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 aim of this study w trial randomized as to investigate the frequencies of human papillomavirus (HPV) and mutation in Ha-ras oncogene and tumour suppressor p53 gene in cervical cancer and precursor lesions. A total of 30 invasive carcinomas (IC), 36 cervical intraepithelial neoplasia grade III (CIN III) and 12 normal tissues adjacent to the tumor (NT) were included. HPV typification and scanning of possible mutations in Ha-ras and p 53 genes were made by SSCP-PCR. The IC cases showed 93% HPV positivity, 41% having mobility shifts for Ha-ras mutations and 17% for p53 mutations while in CIN III, these percentages were 80%, 18% and 11%, respectively. In normal tissues HPV frequency was 17%. All Ha-ras mutated samples were HPV positive but 33% of p53 mutated cases were HPV negative. All mutations were heterozygous. HPV 16 was more prevalent (44%) than HPV 18 (15%) and the high rate of undetermined HPV types (18%) would indicate the circulation in our country of other types different from the assayed HPV controls (6, 11, 16, 18, 31 and 33), being variants or mixed infections. The low frequency of p53 mutations (17%) strengthens the view that wild type p53 inactivation by HPV probably plays a major role in the pathogenesis of cervical cancer. Because mutated Ha-ras was found in HPV associated premalignant lesions, we speculate that it represents an early marker for progression. Our findings provide additional evidence for an interactive effect between high risk types of HPV and oncogene activation in the development of uterine cervical cancer.
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PMID:[Ha-ras and p53 gene mutations scanned by PCR-SSCP in premalignant and malignant lesions of the uterine cervix associated with human papillomavirus]. 1143 98

Conflicting results regarding the association of a polymorphism at codon 72 of the p53 tumour suppressor gene and susceptibility to develop human papilloma virus (HPV)-associated cervical cancer have been published over the last year, implicating differences in ethnic background, sample origin, sample size and/or detection assay. The material for this study was collected in the identical geographical region as for 2 previous reports with contradictory results regarding the association of codon 72 genotype with squamous cell cancer (SCC). We have used an alternative detection assay, based on pyrosequencing technology, that interrogates the variable position by the accuracy of DNA polymerase. In addition to cervical clinical specimens from SCC, HPV16- and HPV18-infected adenocarcinoma cases as well as cervical intraepithelial neoplasia (CIN) were investigated. No significant association was found between p53 codon 72 genotype and the risk to develop adenocarcinoma, SCC or CIN in the Swedish population.
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PMID:HPV-related cancer susceptibility and p53 codon 72 polymorphism. 1150 50

Association of infection with papillomavirus and dysplasia of the cervix uteri has been firmly established. There are only few cervical cancers where no HPV DNA is detectable. The mechanism of epithelial cell immortalization by interaction with tumour suppressor genes p53 and pRb by viral oncogenes E6 and E7 is elucidated. Progression of the HPV infected cell to a malignant phenotype involves further modification of host gene expression and/or mutations. The appearance of chromosomal aberrations can lead to mutational inactivation or loss of tumour suppressor genes (TSG), activation and amplification of oncogenes, with importance for the process of carcinogenesis. Oncogene amplification, with exception of few reports, seems not to be a major mechanism in cervical carcinogenesis. In contrast, cytogenetic and loss of heterozygosity (LOH) results from CIN and invasive cancer demonstrate alterations at specific chromosomal regions, pointing at localisation of TSG. Genetic alterations at chromosomes 3p, 6p, 1lq were frequently found early in tumour development Primary invasive carcinoma showed additional allelic losses at chromosome arms 6q, 17p and 18q. Useful biological diagnostic and prognostic markers for high-risk HPV infection and malignant progression may be p16NK4 p27Kip, and NET-I/C4.8. Putative senescence genes relevant for HPV-induced carcinogenesis are localized on chromosomes 2, 4 and 10. Genes for Telomerase suppression are presumably located on chromosomes 3, 4 and 6. Natural immune responses to HPV infection exist Therefore, immune therapy is an attractive possibility for prevention and therapy of HPV infection. To date, vaccine development has reached clinical evaluation. Prophylaxis aims at the induction of virus neutralizing antibodies to capsid proteins. Virus-like particle vaccines are currently tested in clinical trials. Due to the long lag period between infection and clinical manifestation trials will take a long time until conclusive results are obtained. Mandatory expression of viral and perhaps certain cellular genes in infected epithelial and tumour cells offers targets for therapeutic approaches. Since most dysplasia clears spontaneously the viral infection is immunogenic to some extent. However, in some individuals the immune response has to be stimulated by vaccination in order to be effective. Several strategies are being tested in clinical trials and others are in preclinical development The task will be to circumvent immunosuppressive features of the HPV infected cells.
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PMID:HPV induced cervical carcinogenesis: molecular basis and vaccine development. 1279 44

Microsatellite-stable, near-diploid (MSI-CIN-) colorectal carcinomas have been reported, but it is not clear as to whether these tumours form a discrete group or represent one end of the distribution of MSI-CIN+ cancers. In order to address this question, we screened 23 MSI-CIN- colorectal cancers for gains and losses using array-based comparative genomic hybridization (aCGH) based on large-insert clones at about 1 Mb density. We compared our findings with those from a small set of MSI+CIN+ cancers, and with our reported data from MSI-CIN+ and MSI+CIN- cancers. We found no evidence of any form of genomic instability in MSI-CIN- cancers. At the level of the chromosome arm, the MSI-CIN- cancers had significantly fewer gains and losses than MSI-CIN+ tumours, but more than the MSI+CIN- and MSI+CIN+ lesions. The chromosomal-scale changes found in MSI-CIN- cancers generally involved the same sites as those in MSI-CIN+ tumours, and in both cancer groups, the best predictor of a specific change was the total number of such changes in that tumour. A few chromosomal-scale changes did, however, differ between the MSI-CIN- and MSI-CIN+ pathways. MSI-CIN- cancers showed: low frequencies of gain of 9p and 19p; infrequent loss of 5q and a high frequency of 20p gain. Overall, our data suggested that the MSI-CIN- group is heterogeneous, one type of MSI-CIN- cancer having few (< or =6) chromosomal-scale changes and the other with more (> or =10) changes resembling MSI-CIN+ cancers. At the level of individual clones, frequent and/or discrete gains or losses were generally located within regions of chromosomal-scale changes in both MSI-CIN- and MSI-CIN+ cancers, and fewer losses and gains were present in MSI-CIN- than MSI-CIN+ tumours. No changes by clone, which were specific to the MSI-CIN- cancers, were found. In addition to indicating differences among the cancer groups, our results also detected over 50 sites (amplifications, potential homozygous deletion and gains or losses which extended over only a few megabases) which might harbour uncharacterized oncogenes or tumour suppressor loci. In conclusion, our data support the suggestion that some MSI-CIN- carcinomas form a qualitatively different group from the other cancer types, and also suggest that the MSI-CIN- group is itself heterogeneous.
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PMID:Array-CGH analysis of microsatellite-stable, near-diploid bowel cancers and comparison with other types of colorectal carcinoma. 1553 20

The retinoblastoma gene was the first tumour suppressor gene identified that was altered not only in retinoblastomas but has been described in a wide variety of human neoplasms. The retinoblastoma gene encodes a nuclear phosphoprotein that in its hypophosphorylated state plays an important role in regulating the cell cycle, thus preventing from tumour formation. Expression of retinoblastoma gene protein product (pRB) was investigated in 118 formalin-fixed, paraffin-embedded cervical tissues by immunohistochemistry using commercially available antibody directed against RB protein. Ten normal ectocervical epithelium, 16 cervical intraepithelial neoplasia (CIN) I, 13 CIN II, 14 CIN III, 53 invasive squamous cell carcinoma, 11 adenocarcinoma and 1 small cell carcinoma were selected for this study. The proportions of pRB-positive cells as well as the extent of pRB expression in ectocervical squamous epithelium were assessed and compared among the lesions. The pRB expression was observed in 100% of normal ectocervical epithelium (n=10), 100% of CIN lesions (n=43) and 98.5% of invasive carcinoma of the uterine cervix (n=65) and were statistically significant when CIN or CIN/invasive were compared to normal cases (P < 0.01, P < 0.05 respectively). While in invasive squamous cell carcinoma (SCC), 81.8% (9/11) pRB-positive cells were found in much higher percentages in well differentiated SCC compared to 64.3% (18/28) of moderately differentiated cases and only 7.1% (1/14) of poorly differentiated SCC (P < 0.01, respectively). The results of this study suggest that loss of RB protein expression is rare in carcinoma of the uterine cervix and this protein may be important in the pathogenesis of cervical carcinoma.
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PMID:An immunohistochemical study of retinoblastoma gene product in normal, premalignant and malignant tissues of the uterine cervix. 2336 1

High-risk human papillomaviruses (HPV) are the causative agents of cervical and other anogenital cancers as well as a subset of head and neck cancers. The E6 and E7 oncoproteins of HPV contribute to oncogenesis by associating with the tumour suppressor protein p53 and pRb, respectively. For HPV types 16 and 18, intratypic sequence variation was shown to have biological and clinical significance. The functional significance of sequence variation among HPV 31 variants was studied less intensively. HPV 31 variants belonging to different variant lineages were found to have differences in persistence and in the ability to cause high grade cervical intraepithelial neoplasia. In the present study, we started to explore the functional effects of natural sequence variation of HPV 31 E6 and E7 oncoproteins. The E6 variants were tested for their effects on p53 protein stability and transcriptional activity, while the E7 variants were tested for their effects on pRb protein level and also on the transcriptional activity of E2F transcription factors. HPV 31 E7 variants displayed uniform effects on pRb stability and also on the activity of E2F transcription factors. HPV 31 E6 variants had remarkable differences in the ability to inhibit the trans-activation function of p53 but not in the ability to induce the in vivo degradation of p53. Our results indicate that natural sequence variation of the HPV 31 E6 protein may be involved in the observed differences in the oncogenic potential between HPV 31 variants.
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PMID:Phylogenetic and functional analysis of sequence variation of human papillomavirus type 31 E6 and E7 oncoproteins. 2719 52

Cervical cancer is the fourth most common cancer among women. Infection by high-risk human papillomavirus (HPV) is the main aetiology for the development of cervical cancer. Infection by high-risk human papillomavirus (HPV) and the integration of the HPV genome into the host chromosome of cervical epithelial cells are key early events in the neoplastic progression of cervical lesions. The viral oncoproteins, mainly E6 and E7, are responsible for the initial changes in epithelial cells. The viral proteins inactivate two main tumour suppressor proteins, p53, and retinoblastoma (pRb). Inactivation of these host proteins disrupts both the DNA repair mechanisms and apoptosis, leading to rapid cell proliferation. Multiple genes involved in DNA repair, cell proliferation, growth factor activity, angiogenesis, as well as mitogenesis genes become highly expressed in cervical intraepithelial neoplasia (CIN) and cancer. This genomic instability encourages HPV-infected cells to progress towards invasive carcinoma. The key molecular events involved in cervical carcinogenesis will be discussed in this review.
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PMID:Key Molecular Events in Cervical Cancer Development. 3131 55

Cervical cancer is the most prevalent cancer among women in India. The main cause of cervical cancer is persistent human papilloma viral (HPV) infection. HPV inactivates the pRb tumour suppressor protein; thus p16 expression, which is controlled by a negative feedback mechanism, is relatively increased. Galectin-3 is directly and indirectly connected to cancer cell activity and contributes to oncogenesis, angiogenesis, cancer progression and metastasis. Thus, the aim of this study was to study the expression of p16 and galectin-3 in Cervical Intraepithelial Neoplasia (CIN) and Squamous Cell Carcinoma (SCC) and to correlate p16 and galectin-3 expression. On hundred and eighteen newly-diagnosed untreated cases of CIN and SCC of uterine cervix were included in the study. Expression of p16 and galectin 3 was more pronounced in invasive SCC and High-grade Intraepithelial Lesion (HSIL), as compared to Low-grade Intraepithelial Lesion (LSIL).Thus, it may be used in clinical setting to monitor cervical lesions and to predict their progression. Impact statement What is already known on this subject? p16 overexpression is a surrogate biomarker of HPV infection and useful in evaluating HPV-associated squamous and glandular neoplasia of the lower gynaecologic tract. Increased galectin-3 expression is seen in SCC cervical, with less consistent results in CIN. What do the results of this study add? The results of our study adds to the growing literature that p16 and galectin-3 expression have direct statistically significant correlation with a degree of dysplasia and SCC cervix. Expression of p16 and galectin-3 was more pronounced in invasive SCC and high-grade intraepithelial lesion (HSIL), as compared to low-grade intraepithelial lesion (LSIL). What are the implications of these findings for clinical practice and/or further research? This correction of p16 and galectin-3 expression with degree of dysplasia and SCC cervix can be used for screening and early detection of cervical lesions and thus aid their early treatment and increased survival.
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PMID:The expression of p16 and galectin-3 in cervical intraepithelial neoplasia (CIN) and squamous cell carcinoma (SCC) uterine cervix. 3307 44