Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatocellular carcinoma (HCC) is one of the most fatal human malignancies, but the molecular mechanisms of hepatocarcinogenesis remain unclear. Although p53 mutations are frequently observed in Asian HCC, it is not a common event in Western HCC. Recent studies suggest that tumor suppressor genes (TSGs) can also be silenced through epigenetic disruption, such as promoter CpG island methylation, during carcinogenesis. To further understand the molecular mechanism of hepatocarcinogenesis, we have investigated the promoter methylation status of nine TSGs (SOCS-1, GSTP, APC, E-cadherin, RAR-beta, p14, p15, p16, and p73) in 51 cases of HCC using methylation-specific polymerase chain reaction. We found that 82% of HCCs had methylation of at least one TSG promoter. The most frequently methylated TSGs in HCC were: SOCS-1 (65%), GSTP (54%), APC (53%), E-cadherin (49%), and p15 (49%). Methylation of SOCS-1, GSTP, APC, E-cadherin, and p15 was more frequent in HCC than in nontumor liver (P < 0.05). Methylation of SOCS-1, GSTP, and p15 was also significantly more frequent in HCC than cirrhotic liver (P < 0.05). Although methylation of one or two genes could be seen in both nontumor and cirrhotic livers, 53% of the HCC cases had three or more TSG promoters methylated, in comparison to 0% in nontumor liver and 13% in cirrhosis (P = 0.001). Methylation of SOCS-1, APC, and p15 was more frequently seen in hepatitis C virus-positive HCC than hepatitis C virus/hepatitis B virus-negative HCC. Our data suggest that promoter hypermethylation of TSGs is a common event in HCC and may play an important role in hepatocarcinogenesis.
 ...
PMID:Aberrant promoter methylation profiles of tumor suppressor genes in hepatocellular carcinoma. 1293 51

The p14(ARF), p15(INK4B), and p16(INK4A) genes are important negative cell-cycle regulators often inactivated by deletions, mutations, or hypermethylation in malignancy. Hypermethylation of the three genes was studied in 81 patients with therapy-related myelodysplasia (t-MDS) or acute myeloid leukemia (t-AML) by methylation-specific PCR, and p15 methylation additionally by bisulfite genomic sequencing. In all, 55 patients disclosed p15 methylation, five patients showed p16 methylation, whereas p14 methylation was not observed. Methylation of p15 was closely associated with deletion or loss of chromosome arm 7q (P=0.0006). In t-MDS, the p15 methylation frequency and the p15 methylation density both increased significantly by stage (P=0.004 and 0.0002), and p15 methylation frequency increased with an increasing percentage of myeloblasts in the bone marrow (P=0.006). In a two-variable Cox model including the percentage of myeloblasts, p15 methylation was an independent prognostic factor (P=0.005). Methylation of p15 was less common in t-AML of subtype M5 than in other FAB subtypes (P=0.03). Methylation of p15 was unrelated to type of previous therapy, to latent period from start of therapy, to platelet count, and to p53 mutations. Inactivation of p15 and deletion of genes on chromosome arm 7q possibly cooperate in leukemogenesis.
 ...
PMID:Methylation of p15INK4B is common, is associated with deletion of genes on chromosome arm 7q and predicts a poor prognosis in therapy-related myelodysplasia and acute myeloid leukemia. 1297 Jul 81

Hepatocarcinogenesis may involve multiple mutations with distinctive pathogenetic and clinicopathologic significance. To test this hypothesis, 68 cases of hepatocellular carcinoma (HCC) were studied prospectively for genetic-clinicopathologic correlation. Ten pathologic characteristics were evaluated. TP53 (alias p53) gene mutation was studied by a polymerase chain reaction (PCR)-single-strand conformation polymorphism-sequencing; CDKN2B (alias p15) and CDKN2A (alias p16) gene methylation by methylation-specific PCR; and genetic imbalances by comparative genomic hybridization (CGH). TP53 gene mutations occurred in 25% of cases, more than half being codon 249 G to T transversion. Methylation of CDKN2A was frequent (61.7%); of CDKN2B, rare (5.9%). The CGH analysis showed a median of nine aberrations per case, with amplifications more frequent than deletions. Isochromosomes might be involved in about 25% of cases. Amplifications of 1q and 8q were most frequent. Clinicopathologic correlations showed that CDKN2A methylation was significantly associated with tumors arising in cirrhotic livers; amplifications of 17q was significant in multiple parameters of tumor invasiveness (size, venous invasion, poor cellular differentiation, microsatellite formation); other amplifications (1q, 6p, 10p, and 20p) were also significant in tumor invasion; and deletions (at 1p, 11q, 4q, and 14q) were significant in tumor growth. Consistent patterns of genetic alterations were defined in HCC, which might represent distinctive pathways in hepatocarcinogenesis.
 ...
PMID:Clinicopathologic significance of genetic alterations in hepatocellular carcinoma. 1449 90

Human BRG1, a subunit of the Swi/Snf chromatin remodeling apparatus, has been implicated in regulation of cellular proliferation and is a candidate tumor suppressor. Reintroduction of BRG1 into a breast tumor cell line, ALAB, carrying a defined mutation in the BRG1 gene, induced growth arrest. Gene expression data revealed that the arrest may in part be accounted for by down-regulation of select E2F target genes such as cyclin E, but more dramatically, by up-regulation of mRNAs for the cyclin-dependent kinase inhibitors p21 and p15. Protein levels of both p15 and p21 were induced, and p21 protein was recruited to a complex with cyclin-dependent kinase, CDK2, to inhibit its activity. BRG1 can associate with the p21 promoter in a p53-independent manner, suggesting that the induction of p21 by BRG1 may be direct. Further, using microarray and real-time PCR analysis we identified several novel BRG1-regulated genes. Our work provides further evidence for a role for BRG1 in the regulation of several genes involved in key steps in tumorigenesis and has revealed a potential mechanism for BRG1-induced growth arrest.
 ...
PMID:Role for BRG1 in cell cycle control and tumor suppression. 1467 69

Enteropathy-type T-cell lymphoma (ETL) and ulcerative jejunitis (UJ) are rare disorders often occurring in patients with coeliac disease. The genetic events associated with the accumulation of intraepithelial lymphocytes in coeliac disease and tumour development are largely unknown. Deletions at chromosome 9p21, which harbours the tumour suppressor genes p14/ARF, p15/INK4b, and p16/INK4a, and 17p13, where p53 is located, are associated with the development and progression of lymphomas. To examine whether deletions at 9p21 and 17p13 play a role in ETL, 22 cases of ETL and seven cases of UJ were screened for loss of heterozygosity (LOH) by tissue microdissection and polymerase chain reaction (PCR) analysis for microsatellite markers. Furthermore, p53 and p16 protein expression was examined by immunohistochemistry. In addition, polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) analysis for detection of mutations in exons 5-8 of the p53 gene was performed in five cases of ETL and three cases of UJ. LOH was found in at least one microsatellite marker at the 9p21 locus in 8 of 22 (36%) ETLs, but not in UJ. Five of nine (56%) tumours composed of large cells showed LOH at 9p21, as opposed to two of eight (25%) tumours with small- or medium-sized cell morphology. The region spanning the p14/p15/p16 gene locus was most frequently affected (five cases); LOH at these markers coincided with loss of p16 protein expression in all of these cases. p53 overexpression was demonstrated in all ETLs examined and in four of seven cases of UJ. However, no alterations of the p53 gene were detected by LOH or PCR-SSCP analysis. The results of this study show that LOH at chromosome 9p21 is frequent in ETL, especially in tumours with large cell morphology; this finding suggests that gene loss at this locus may play a role in the development of ETL.
 ...
PMID:Loss of heterozygosity at chromosome 9p21 is a frequent finding in enteropathy-type T-cell lymphoma. 1474 9

Cell proliferation and apoptosis are controlled by tightly orchestrated signaling pathways that culminate in transcriptional activation/repression of multiple proteins. Dysregulation of cell cycle and/or apoptosis control may lead to genomic instability, neoplastic transformation and tumor progression. Under certain conditions, some hexavalent chromium [Cr(VI)] compounds are toxic and carcinogenic in the human respiratory tract, and we have shown that they induce apoptosis and/or cell cycle arrest in a p53-dependent fashion. There is increasing evidence linking extracellular signal-regulated kinase (ERK) activation with the DNA damage response, by both p53-dependent and -independent mechanisms. Here, the aim was to study the effect of Cr(VI) transcriptional regulation of key cell cycle inhibitors and pro- and anti-apoptotic proteins, as well as the role of ERK activation in the Cr(VI) genotoxic response. Diploid human lung fibroblasts were incubated with 3-9 uM Na2CrO4, and RNA was isolated at 4, 8, and 24 h, as well as 24 h after Cr(VI) exposure was terminated (recovery). mRNA expression was quantitated by RNase protection assay with a 32P-labeled multi-transcript probe containing gene sequences for the cdk inhibitors, p21waf1/cip1, p27kip1, p16INK4a, p15INK4b; the pro-apoptotic proteins bcl-XS and bax; the anti-apoptotic proteins bcl-W, bcl-XL, and bcl2, GADD45, and cyclin A. In general, bcl-W and bcl-XL expression were both downregulated after Cr exposure, to around 50% at 24 h, which was more pronounced after the recovery period. At Cr(VI) concentrations < or = 6 uM, bcl2 expression was upregulated. Of particular interest is that bax expression was reduced, in a dose and time-dependent fashion, however that of bcl-XS was elevated by nearly 3-fold after 8 h, and declined to control levels at the end of the recovery period. Expression of GADD45 and p21 were both upregulated by 2-fold at 8 h, but declined to control levels during recovery. Neither the expression of p27 nor that of p16 were apparently affected by Cr(VI) exposure, however the expression of p15 was markedly increased after exposure to all concentrations of Cr(VI). Finally, the expression of cyclin A was decreased after 24 h Cr(VI) exposure. Cr(VI) induced a transient burst of ERK activity (2-6-fold over control) around 0.5-3 h after exposure. However, inhibition of ERK activation with PD98059 had no effect on the Cr-induced alterations in gene expression. Moreover, Cr(VI)-induced clonogenic lethality, as assessed after 24 h exposure to 1 and 2 uM Cr(VI), was also not affected by ERK inhibition. These data suggest that both p53-dependent and -independent apoptotic and growth-inhibitory pathways are markedly affected by Cr(VI) exposure. However, the ability of Cr(VI) to affect key apoptotic and growth arresting genes, and thus clonogenic lethality, appears to be independent of ERK. Continued investigation into the cellular and molecular mechanisms of Cr(VI)-induced cell cycle and apoptosis control should further the understanding of Cr(VI)-associated carcinogenesis.
 ...
PMID:Induction of pro-apoptotic and cell cycle-inhibiting genes in chromium (VI)-treated human lung fibroblasts: lack of effect of ERK. 1497 55

Squamous cell carcinoma (ESCC) is the most frequent histological subtype in esophageal cancer, although the incidence of esophageal adenocarcinoma (EAC) is increasing faster than any other malignancy in the western world. New developments in the understanding of molecular mechanisms in esophageal cancer comprise analysis of the genetic tumor profiles by CGH (comparative genomic hybridization), the detection of tumor suppressor gene inactivation, and the analysis of proto-oncogenes. Especially the inactivation of the p53 gene proved to be of particular importance for the development of esophageal cancer. Also p15 and p16 have been identified to be involved in the pathogenesis of esophageal cancer by influencing the cyclin kinase inhibitor cascade and DNA mismatch repair processes. Amplification of cyclin D1 results in growth advantage for tumor cells and enhances tumorigenesis; gene amplification and overexpression of cyclin D1 were frequently demonstrated especially in ESCC. Regarding the dysplasia-metaplasia-carcinoma sequence of Barrett's esophagus, inhibition of apoptosis by overexpression of bcl-2 proteins occurs as an early event.
 ...
PMID:Molecular biology of esophageal cancer. 1513 56

The expression of genes from genomic loci can be relatively complex, utilizing exonic, intronic and flanking sequences to regulate tissue and developmental specificity. Infectious bacterial artificial chromosomes (iBACs) have been shown to deliver and express large genomic loci (up to 135 kb) into primary cells for functional analyses. The delivery of large genomic DNA inserts allows the expression of complex loci and of multiple splice variants. Herein, we demonstrate for the first time that an iBAC will deliver and correctly express in human glioma cells the entire CDKN2A/CDKN2B genomic region, which encodes for at least three important cell-cycle regulatory proteins (p16(INK4a), p14(ARF) and p15(INK4b)). Two of these proteins are expressed from overlapping genes, utilizing alternative splicing and promoter usage. The delivered locus expresses each gene at physiological levels and cellular responses (apoptosis versus growth arrest) occur dependent on cellular p53 status, as expected. The work further demonstrates the potential of the iBAC system for the delivery of genomic loci whose expression is mediated by complex splicing and promoter usage both for gene therapy applications and functional genomics studies.
 ...
PMID:Infectious delivery of the 132 kb CDKN2A/CDKN2B genomic DNA region results in correctly spliced gene expression and growth suppression in glioma cells. 1516 98

The cell cycle is the process by which cells grow, replicate their genome and divide. The cell cycle control system is a cyclically-operating biochemical device constructed from a set of interacting proteins that induce and coordinate proper progression through the cycle, and includes cyclins, cyclin-dependent kinases (CDK) and their inhibitors (CDKI). There are mainly two families of CDKI, the INK family (INK4a/p16; INK4b/p15; INK4c/p18 and INK4d/p19) and the WAF/KIP family (WAF1/p21; KIP1/p27; KIP2/p57). Progression through the cell cycle is mainly dependent on fluctuations in the concentration of cyclins and CDKI achieved through the programmed degradation of these proteins by proteolysis within the ubiquitin-proteasome system. There is also a transcriptional regulation of cyclin expression, probably dependent on CDK phosphorylation. The p53 family--p53, p63 and p73--function as transcription factors that play a major role in regulating the response of mammalian cells to stressors and damage, in part through the transcriptional activation of genes involved in cell cycle control (e.g. p21), DNA repair, senescence, angiogenesis and apoptosis. Essential for the maintenance of euploidy during mitosis is human securin, identical to the product of the pituitary tumour-transforming gene (PTTG). Loss of regulation at the G1/S transition appears to be a common event among virtually all types of human tumours. Aberrations of one or more components of the pRb/p16/cyclin D1/CDK4 pathway seem to be a frequent event (80%) in pituitary tumours. The role of p27 is rather that of a haploinsufficient gene. p27-/- mice show an increased growth rate, due to increased cellularity, testicular and ovarian cell hyperplasia and infertility, and hyperplasia of the pituitary intermediate lobe with nearly 100% mortality caused by such a benign pituitary tumour. Although the p27 gene was not found to be mutated in human pituitary tumours and its mRNA expression was similar in tumour samples in comparison with normal pituitaries, the load of p27 protein expression in corticotroph adenomas and pituitary carcinomas was shown to be much lower than those in normal pituitary tissue or other types of pituitary adenoma, suggesting that post-translational processing of p27 accelerates its removal from the nucleus. In respect to p27 degradation and its cellular compartmentalization, several pathways have been explored. Malignant tumours are associated with increased nuclear immunostaining for Jun-activation binding protein-1 (Jab1) which is responsible for phosphorylated p27 export from the nucleus. Corticotrophinomas are characterized by massively increased phosphorylation of p27 on Thr187, but are not associated with changes in Jab1. Macrophage inhibitory factor (MIF), which binds and inactivates Jab1, was noted to be over-expressed in tumours with abundant Jab1, suggesting that it may be part of a compensatory mechanism to moderate Jab1 activity. Proteasomal degradation of p27 requires its ubiquitylation by the SCF ubiquitin ligase, with specific addressing by the F-box protein Skp2 and its co-factor Cks1. Pituitary tumours with high p27 protein expression showed significantly less Skp2 expression than samples with low p27 immunostaining, suggesting that increased Skp2 could play at least a part in this process. No difference was observed in Cks1 mRNA levels between normal pituitaries and pituitary adenomas. The present data suggest that inhibition of growth and tumour development is sensitive not only to the absolute levels of p27 protein, but also to its cellular compartmentalization. Very recent findings from our group have established up-regulation of the serine-threonine kinase Akt in pituitary tumours compared to normal pituitary, which may cause phosphorylation of p27 on Thr157 and cytoplasmic retention of p27. PTTG protein is highly expressed in various human tumours, including pituitary tumours. While its mRNA levels are low in normal pituitary, increases in PTTG transcripts from more than 50% to more than 10-fold were recorded in the majority of a series of pituitary adenomas. Control of the cell cycle is a vital part of the cell's replication machinery. Disruption of this process is commonly seen in pituitary tumours and we are now beginning to identify regulatory elements which are likely to play a major role in pituitary oncogenesis.
 ...
PMID:Cell cycle dysregulation in pituitary oncogenesis. 1528 39

Tbx2 is a member of the T-box transcription factor gene family, and is expressed in a variety of tissues and organs during embryogenesis. In the developing heart, Tbx2 is expressed in the outflow tract, inner curvature, atrioventricular canal and inflow tract, corresponding to a myocardial zone that is excluded from chamber differentiation at 9.5 days post coitus (dpc). We have used targeted mutagenesis in mice to investigate Tbx2 function. Mice heterozygous for a Tbx2 null mutation appear normal but homozygous embryos reveal a crucial role for Tbx2 during cardiac development. Morphological defects are observed in development of the atrioventricular canal and septation of the outflow tract. Molecular analysis reveals that Tbx2 is required to repress chamber differentiation in the atrioventricular canal at 9.5 dpc. Analysis of homozygous mutants also highlights a role for Tbx2 during hindlimb digit development. Despite evidence that TBX2 negatively regulates the cell cycle control genes Cdkn2a, Cdkn2b and Cdkn1a in cultured cells, there is no evidence that loss of Tbx2 function during mouse development results in increased levels of p19(ARF), p16(INK4a), p15(INK4b) or p21 expression in vivo, nor is there evidence for a genetic interaction between Tbx2 and p53.
 ...
PMID:Tbx2 is essential for patterning the atrioventricular canal and for morphogenesis of the outflow tract during heart development. 1545 98


<< Previous 1 2 3 4 5 6 7 8 9 10