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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Infection of high risk human papillomaviruses (HPVs) specifically the types 16 and 18 has been strongly implicated in the development of cervical cancer. The E6 oncoproteins of these high risk HPVs are known to bind and induce degradation of p53 tumour suppressor protein through the ubiquitin pathways. This degradation is controlled by a common polymorphism of the p53 gene encoding either a proline or an arginine at its codon 72 in exon 4. Recently, it has been demonstrated that the presence of homozygous arginine at codon 72 renders p53 about seven times more susceptible to E6-mediated proteolytic degradation as well as to cervical cancer than those with proline homozygotes or proline/arginine heterozygotes. In India, prevalence of HPV as well as cancers of the uterine cervix and the oral cavity are highest in the world. We have examined this allele-specific predisposition in cervical and oral cancer which is associated with HPV as well as in a non-HPV-linked cancer of the breast. We have carried out investigation in women comprising whole spectrum of cervical lesions with 128 HPV 16/18 positive and 35 HPV negative invasive cervical carcinomas and 34 cases of HPV (16/18) positive and 16 HPV negative cervical dysplasias (mild, moderate and severe) and 104 age-group-matched healthy women as controls. Additionally, we have analysed p53Arg-Pro polymorphism in 13 high risk HPV positive and 31 HPV negative oral cancers along with 20 normal controls and 77 breast cancers with 41 age-matched healthy controls. We observed more than two fold higher risk for homozygous arginine (chi2 = 6.3, df = 2, p = 0.04; OR = 2.3; 95% CI: 1.08-5.16) for HPV 16/18-positive cervical carcinomas when comparison was made only between HPV positive cervical cancers and normal controls but most interestingly, no significant association either in the frequency of homozygous arginine or proline alleles or their heterozygotes could be observed when all the three groups i.e. HPV-positive, HPV-negative cervical cancers and controls were considered simultaneously. No difference was also observed for either arginine or proline polymorphism between women with precancerous lesions of the uterine cervix carrying HPV 16/18 infection and controls. Similarly, increased risk of oral or breast cancer could not be correlated with the polymorphism of arginine/proline allele. Thus the interaction between HPV oncoproteins and the p53 gene polymorphism specifically, homozygous arginine at codon 72 appears to play no role in the development of either cervical or oral cancer and also it can not serve as a biomarker for early identification of cervical, oral or breast cancer.
Mol Cell Biochem 2003 Oct
PMID:Polymorphism of the p53 codon 72 Arg/Pro and the risk of HPV type 16/18-associated cervical and oral cancer in India. 1457 84

Cyclin Dependent Kinase 4 (Cdk4) is known to be an oncogene and is involved in various cancers. It is over-expressed either by genomic amplification or by c-myc dependent manner. Our preliminary results indicate high expression of protein and mRNA as well as absence of genomic amplification in early oral cancer development. One transcription factor (TF) binding site has been detected from -281 to -298 by using DNase I foot printing and confirmed by electrophoretic mobility shift assay. This is a novel DNA sequence. The recruitment of this new TF as well as the earlier reported c-myc was analyzed in various stage of oral cancer development. The binding activity of the new TF is present in normal tissues and observed more in initial stage samples whereas c-myc expression was absent in normal and more in higher stage of oral cancer development. On the basis of these findings we propose the new TF to be a possible CdK4 Regulating Factor (KRF). This might maintain the basal level transcription in normal and activates Cdk4 transcription in the initial stage, where as the same role is carried by c-myc in higher stage of chewing tobacco mediated oral cancer development.
Mol Biol Rep 2003 Dec
PMID:Early overexpression of Cdk4 and possible role of KRF and c-myc in chewing tobacco mediated oral cancer development. 1467 6

Relative expression levels of 9500 genes were determined by cDNA microarray analyses in mouse skin JB6 cells susceptible (P+) and resistant (P-) to 12-O-tetradecanoyl phorbol-13 acetate (TPA)-induced neoplastic transformation. Seventy-four genes in 6 functional classes were differentially expressed: (I) extracellular matrix (ECM) and basement membrane (BM) proteins (20 genes). P+ cells express higher levels than P- cells of several collagens and proteases, and lower levels of protease inhibitors. Multiple genes encoding adhesion molecules are expressed preferentially in P- cells, including six genes implicated in axon guidance and adhesion. (II) Cytoskeletal proteins (13 genes). These include actin isoforms and regulatory proteins, almost all preferentially expressed in P- cells. (III) Signal transduction proteins (12 genes). Among these are Ras-GTPase activating protein (Ras-GAP), the deleted in oral cancer-1 and SLIT2 tumor suppressors, and connexin 43 (Cx43) gap junctional protein, all expressed preferentially in P- cells. (IV) Interferon-inducible proteins (3 genes). These include interferon-inducible protein (IFI)-16, an Sp1 transcriptional regulator expressed preferentially in P- cells. (V) Other transcription factors (4 genes). Paired related homeobox gene 2 (Prx2)/S8 homeobox, and retinoic acid (RA)-regulated nur77 and cellular retinoic acid-binding protein II (CRABPII) transcription factors are expressed preferentially in P- cells. The RIN-ZF Sp-transcriptional suppressor exhibits preferential P+ expression. (VI) Genes of unknown functions (22 sequences). Numerous mesenchymal markers are expressed in both cell types. Data for multiple genes were confirmed by real-time PCR. Overall, 26 genes were newly implicated in cancer. Detailed analyses of the functions of the genes and their interrelationships provided converging evidence for their possible roles in implementing genetic programs mediating cancer susceptibility and resistance. These results, in conjunction with cell wounding and phalloidin staining data, indicated that concerted genetic programs were implemented that were conducive to cell adhesion and tumor suppression in P- cells and that favored matrix turnover, cell motility, and abrogation of tumor suppression in P+ cells. Such genetic programs may in part be orchestrated by Sp-, RA-, and Hox-transcriptional regulatory pathways implicated in this study.
Mol Carcinog 2004 Jan
PMID:Adhesion, migration, transcriptional, interferon-inducible, and other signaling molecules newly implicated in cancer susceptibility and resistance of JB6 cells by cDNA microarray analyses. 1469 46

Betel quid (BQ) chewing shows a strong correlation to the incidence of oral submucous fibrosis (OSF), leukoplakia and oral cancer. BQ contains mainly areca nut, lime, Piper betle leaf (PBL) and the inflorescence of P. betle (IPB). Hydroxychavicol (4-allyl-catechol, HC), as a major phenolic compound in PBL and IPB, is shown to induce oxidative stress, glutathione (GSH) depletion and cell cycle deregulation. Using bivariate BrdU/PI flow cytometry, KB cells in DNA synthesis (S phase) are shown to be sensitive to the toxic effect of HC and show cell cycle arrest and apoptosis following exposure to 0.1 and 0.3 mM HC. HC-induced apoptosis and cell cycle arrest are associated with mitochondrial membrane potential (delta Psim) depolarization as revealed by a decrease in rhodamine fluorescence. N-acetyl-L-cysteine (1 mM), superoxide dismutase (100 U/ml) and catalase (1000 U/ml) were effective in prevention of HC-induced GSH depletion (as indicated by chloromethylfluorescein fluorescence), reactive oxygen species (ROS) production (by dichlorofluorescein fluorescence), cell cycle arrest and apoptosis. However, dimethylthiourea (2 mM), neocuproine (1 mM), 1,10-phenanthroline (200 microM) and desferrioxamine (0.5 mM) showed little effect on HC-induced cell changes. HC elevated the cellular and mitochondrial GSH levels at moderate concentrations (0.05-0.1 mM), whereas at a concentration of 0.3 mM, inhibitory effects were noted. These results indicate that HC consumption may be associated with BQ-chewing-related oral mucosal diseases via GSH depletion, ROS production, mitochondrial dysfunction, cell cycle disturbance and the induction of apoptosis. These events are related to the production of superoxide radicals and hydrogen peroxide.
Cell Mol Life Sci 2004 Jan
PMID:Reactive oxygen species are crucial for hydroxychavicol toxicity toward KB epithelial cells. 1470 56

Understanding the development and progression of oral cancer is critical in the quest for successful therapeutic intervention. The hypoxic microenvironment present in human oral tumor in vivo may actively influence tumor growth and neovascularization. This study correlates expression of both VEGF and HIF-1alpha in normal keratinocytes and oral cancer cell lines and determine whether hypoxia played a role in VEGF and HIF-1alpha regulation. Three human oral cancer cell lines and three normal keratinocytes were exposed to both normoxia and hypoxia culture conditions. Northern and Western blot analysis were used to assess VEGF and HIF-1alpha expression in the different culture conditions. ELISA assays were performed to measure VEGF production in the different cell lines tested. Hypoxia upregulated VEGF and HIF-1alpha expression on both normal and oral cancer cell lines, with a statistically significant difference between normal and oral cancer cell lines. Pattern of hypoxia-induced VEGF mRNA level tightly followed the HIF-1alpha mRNA expression in the cell lines tested. These results suggest that hypoxia regulates both VEGF and HIF-1alpha expression in head and neck carcinoma cell lines, thus establishing a biochemical pathway between tumor hypoxia and neoangiogenesis in these aggressive neoplasms.
Exp Mol Pathol 2004 Apr
PMID:Correlation between VEGF and HIF-1alpha expression in human oral squamous cell carcinoma. 1501 Feb 93

The p16/INK4A is one of the major target genes in carcinogenesis and its inactivation has frequently been reported in other types of tumors. The purpose of this study is to evaluate inactivation patterns of p16/INK4A in oral squamous cell carcinoma. Six different oral cancer cell lines, SCC-4, SCC-9, SCC-15, SCC-25, KB, and SNUDH- 379 were examined for inactivation of p16/INK4A genes. In the analysis of p16/INK4A gene inactivation, PCR amplification, direct sequencing, and methylation-specific PCR methods were adopted for evaluation of homozygous deletion, point mutation, and promoter hypermethylation, respectively. Homozygous deletion was detected in SCC-25 and SCC-9. SCC-15 showed hypermethylated promoter region within p16/INK4A gene. It is suggestive in the present study that inactivation patterns of p16/INK4A were mainly homozygous deletion, promoter methylation rather than point mutation in oral squamous cancer cell lines, so treatment modalities of oral squamous cell carcinoma should be focused on these types of inactivation.
Exp Mol Med 2004 Apr 30
PMID:Inactivation patterns of p16/INK4A in oral squamous cell carcinomas. 1515 Apr 45

The oral cavity is the sixth most common anatomical localization of head and neck carcinoma in men. Detection of oral carcinomas in the early asymptomatic stages improves cure rates and the quality of life. Tobacco smoking and alcohol drinking are the most important known risk factors for the development of head and neck tumors, suggesting that the exposure to these risk factors may increase the predisposition for genetic and epigenetic alterations, such as DNA methylation. The presence of methylated CpG islands in the promoter region of human genes can suppress their expression due to the presence of 5-methylcytosine that interferes with the binding of transcription factors or other DNA-binding proteins repressing transcription activity. Hypermethylation leading to the inactivation of some tumor suppressor genes, such as p16, has been pointed out as an initial event in head and neck cancer. Our aim was to evaluate an early diagnostic method of oral pre-cancerous lesions through the analysis of methylation of the p16 gene. DNA samples from normal oral mucosa and posterior tongue border from 258 smokers, without oral cancer, were investigated for the occurrence of p16 promoter hypermethylation. The methylation status of the p16 gene was analyzed using MS-PCR (methylation-sensitive restriction enzymes and PCR amplification), MSP (Methylation-specific PCR) or direct DNA sequence of bisulfite modified DNA. Hyper-methylation was detected in 9.7% (25/258) of the cases analyzed. These findings provide further evidence that epigenetic alteration, leading to the inactivation of the p16 tumor suppressor gene is an early event that might confer cell growth advantages contributing to the tumorigenic process. Thus, the detection of abnormal p16 methylation pattern may be a valuable tool for early oral cancer detection.
Int J Mol Med 2004 Nov
PMID:Hypermethylation of the p16 gene in normal oral mucosa of smokers. 1549 49

Studies in cell culture and laboratory animals have shown that green tea and its major component, epigallocatechin-3-gallate, inhibit cell growth and reduce tumor incidence. However, results of epidemiological studies have generated inconsistent, sometimes conflicting data regarding protection by green tea against human cancers. To clarify the findings of these laboratory studies in application to humans, we conducted a pilot intervention study with three heavy smokers (> 10 cigarettes/day) and three nonsmokers (never smokers) in order to evaluate the molecular and cellular effects of drinking green tea using human oral cells as an investigative tool. Green tea total extract (400-500 mg/cup, 5 cups/day) was administered in drinking water to the subjects for four weeks. Two oral cytology samples were taken weekly for measurements of tobacco carcinogen-induced DNA damage, including bulky adducts and oxidized bases, cell growth, DNA content, and apoptosis. The study showed that during the course of green tea administration smoking-induced DNA damage was decreased, cell growth was inhibited, and the percentage of cells in S phase was reduced, cells accumulated in G1 phase (cyclin D1 positive), DNA content became more diploid and less aneuploid, and p53, Caspase-3, and TUNEL, markers of apoptosis, were increased. The study, although preliminary, indicates that drinking green tea reduced the number of damaged cells in smokers by inducing cell growth arrest and apoptosis, a mechanism similar to that observed in cultured cells and animals. These results warrant a large-scale intervention trial to further verify the role of green tea in the prevention of oral cancer in smokers.
Mol Nutr Food Res 2005 Jan
PMID:Molecular and cellular effects of green tea on oral cells of smokers: a pilot study. 1553 15

Rapid advances in multimodality therapy have not significantly improved the overall 5-yr survival of oral cancer patients in the past two decades, thereby underscoring the need for molecular therapeutics. The development of new treatment strategies for more effective management of oral cancer requires identification of novel biological targets. Therefore, the aim of this study was to identify novel genes associated with oral tumorigenesis by comparing gene expression profile of oral squamous cell carcinomas (OSCCs) and matched nonmalignant oral epithelial tissues with differential display. Of the 180 differentially expressed cDNAs isolated, reamplified, and cloned into pGEMT-Easy Vector, 26 cDNAs were confirmed to be upregulated in OSCCs by reverse Northern blot analysis. The differentially expressed genes included components of immune system, signaling pathways, angiogenesis, cell structure, proliferation, apoptosis, cell-adhesion, and cellular metabolism. Reverse transcription (RT)-polymerase chain reaction (PCR) analysis of 15 OSCCs and matched nonmalignant oral tissues provided the first evidence that 14-3-3-zeta, melanoma metastasizing clone D (MEMD), KIAA0471, sperm protein 17 (SP17), TC21, and anti-TNF alpha antibody are upregulated in OSCCs. Immunohistochemical analysis confirmed overexpression of 14-3-3-zeta and TC21 protein, a member of the Ras family, in OSCCs as compared to histologically normal oral tissues validating the differential display analysis. Identification of six novel differentially expressed genes in oral tumors adds to the repertoire of genes associated with oral carcinogenesis and provides candidate potential biological targets for diagnosis and/or therapy. Further characterization of the 14 unknown differentially expressed cDNAs identified in this study may provide significant clues for understanding the molecular mechanisms underlying oral tumorigenesis.
Mol Carcinog 2005 Feb
PMID:Identification of differentially expressed genes in oral squamous cell carcinoma. 1559 30

The aim of this study was to assess the temporal patterns of (the formation of) thiobarbituric acid reactive substances and the activities of antioxidant enzymes in the erythrocytes of ten healthy adult subjects and ten oral cancer patients of comparable age. The levels of thiobarbituric acid reactive substances and the activities of antioxidant enzymes were assayed at 6-hour intervals using colorimetric methods. The Cosinorwin computer software program was used to analyse the characteristics of biochemical rhythms, such as acrophase, amplitude, and mesor (rhythms: acrophase, amplitude, mesor, etc.). There is a phase delay in erythrocyte thiobarbituric acid reactive substance levels and enzymatic antioxidant activities in oral cancer patients as compared to healthy subjects. The desynchronisation of thiobarbituric acid reactive substance production and enzymatic antioxidant rhythms reflected an alteration of circadian clock function in oral cancer patients and may require specific measures for chronotherapy.
Cell Mol Biol Lett 2004
PMID:Temporal patterns of lipid peroxidation product formation and antioxidants activity in oral cancer patients. 1564 89


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