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:Q86TM3 (cage)
29,987 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The tumour suppressor p16 is a member of the INK4 family of inhibi tors of the cyclin D-dependent kinases, CDK4 and CDK6, that are involved in the key growth control pathway of the eukaryotic cell cycle. The 156 amino acid residue protein is composed of four ankyrin repeats (a helix-turn-helix motif) that stack linearly as two four-helix bundles resulting in a non-globular, elongated molecule. The thermodynamic and kinetic properties of the folding of p16 are unusual. The protein has a very low free energy of unfolding, Delta GH-2O/D-N, of 3.1 kcal mol-1 at 25 degreesC. The rate-determining transition state of folding/unfolding is very compact (89% as compact as the native state). The other unusual feature is the very rapid rate of unfolding in the absence of denaturant of 0.8 s-1 at 25 degreesC. Thus, p16 has both thermodynamic and kinetic instability. These features may be essential for the regulatory function of the INK4 proteins and of other ankyrin-repeat-containing proteins that mediate a wide range of protein-protein interactions. The mechanisms of inactivation of p16 by eight cancer-associated mutations were dissected using a systematic method designed to probe the integrity of the secondary structure and the global fold. The structure and folding of p16 appear to be highly vulnerable to single point mutations, probably as a result of the protein's low stability. This vulnerability provides one explanation for the striking frequency of p16 mutations in tumours and in immortalised cell lines.
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PMID:Stability and folding of the tumour suppressor protein p16. 991 18

Invasive breast carcinomas are characterized by a complex pattern of chromosomal alterations. We applied comparative genomic hybridization (CGH) to analyze 105 primary breast carcinomas using histograms to indicate the incidence of DNA imbalances of tumor subgroups and difference histograms to compare invasive ductal carcinomas (IDC) with lobular carcinomas (ILC), well and poorly differentiated carcinomas (G1/G3) and estrogen receptor-positive and -negative tumors (ER(+)/ER(-)). Only single imbalances showed a higher incidence in ILC compared with IDC, i.e., gains on chromosomes 4 and 5q13-q23 as well as deletions on chromosomes 6q, 11q14-qter, 12p12-pter, 16q, 17p, 18q, 19, and 22q. Of these, particularly gains of 4 and losses at 16q21-q23, and 18q12-q21 were statistically significant. For most loci, IDC showed more alterations providing a genetic correlate to the fact that ductal carcinoma overall is associated with a worse prognosis than ILC. Of these, many imbalances showing statistical significance were also observed in G3 and ER(-) tumors, i.e., deletions at 2q35-q37, 3p12-p14, 4p15-p16, 5q, 7p15, 8p22-p23, 10q, 11p, 14q21-q31, 15q, and gains at 2p, 3q21-qter, 6p, 8q21-qter, 10p, 18p11-q11, and 20q, suggesting that they contribute to a more aggressive tumor phenotype. By contrast, gains on chromosome 5q13-q23 as well as deletions at 6q, 16q and 22q were more prevalent in G1 and ER(+) tumors. The ratio profiles of all cases as well as histograms are accessible at our CGH online tumor database at http://amba.charite.de/cgh. Our results highlight distinct chromosomal subregions for cancer-associated genes. In addition, these imbalances may serve as markers for a genetic classification of invasive breast cancer.
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PMID:Patterns of chromosomal imbalances in invasive breast cancer. 1086 9

AIM:To study hepatocarcinogenesis of hepatitis C virus (HCV).METHODS: Expression of HCV antigens (CP10, NS3 and NS5) and several cancer-associated gene products (ras p21, c-myc, c-erbB-2, mutated p53 and p16 protein) in the tissues of hepatocellular carcinoma (HCC, n = 46) and its surrounding liver tissue were studied by the ABC(avidin-biotin complex) immunohistochemical method. The effect of HCV infection on expression of those gene products in HCC was analyzed by comparing HCV antigen positive group with HCV antigen negative group.RESULTS:Positive immunostaining with one, two or three HCV antigens was found in 20 (43.5%) cases,with either of two or three HCV antigens in 16 (34.8%) cases, and with three HCV antigens in 9 (19.6%) cases.Deletion rate of p16 protein expression in HCC with positive HCV antigen (80%, 16/20)was significantly higher than that in HCC with negative HCV antigen. Whereas no significant difference of the other gene product expression was observed between the two groups.CONCLUSION:HCV appears related to about one third of cases of HCC in Chongqing, the southwest of China, and it may be involved in hepatocarcinogenesis by inhibi ting the function of p16 gene, which acts as a negative regulator of cell cycle.
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PMID:Effect of HCV infection on expression of several cancer-associated gene products in HCC. 1181 78

Promoter hypermethylation is an important means for the transcriptional repression of a number of cancer-associated genes. However, the underlying mechanism of this aberration in cancer remains unclear. Here, we examined 5' CpG island methylation status and expression of the p14(ARF), p16(INK4a) and RASSF1A tumor suppressor genes, and investigated the relationship of these factors with the mRNA expression of DNA methyltransferases (DNMTs) and/or methyl-CpG-binding proteins (MBPs) in 30 lung cancer cell lines including 12 small cell lung cancers (SCLCs) and 18 non-small cell lung cancers (NSCLCs). When beta-actin was used as an internal control, the mRNA expression of three DNMTs (DNMT1, DNMT3A, and DNMT3B) and five MBPs (MBD1, MBD2, MBD3, MBD4, and MeCP2) was upregulated in SCLC, while only that of DNMT1, DNMT3B and MBD3 was upregulated in NSCLC, compared with normal lung tissues. However, when normalized using proliferating cell nuclear antigen (PCNA) as an internal control, these differences disappeared or diminished; there was even a significant reduction in the expression ratios of DNMT1, MBD2 and MeCP2 in SCLC and DNMT1, MBD2 and MBD4 in NSCLC. Furthermore, although significant correlations between PCNA expression and mRNA expression levels of the three DNMTs and four of the MBPs (excluding MeCP2) were observed, there was no obvious correlation between promoter hypermethylation of these tumor suppressor genes and the expression level of any of the DNMTs or MBPs. Our results suggest that upregulation of DNMTs and MBPs probably reflects an increased cell proliferation in human lung cancers and that there are likely to exist gene-specific mechanisms for epigenetic gene silencing.
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PMID:The expression of DNA methyltransferases and methyl-CpG-binding proteins is not associated with the methylation status of p14(ARF), p16(INK4a) and RASSF1A in human lung cancer cell lines. 1210 20

The ANK repeat is a ubiquitous 33-residue motif that adopts a beta hairpin helix-loop-helix fold. Multiple tandem repeats stack in a linear manner to produce an elongated structure that is stabilized predominantly by short-range interactions between residues close in sequence. The tumor suppressor p16(INK4) consists of four repeats and represents the minimal ANK folding unit. We found from Phi value analysis that p16 unfolded sequentially. The two N-terminal ANK repeats, which are distorted from the canonical ANK structure in all INK4 proteins and which are important for functional specificity, were mainly unstructured in the rate-limiting transition state for folding/unfolding, while the two C-terminal repeats were fully formed. A sequential unfolding mechanism could have implications for the cellular fate of wild-type and cancer-associated mutant p16 proteins.
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PMID:Sequential unfolding of ankyrin repeats in tumor suppressor p16. 1251 41

Cells expressing the neuronal stem cell marker Nestin are present in the human pancreas but the biological role of these cells has yet to be resolved. We report here the establishment with the catalytic subunit of human telomerase (hTERT) of a line of normal human cells representing this cell type. Primary human cells derived from the ducts of the pancreas were transduced with an hTERT cDNA. The infected cells became positive for telomerase, failed to senesce, and were still proliferating after more than 150 doublings. The immortalized cells were positive for the expression of Nestin (at both the mRNA and protein levels) and were found to be free of cancer-associated changes: diploid and expressing wild type p16(INK4a), p53, and K-Ras. An established line of normal human cells representing this cell type should be of great value to help define the biological properties of this novel cell type.
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PMID:Immortalization with telomerase of the Nestin-positive cells of the human pancreas. 1258 17

Aberrant promoter hypermethylation of tumor-associated genes leading to their inactivation is a common event in many cancer types. Using a sensitive restriction-multiplex PCR method, we studied the promoter hypermethylation profile of the p16, p15, hMLH1, MGMT and E-cad genes in oral squamous cell carcinoma (OSCC) of Indians. We analyzed a total of 51 samples for the p15 tumor-suppressor gene and 99 samples for each of the remaining genes. Our studies indicate an incidence of promoter hypermethylation of 23% each for p16 and p15, 8% for hMLH1, 41% for MGMT and 35% for E-cad. We observed aberrant hypermethylation of the promoter region of at least 1 of these genes in 74.5% of cases (n = 51) for which all the 5 genes were studied. Abnormal methylation was detected in tumors irrespective of stage and location in the oral cavity, whereas no abnormal methylation was detectable in normal oral squamous tissues obtained from 25 OSCC patients. Detection of aberrant hypermethylation patterns of cancer-associated genes listed above is therefore suitable for diagnosis of OSCC in individuals at high risk for this disease.
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PMID:Promoter hypermethylation profile of tumor-associated genes p16, p15, hMLH1, MGMT and E-cadherin in oral squamous cell carcinoma. 1267 28

The methylthioadenosine phosphorylase (MTAP) gene is localized in the chromosomal region 9p21. Here, frequently homozygous deletions occur in several kinds of cancer associated with the loss of tumour suppressor genes as p16 and p15. The aim of this study was to analyse MTAP expression in hepatocellular carcinoma (HCC) and to get an insight into the regulation and functional role of MTAP in hepatocancerogenesis. Compared with primary human hepatocytes MTAP expression was markedly downregulated in three different HCC cell lines as determined by real-time PCR and western blotting. This was not due to genomic losses or mutations but to promoter-hypermethylation. Reduced MTAP-expression was confirmed in vivo in HCC compared with non-cancerous liver tissue on both mRNA and protein levels. To study the functional relevance of the downregulated MTAP expression in HCC, MTAP expression was re-induced in HCC cell lines by stable transfection. In these MTAP re-expressing cell clones the invasive potential was strongly reduced, whereas no effects on cell proliferation were observed in comparison with mock transfected cell clones. Furthermore, in MTAP re-expressing cells interferon (IFN)-alpha and IFN-gamma induced a significantly stronger inhibition of cell proliferation than in mock transfected cells. In conclusion, our results suggest a functional role of MTAP inactivation in HCC development and invasiveness. Furthermore, in the light of a recent report revealing an association between MTAP activity and IFN sensitivity, our findings may have clinical significance for therapeutic strategies.
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PMID:Promoter-hypermethylation is causing functional relevant downregulation of methylthioadenosine phosphorylase (MTAP) expression in hepatocellular carcinoma. 1608 15

The extent of unilateral chromosomal losses and the presence of microsatellite instability (MSI) have been classified into high-risk (high- and baseline-level loss) and low-risk (low-level loss and MSI) stem-line genotypes in gastric carcinomas. A unilateral genome-dosage reduction might stimulate compensation mechanism, which maintains the genomic dosage via CpG hypomethylation. A total of 120 tumor sites from 40 gastric carcinomas were examined by chromosomal loss analysis using 40 microsatellite markers on 8 chromosomes and methylation analysis in the 13 CpG (island/non-island) regions near the 10 genes using the bisulfite-modified DNAs. The high-level-loss tumor (four or more losses) showed a tendency toward unmethylation in the Maspin, CAGE, MAGE-A2 and RABGEF1 genes, and the other microsatellite-genotype (three or fewer losses and MSI) toward methylation in the p16, hMLH1, RASSF1A, and Cyclin D2 genes (p<0.05). The non-island CpGs of the p16 and hMLH1 genes were hypomethylated in the high-level-loss and hypermethylated in the non-high-level-loss sites (p<0.05). Consequently, hypomethylation changes were related to a high-level loss, whereas the hypermethylation changes were accompanied by a baseline-level loss, a low-level loss, or a MSI. This indicates that hypomethylation compensates the chromosomal losses in the process of tumor progression.
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PMID:Relationship between the extent of chromosomal losses and the pattern of CpG methylation in gastric carcinomas. 1622 53

There is increasing evidence for the role of epigenetic gene silencing in superficial bladder cancer. The aim of the current study was to investigate the prognostic value of epigenetic alterations in patients with non-muscle invasive bladder carcinoma. We checked the methylation status of 20 cancer associated genes (p14ARF, p16 CDKN2A, STAT-1, SOCS-1, DR-3, DR-6, PIG-7, BCL-2, H-TERT, BAX, EDNRB, DAPK, RASSF-1A, FADD, TMS-1, E-Cadherin, ICAM-1, TIMP-3, MLH-1, COX-2) for DNA methylation. We analysed microdissected tumour samples from 105 consecutive patients with primary non-muscle invasive bladder carcinoma. Quantitative methylation analysis of CpG sites in the promoter region of the genes was performed with methylation sensitive quantitative real time PCR ('Methylight'). Univariate analysis for association with tumour recurrence was carried out with the Kaplan-Meier analysis and the log-rank test. Follow-up data were available in 95/105 patients (91.4%). A tumour recurrence was observed in 26 patients (27.3%). We could identify six genes (SOCS-1, STAT-1, BCL-2, DAPK, TIMP-3, E-Cadherin), where methylation was associated with tumour recurrence. In Kaplan-Meier analysis, TIMP-3 showed a significant association with recurrence free survival. Methylation of TIMP-3 predicted prolonged disease free interval. In this study, we report a comprehensive analysis on prognostic relevance of gene methylation in non-muscle invasive bladder cancer. We identified one gene (TIMP-3) where methylation was associated with a more favourable outcome. Our data strongly support the usefulness of gene methylation as a prognostic marker in patients with non-muscle invasive bladder cancer.
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PMID:Prognostic relevance of methylation markers in patients with non-muscle invasive bladder carcinoma. 1624 28


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