidine triad (FHIT) gene in lobular breast cancer. 1093 Aug 3

FHIT (fragile histidine triad), a candidate tumour suppressor gene, has recently been identified at chromosomal region 3p14.2, and deletions of the gene have been reported in many types of human cancer. However, the biological function of the Fhit protein has not been fully characterized yet. Using the yeast two-hybrid screen to search for proteins that interact with Fhit in vivo, we identified a protein that is specifically associated with Fhit. This association was confirmed in both immunoprecipitation and glutathione S-transferase pull-down assays. The sequence of the protein is identical with that of human ubiquitin-conjugating enzyme 9 (hUBC9). The last 21 amino acids at the C-terminus of hUBC9 appear to be unimportant for its biological activity, since an hUBC9 mutant harbouring a deletion of these amino acids could still restore normal growth of yeast containing a temperature-sensitive mutation in the homologue UBC9 gene. Mutational analysis indicated that hUBC9 was associated with the C-terminal portion of Fhit. Neither a single amino acid substitution at codon 96 (His-->Asn) nor triple amino acid substitutions (His-->Asn) at a histidine triad (codons 94, 96 and 98) affected the association, whereas Fhit triphosphate (diadenosine 5',5"'-P(1),P(3)-triphosphate) hydrolase activity has been reported to be eliminated by either type of mutation, suggesting that the interaction between Fhit and hUBC9 is independent of Fhit enzymic activity. Given that yeast UBC9 is involved in the degradation of S- and M-phase cyclins, Fhit may be involved in cell cycle control through its interaction with hUBC9.
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PMID:Association of FHIT (fragile histidine triad), a candidate tumour suppressor gene, with the ubiquitin-conjugating enzyme hUBC9. 1108 38

The FHIT (fragile histidine triad) gene on chromosome 3p14.2 is a candidate tumour suppressor gene. To define the role of the FHIT gene in the development of ovarian cancer, we have examined 33 ovarian carcinomas, 2 borderline tumours and 10 benign adenomas for the presence of FHIT gene alterations. FHIT transcripts were analysed by RT-PCR and sequencing. Aberrant FHIT transcripts were observed in 5/33 carcinomas (15%) and in 1 of 2 borderline tumours. Loss of normal FHIT transcript was observed in 5/33 carcinomas (15%) but not in 2 borderline tumours or 10 benign adenomas. Allelic losses at D3S1300 and D3S4103, both located within intron 5 of FHIT, were detected in 5/24 (21%) and 5/25 (20%) informative ovarian carcinomas, respectively. Expression of Fhit protein was analysed by immunohistochemistry in 44 carcinomas, 19 borderline tumours and 16 benign adenomas. Loss or significantly reduced expression of Fhit protein was observed in 6/44 (14%) ovarian carcinomas but not in any of 19 borderline tumours or 16 benign adenomas. The impaired Fhit protein expression was significantly correlated with the loss of normal FHIT transcription. Most notably, loss of normal FHIT transcript and impaired expression of Fhit protein occurred only in serous adenocarcinomas of grade 2 and 3 (5/15; 33% and 6/19; 32%, respectively). The present data suggest that inactivation of the FHIT gene by loss of expression is one of the important molecular events associated with the genesis of ovarian carcinoma, especially of high-grade serous carcinoma.
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PMID:Impaired FHIT expression characterizes serous ovarian carcinoma. 1146 Oct 85

Clear cell renal cell carcinomas (RCCs) are characterized by a deletion of chromosome 3p, which might result in the inactivation of the FHIT (fragile histidine triad) gene, a putative tumour suppressor gene. To explore the relevance of FHIT aberrations for tumour progression and prognosis in clear cell RCCs, FHIT protein expression was analysed in formalin-fixed tissue from 149 clear cell RCCs by immunohistochemistry. FHIT protein expression was found to be markedly reduced in all RCCs, when compared with adjacent non-neoplastic tubule epithelia. Although remaining below the FHIT levels of normal tubule epithelia, a significant increase of FHIT expression became evident from well (G1) to poorly (G3) differentiated clear cell RCCs (p=0.0001) and from low (pT1) to advanced (pT3) tumour stages (p=0.001). The log-rank test demonstrated a significant inverse correlation (p=0.0074) between FHIT expression and tumour aggressiveness as indicated by patient survival. Cox regression analysis revealed that FHIT expression is an independent prognostic parameter (p=0.0139) in clear cell RCCs. In conclusion, clear cell RCCs show a marked reduction of FHIT protein expression when compared with their putative cells of origin. In contrast to other tumour types, however, loss of FHIT protein expression is significantly less pronounced in poorly differentiated RCCs or advanced tumour stages. This versatility of FHIT expression during tumour progression suggests a role for reversible mechanisms of FHIT inactivation during the initiation and progression of clear cell RCCs.
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PMID:FHIT expression in clear cell renal carcinomas: versatility of protein levels and correlation with survival. 1192 Jul 39

Fragile histidine triad (FHIT) is a tumour suppressor gene, which is altered in a variety of epithelial tumours, including lung cancer. Biochemical and functional pathways of its tumourigenicity are not yet understood. Its role in tumour proliferation is particularly controversial. The purpose of this study was to correlate the expression of FHIT protein in nonsmall cell lung cancer (NSCLC) with tumour proliferation as estimated by Ki-67 antigen and with p53, a suppressor gene. FHIT, Ki-67 and p53 expression were evaluated by immunohistochemistry in 119 resected NSCLC. Altogether, 58 tumours were negative (expression <10%) for FHIT. The median expression in tumours was 15% positive cells, in comparison with 100% in normal matched lung tissue. The expression was as strong as in normal tissue in only 19 cases. FHIT expression was significantly lower in squamous cell carcinoma (SCC) (5%) than in adenocarcinoma (ADC) (64%). The median expression of Ki-67 was 20% and 69% of tumours were positives (expression >10%). Ki-67 expression was significantly higher in SCC (33.3%) than in ADC (10%). The loss of FHIT protein was not correlated with the expression of p53 (median: 7.5%, 58% of positive tumours for a cut-off of 10% of positive cells) or Ki-67. But percentage of labelled cells for p53 and Ki-67 were significantly correlated. The results suggest that for fragile histidine triad, the pathway of tumourigenesis is independent of p53 and of tumoural proliferation, as reported previously in vitro.
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PMID:Fragile histidine triad protein expression in nonsmall cell lung cancer and correlation with Ki-67 and with p53. 1276 16

Human malignant mesothelioma (MM) is an aggressive neoplasm related to occupational exposure to asbestos and characterised by a long latency time. Multiple chromosomal deletions and DNA losses have been revealed in MM by studies performed with karyotypic, comparative genomic hybridisation and loss of heterozygosity (LOH) analyses. Among frequently deleted chromosomal sites, LOH at chromosome 3p has been detected in MM, suggesting the presence of one or several tumour suppressor genes that have an important role in development of the disease. The FHIT (fragile histidine triad) tumour suppressor gene, located at 3p14.2, has been proposed to be a target to major human lung carcinogens, such as tobacco smoke and asbestos. Although many studies have indicated decreased Fhit protein expression in a variety of malignancies, there is no report of FHIT gene aberrations or Fhit protein abnormalities in MM. We examined expression of the Fhit protein and LOH at the FHIT gene in malignant mesothelioma. Altogether, 13 paraffin embedded MM tumours were analysed for Fhit protein expression, and 21 fresh tumours and 10 cell cultures for LOH at the FHIT gene with two intragenic microsatellite markers. All tumours showed less intense immunostaining than normal bronchial epithelium or mesothelium. Fhit expression was absent or reduced in 54% (7 of 13) of the tumours, with the weakest staining observed in poorly differentiated areas. Allele loss was seen in 3 of 10 (30%) of the MM cell lines, but only in 1 of the 21 fresh tumours studied, suggesting concealment of LOH by normal cells present in MM tumours. In conclusion, our present data indicate a frequent decrease of Fhit protein expression, thus supporting the significance of FHIT inactivation in development of MM.
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PMID:Reduced Fhit protein expression in human malignant mesothelioma. 1456 98

The fragile histidine triad (FHIT) gene, encompassing the FRA3B fragile site at chromosome 3p14.2, is a candidate tumour suppressor gene involved in a variety of tumours, including gastric carcinomas. Recently, it has been reported that the FHIT gene may be a target of damage in some of mismatch-deficient tumours. To clarify further the role of the Fhit protein in gastric carcinogenesis, we investigated whether Fhit expression in early gastric neoplasia is associated with mismatch repair protein expression and cellular phenotype. Fhit, Mlh1 and phenotypic expression were evaluated immunohistochemically in 87 early gastric neoplasias, comprising 32 adenomas and 55 intramucosal carcinomas, resected by endoscopic mucosal resection therapy. Significant loss or reduction of Fhit expression was noted in four (12.5%) of the 32 adenomas and 21 (38.2%) of the 55 intramucosal carcinomas. The rate of abnormal Fhit expression was significantly higher in intramucosal carcinomas than in adenomas (P=0.021). Moreover, reduced Fhit expression was found to be significantly associated with loss of Mlh1 expression in early gastric neoplasia (P=0.0011). Furthermore, we also detected a significant association between reduced Fhit expression and gastric phenotype (P=0.0018). These results suggested that reduced Fhit expression occurs in the early stage of gastric carcinogenesis and could be correlated with a lack of Mlh1 expression and gastric phenotype.
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PMID:Fhit expression in human gastric adenomas and intramucosal carcinomas: correlation with Mlh1 expression and gastric phenotype. 1476 Mar 83


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