Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P04637 (p53)
77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The genetics of renal cell tumors (RCT), which occur at a high frequency in patients with end-stage renal failure (ESRF), is not yet known. Using a fluorescence microsatellite assay and comparative genomic hybridization, 18 renal tumors obtained from nine patients with ESRF were analyzed for genetic alterations, which are known to be characteristic of common nonpapillary and papillary RCT in the general population. Deletion of chromosome 3p was detected in six nonpapillary tumors, whereas trisomies of 7 and 17 or 3, 8, and 16 were seen in four of 18 tumors. No alterations were found in four tumors, and another four tumors had unspecific changes. The fragile histidine triad (FHIT) gene is localized at the most common fragile site at chromosome 3p14.2. The FHIT and the p53 tumor suppressor gene are targets of different environmental agents. Because both toxic effect and genomic instability are implicated in the development of renal cysts in ESRF, the alteration of both genes in tumor cells was analyzed. No abnormal expression of the FHIT gene or mutation of the p53 gene were found. This study suggests that the genetics and also the morphology of some of the ESRF RCT differ from those known for RCT in the general population.
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PMID:The genetics of renal tumors in end-stage renal failure differs from those occurring in the general population. 962 Dec 87

The fragile histidine triad (FHIT) gene at chromosome 3p14.2 is a candidate tumor suppressor gene linked to cancers of the lung, breast, colon, pancreas, and head and neck. Reports of frequent allelic deletion and abnormal transcripts in primary lung tumors plus recent evidence that it is targeted by tobacco smoke carcinogens suggest that it plays an important role in lung carcinogenesis. Non-small cell lung carcinoma still maintains a poor 5-year survival rate with the stage of disease at presentation as a major determinant of prognosis. We examined for allelic deletion at the FHIT locus in a series of 106 non-small cell lung carcinomas for which a full clinical, epidemiological, and 5-year survival profile was available. We found an allelic deletion frequency of 38% at one or two intragenic microsatellites. Allelic deletion of FHIT was related to tumor histology with 4 of 20 adenocarcinomas (20%) displaying loss of heterozygosity (LOH) compared with 12 of 22 (55%) nonadenocarcinomas (P = 0.03). We found that 63% of tumors with LOH of FHIT also had p53 missense mutations whereas only 26% with LOH had wild type p53 negative sequence (P = 0.02). We also found a significant trend toward poorer survival in patients with LOH of at least one locus of the FHIT gene (log rank, P = 0.01). This survival correlation is independent of tumor stage, size, histological subtype, degree of differentiation, and p53 mutation status. Our data support the hypothesis that the loss of the FHIT contributes to the molecular pathogenesis of human lung cancer and is an indicator of poor prognosis.
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PMID:Allelic deletion analysis of the FHIT gene predicts poor survival in non-small cell lung cancer. 963 74

A new human cancer cell line was established from a metastatic lesion of a small cell lung carcinoma (SCLC-R1) and maintained in continuous culture with a doubling time of 62 h. The SCLC-R1 line, whose ultrastructural features are presented, showed a diploid DNA content, a translocation involving chromosome 16 [t(16;?)(q24;?)] and noticeable deletions in the FHIT (fragile histidine triad) region in the short arm of chromosome 3 [del(3)(p14)] and in the telomeric region of the short arm of chromosome 12 [del(12)(p13)]. The involvement of 12p in metastatic small cell lung cancer is reported here for the first time. No amplification or rearrangements were evident in the c-myc, L-myc, N-myc, int-2, c-erbB-2, H-ras, K-ras, c-mos, and hst-1 genes by Southern blot analysis. Wild-type p53, RB, K-ras and H-ras genes were evident by polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) analysis. The neuron specific enolase (NSE) level was much higher in the cell line's cytosol than in the patient's serum and the cell line also had high expression of chromogranin A and cytokeratin 19. SCLC-R1 cells were sensitive to cisplatin, carboplatin and doxorubicin. The clinical history of the patient from whom the cell line was derived is reported. The characteristics of this new cell line indicate it to be a useful experimental model to investigate lung cancer biology and anticancer drug response.
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PMID:Chromosomal alterations, biological features and in vitro chemosensitivity of SCLC-R1, a new cell line from human metastatic small cell lung carcinoma. 971 81

We previously cloned and characterized the tumor suppressor gene FHIT (fragile histidine triad) at chromosome 3p14.2 and found that this gene is altered by deletions in human tumors, including lung cancer. To assess the frequency and specificity of inactivation and its relevance in a clinical setting, we have produced antibodies against the Fhit protein and studied its expression in a series of non-small cell lung cancers and normal bronchial mucosa and a spectrum of preinvasive lesions by immunohistochemistry. The data indicate that the loss of Fhit protein is the most frequent alteration in non-small cell lung cancer (73%) and precancerous lesions (93%), is significantly higher in the tumors of smokers (75%) than in those of nonsmokers (39%; P < 0.0005), and is an independent and more frequent event than p53 overexpression in tumors and precancerous lesions (73 versus 46%). The percentage of cases lacking Fhit expression was higher in the squamous type compared to adenocarcinoma (87 versus 57%; P < 0.00001), whereas other histotypes (large cell, mucoepidermal) showed an intermediate value (69%). Loss of Fhit expression in a very high percentage of primary lung carcinomas and precancerous lesions supports the notion that FHIT alterations play an important role in the growth control of bronchial cells. FHIT inactivation is particularly important in squamous cell carcinomas that are often associated with precursor dysplastic lesions. The overall high frequency and precocity of Fhit loss in lung carcinogenesis and the development of the presently described immunohistochemical approach suggest a potential use of this gene in the early detection of lung cancer and in chemopreventive studies as an intermediate biomarker.
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PMID:Loss of FHIT function in lung cancer and preinvasive bronchial lesions. 982 4

Alteration of the FHIT (fragile histidine triad) gene occurs as an early and frequent event in lung carcinogenesis. FHIT gene transfer into lung cancer cell line H460 lacking Fhit protein expression resulted in reversion of tumorigenicity. To gain insight into the biological function of FHIT, we compared the H460 cell line with its Fhit transfectants (H460/FHIT). A significant inhibition of cell growth was observed in H460/FHIT cells. The analysis of apoptosis by in situ terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling revealed a high rate of apoptosis-induced DNA strand breaks in stable clones. In situ results were confirmed by FACScan analysis that showed an apoptotic rate of 44-47% compared with a 15% level in the control H460 cells. Analysis of cell cycle-phase distribution indicated a significant G(0)/G(1) arrest and the presence of a sub-G(1) peak in the stable clones. No significant changes in Bcl2, BclX, and Bax protein expression level were observed in the transfected clones as compared with the control H460 cells whereas a 2-fold increase in Bak protein levels was noticed. An increased level of p21(waf) protein paralleled by an up-regulation of p21(waf) transcripts also was found in Fhit-expressing clones compared with the H460 cell line. No differences in p53 levels were observed in the same cells, suggesting a p53-independent effect. These data suggest that the observed growth-inhibitory effect in FHIT-reexpressing cells could be related to apoptosis and cell cycle arrest and link the tumor-suppressor activity of FHIT to its proapoptotic function.
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PMID:The tumor-suppressor gene FHIT is involved in the regulation of apoptosis and in cell cycle control. 1041 2

Abnormalities in structure and expression of the fragile histidine triad transcription (FHIT) gene have been reported in a variety of cancers, including endometrial cancers. A good correlation between FHIT gene alteration and loss of Fhit expression was observed in endometrial cancers, although those are the selected cases. Therefore, we investigated the association of Fhit expression with clinicopathological features in 111 cases of endometrial cancer. Loss of Fhit expression was associated with high malignant potential, including extensive muscular invasion, advanced surgical stage, high histological grade, nonendometrioid types of adenocarcinoma, negative estrogen receptor status, and p53 overexpression. The presence of personal cancer history was also related to the loss of Fhit with a marginal significance. Survival curves determined by the Kaplan-Meier method and univariate analysis demonstrated that decreased expression of Fhit was associated with a poor outcome. However, multivariate analysis using the stepwise Cox proportional hazard model showed that whereas lymph node metastasis, advanced stage, and high tumor grade were related to poor survival rates, loss of Fhit expression was not. Consequently, loss of Fhit expression is associated with advanced surgical stage and does not appear to be an independent prognostic factor in endometrial cancers, although a still larger sample of patients will be required to asses this issue definitively.
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PMID:Clinicopathological significance of fragile histidine triad transcription protein expression in endometrial carcinomas. 1087 85

The fragile histidine triad (Fhit) gene, which is frequently lost in many cancers, was identified as a candidate tumor suppressor gene at chromosome 3p locus 14.2. Loss of Fhit expression is an important step in tumor progression from premalignancy, to in situ, to invasive breast carcinoma. To determine whether the absence of Fhit protein correlates with other established pathological-clinical parameters or prognosis, we assessed Fhit expression using immunohistochemistry in 166 invasive breast carcinomas. Lost or significantly decreased Fhit protein expression was identified in 70 cases (42.2%). Fhit expression was inversely correlated with histological grade (P < 0.0001), negative estrogen receptor status (P = 0.0016), p53 overexpression (P = 0.0040), and tumor proliferation activity (P = 0.0006). Survival curves determined by the Kaplan-Meier method and univariate analysis demonstrated that reduced expression of Fhit was associated with a poor outcome (P = 0.0086, by log-rank test). Multivariate analysis using the stepwise Cox proportional hazard model showed that lymph node metastasis was related to poor survival rates; in addition, patients with loss of Fhit expression still tended to have poor survival (P = 0.0563). Therefore, loss of Fhit expression is associated with higher malignant phenotypes and appears to be a prognostic factor in breast carcinoma.
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PMID:Clinicopathological significance of fragile histidine triad transcription protein expression in breast carcinoma. 1175 77

Two developmentally highly divergent nonmelanoma skin cancers, the epidermal squamous cell carcinomas (SCC) and the neuroendocrine Merkel cell carcinomas (MCC), occur late in life at sun-exposed body sites. To determine whether these similarities may indicate common genetic alterations, we studied the genetic profile of 10 MCCs and analyzed 6 derived cell lines and 5 skin SCC lines by comparative genomic hybridization (CGH) and molecular genetic analyses. Although the MCCs were highly divergent-only 3 of the 10 tumors exhibited common gains and losses-they shared gain of 8q21-q22 and loss of 4p15-pter with the genetically much more homogeneous SCC lines. In addition, 2 of 5 SCC and 2 of 6 MCC lines exhibited UV-B-type-specific mutations in the p53 tumor-suppressor gene and a high frequency (9/11) of CC-->TT double base changes in codon 27 of the Harvey (Ha)-ras gene. Since 45% of the tumor lines were homozygous for this nucleotide substitution compared to 14% of the controls and in 1 MCC patient the wild-type allele was lost in the tumor, this novel polymorphism may contribute to tumor development. On the other hand, loss of 3p, characteristic for SCCs, was rare in MCCs. Although in 2 of 3 SCC lines 3p loss was correlated with reduced expression of the FHIT (fragile histidine triad) gene, the potential tumor suppressor mapped to 3p14.2 and 2 MCC lines with normal 3p showed aberrant or no FHIT transcripts. Taken together, in addition to the common UV-B-specific mutations in the p53 and Ha-ras gene, MCCs and SCCs also share chromosomal imbalances that may point to a common environmental-derived (e.g., UV-A) oxidative damage.
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PMID:UV-B-type mutations and chromosomal imbalances indicate common pathways for the development of Merkel and skin squamous cell carcinomas. 1199 3

We previously reported the identification of three minimal regions of deletion on the short arm of chromosome 3 (3p) in epithelial ovarian tumor specimens, suggesting that the inactivation of tumor-suppressor genes in these regions may be important in terms of ovarian tumorigenesis. Another previous study of ovarian cancer observed that allele loss of chromosome 179 was frequently found in ovarian tumors that also showed loss of heterozygosity (LOH) of chromosomes 3p, 13q, 17p, and Xp. In an independent study, we also reported a high frequency of LOH for selected chromosome 17 loci in high-grade and late-stage ovarian tumors. We have extended our LOH analysis of chromosome 3p to include 102 ovarian tumor specimens (29 and 73 samples were previously examined for LOH of chromosome 3p and 17 markers, respectively), using additional polymorphic markers, to assess the coordinate LOH of loci representing the three chromosome 3p minimal regions of deletions [von Hippel-Lindau syndrome (VHL), thyroid hormone receptor beta, and fragile histidine triad (FHIT)] and LOH of other important loci [tumor protein 53 (TP53), breast cancer 1 early onset (BRCA1), breast cancer 2 early onset, retinoblastoma 1, ornithine carbamoyltransferase, and androgen receptor] or somatic mutations in TP53. There was a significant association between LOH of any chromosome 3p marker and LOH of any chromosome 17 marker (P = 0.026). The frequency of LOH at the TP53 locus was higher in the group of samples that displayed LOH of a 3p marker (P = 0.019), as was the frequency of LOH at the BRCA1 locus (P = 0.014). LOH of chromosome 3p was noted in four specimens that did not display LOH of either the BRCA1 or the TP53 locus, indicating that LOH of these loci need not precede LOH of the chromosome 3p loci. We found a significant association between LOH of the VHL (3p25) locus and LOH of any chromosome 17 marker (P = 0.005), suggesting that there may be an important relationship, in the tumorigenesis of epithelial ovarian cancer, between a gene at 3p25 and a gene located on chromosome 17. Our results indicate that inactivation of p53 by somatic mutation is unlikely to be a prerequisite to chromosome 3p LOH, because we found no significant association between mutations in TP53 and LOH of the three chromosome 3p loci. The frequency of LOH at the FHIT locus at 3p14 increased significantly with advancing age at diagnosis (P = 0.018), as did the frequency of somatic TP53 mutations (P = 0.008).
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PMID:Comparative analysis of loss of heterozygosity of specific chromosome 3, 13, 17, and X loci and TP53 mutations in human epithelial ovarian cancer. 1211 14

In various studies of sporadic breast cancers, 40-70% were strongly positive for fragile histidine triad (Fhit) protein expression, whereas only 18% of BRCA2 mutant breast cancers demonstrated strong Fhit expression, suggesting that the BRCA2 repair function may be necessary to retain intact fragile common chromosome fragile site 3B(FRA3B)/FHITloci. In the current study, 22 breast tumors with deleterious BRCA1 mutations were analyzed for Fhit expression by immunohistochemistry in a case-control matched pair analysis. Loss of Fhit expression was significantly more frequent in the BRCA1 cancers compared with sporadic breast tumors (9% Fhit positive versus 68% Fhit positive), suggesting that the BRCA1 pathway is also important in protecting the FRA3B/FHIT locus from damage. To investigate the relationship between repair gene deficiencies and induction of chromosome fragile sites in vitro, we have analyzed the frequency of aphidicolin induction of chromosome gaps and breaks in PMS2-, BRCA1-, MSH2-, MLH1-, FHIT-, and TP53-deficient cell lines. Each of the repair-deficient cell lines showed elevated expression of chromosome gaps and breaks, consistent with the proposal that proteins involved in mismatch and double-strand break repair are important in maintaining the integrity of common fragile regions. Correspondingly, genes at common fragile sites may sustain elevated levels of DNA damage in cells with deficient DNA repair proteins such as those mutated in several familial cancer syndromes.
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PMID:The fragile histidine triad/common chromosome fragile site 3B locus and repair-deficient cancers. 1212 41


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