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)

While most authors currently classify dural-based hemangiopericytoma (HPC) as a distinct entity rather than as a subtype of meningioma, the histogenesis of HPC has long been debated. We have recently shown that meningiomas contain frequent mutations of the neurofibromatosis 2 gene, while HPCs do not, suggesting that HPC is genetically distinct from meningioma. In the present study, we evaluated a series of 31 dural HPCs (including 3 pairs of primary and recurrent tumor) and 26 meningiomas for alterations in the cell-cycle regulatory genes CDKN2/p16 and p53. Homozygous deletions of the CDKN2/p16 gene were detected using a comparative multiplex polymerase chain reaction assay in 7 of 28 primary HPCs (25%), but in only one of 26 meningiomas (P = 0.03). Among the HPCs with recurrence, 1 pair of 3 had a homozygous CDKN2/p16 deletion. The 1 meningioma with a CDKN2/p16 deletion was a meningothelial meningioma, without atypical or malignant features. Single-strand conformational polymorphism analysis of all three exons of CDKN2/p16 and exons 5-8 of p53 revealed no mutations in either HPCs or meningiomas. These results illustrate that homozygous deletions of CDKN2/p16 occur in HPCs and suggest that alterations of the p16-mediated cell-cycle regulatory pathway may underlie the formation or progression of some HPCs. The data also provide further genetic evidence that HPC is not a subtype of meningioma.
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PMID:Homozygous deletions of the CDKN2/p16 gene in dural hemangiopericytomas. 883 33

Exons 1-3 of the p16/CDKN2 gene, exons 4-9 of the p53 gene and exons 1 and 2 of H-, K- and N-ras genes were screened for mutations by a combination of immunohistochemistry and single-strand conformational polymorphism (SSCP) analyses of polymerase chain reaction products from human surgical samples of both frank oral squamous cell carcinomas and premalignant lesions. The samples included 20 squamous cell carcinomas, 10 epithelial dysplasias and 10 epithelial hyperplasias. No identifiable gene mutations were detected in any of the dysplasias or hyperplasias, while 2 (10%) deletions and 2 (10%) mutations of p16/CDKN2, along with 5 (25%) p53 mutations were found in the advanced carcinomas, yielding characteristic p16/ CDKN2 and p53 changes. A mutation in the K-ras gene was found in single carcinoma and dysplastic samples. From the data, it can be argued that p16/CDKN2 and p53 mutations are relatively late occurrences in human oral tumorigenesis and that genetic alterations of the ras genes may not play a significant role in squamous neoplasia.
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PMID:Alterations of p16/CDKN2, p53 and ras genes in oral squamous cell carcinomas and premalignant lesions. 883 20

Most colon cancers exhibiting microsatellite instability (MI), a mutator phenotype of mismatch repair failure, are associated with mutations of the transforming growth factor-beta receptor type II genes (TGF-beta RII). Of intestinal- and diffuse-type gastric carcinomas, the former have been thought to arise from intestinal metaplasia in which gastric mucosa resembles intestinal mucosa. To evaluate the preferential histological type of MI-associated mutations in the development of gastric carcinoma, mutations of TGF-beta RII, p53, and p16 were analyzed for the two types of primary gastric carcinomas showing MI. Of 50 primary gastric carcinomas, including 33 intestinal types and 17 diffuse types, 15 cases (30%) demonstrated MI at 1 or more of the 11 microsatellite markers tested. The 15 MI cases were classified into two groups, widespread MI and low-level MI, based on the number of markers exhibiting the instability. Eleven were widespread MIs, and the remaining four cases were low-level MIs. Ten of the 11 (91%) widespread MIs were of the intestinal type, and 1 case (9%) was of the diffuse type. Of the 11 widespread MIs, 10 cases (91%) demonstrated frameshift mutations within the polyadenylate tract of the TGF-beta RII. The frameshift mutation was rarely detected at p53 and p16 (1 of 11, 9%). In contrast, the four low-level MI cases had no frameshift mutations within the repeat sequences of TGF-beta RII, p53, and p16, but two of the four cases demonstrated base substitution mutations within p53. Our results suggest that mismatch repair failure can mutate the TGF-beta RII and may provide one of the pathways for the development of the intestinal-type gastric carcinoma in high-risk populations.
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PMID:Microsatellite instability-associated mutations associate preferentially with the intestinal type of primary gastric carcinomas in a high-risk population. 884 Sep 81

C/EBPalpha has a role in growth arrest and differentiation of mouse preadipocytes. To study the mechanism of C/EBPalpha-induced growth arrest, we developed a cell line, HT1, that contained the human C/EBPalpha gene under Lac repressor control. IPTG-induced C/EBPalpha caused inhibition of cell proliferation and DNA synthesis as measured by colony growth assays, cell counting, and BrdU uptake. A number of proteins that are known to be involved in the regulation of the cell cycle, such as cyclin-dependent kinase (CDK)2 and CDK4, proliferating cell nuclear antigen (PCNA), p53, c-fos, and the CDK inhibitor p16 and p27 were investigated by Western analysis. No change in their expression was observed. However, the p21 (WAF-1/CIP-1/SDI-1) protein was significantly elevated in growth-arrested HT1 cells. Elevation of p21/SDI-1 mRNA (threefold) and activation of the p21/SDI-1 promoter by C/EBPalpha did not account for the 12- to 20-fold increase in p21/SDI-1 protein. Protein synthesis inhibition by cycloheximide (CHX) treatment indicated that the half-life of p21/SDI-1 in dividing HT1 cells was approximately 30 min. However, in C/EBPalpha growth-arrested cells, the level of the p21/SDI-1 did not change for > 80 min after CHX addition. Our studies demonstrate that C/EBPalpha activates p21/SDI-1 by increasing p21/SDI-1 gene expression and by post-translational stabilization of p21/SDI-1 protein. Furthermore, induction of p21/SDI-1 is responsible for the ability of C/EBPalpha to inhibit proliferation because transcription of antisense p21/SDI-1 mRNA eliminated growth inhibition by C/EBPalpha.
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PMID:CCAAT/enhancer-binding protein alpha (C/EBP alpha) inhibits cell proliferation through the p21 (WAF-1/CIP-1/SDI-1) protein. 884 17

Retinoblastoma (Rb) tumour-suppressor protein plays a critical role in cell cycle control. Rb inactivation is a frequent phenomenon in tumours of different cell lineages, in which the absence of Rb protein has been considered to be a marker of Rb disregulation. We used modern immunohistochemical techniques to study the expression of Rb protein in a large series of 130 patients with Hodgkin's disease. Simultaneously, Western blot was used to analyse a more restricted group (12 patients) to confirm the immunohistochemical results and to clarify the phosphorylation status of Rb protein. As the level of Rb expression varied according to cell cycle stage, we also performed immunostaining for Ki67, a protein present in proliferating cells. To make comparison possible, we first characterised the amount and phosphorylation status of Rb protein in reactive lymphoid tissue and phytohaemagglutinin (PHA)-stimulated lymphocytes. The presence of p53 in Sternberg-Reed cells was also included in the study, as both proteins (p53 and Rb) have been found to be closely associated in cell cycle control. PHA-stimulated peripheral blood lymphocytes showed a parallel increase in Rb and cell cycle progression, together with progressive Rb phosphorylation. In reactive lymphoid tissue there was also a clear correlation between Rb expression and the Ki67 proliferation index (R = 0.96, P = 0.038). When analysing Hodgkin's disease samples, a clear difference emerges between cases of nodular lymphocyte predominance, which preserve the relationship between Rb and Ki67 expression (r = 0.8727, P = 0.000), and classical forms of Hodgkin's disease (nodular sclerosis and mixed cellularity), which display a strong deviation from this pattern. Two main anomalies were found: (1) One group of 21/130 cases with partial or total loss of Rb protein expression, which could reflect the existence of genetic alterations, or an altered transcriptional or translational regulation of Rb gene. (2) Another group with an abnormally high Rb/Ki67 ratio, which could support conflicting interpretations: (i) excess Rb protein for controlling cell cycle progression; or (ii) adhesion of Rb protein to other cellular or viral proteins, such as p53 and MDM2. The results of this study indicate an anomalous pattern of expression of Rb in classical forms of Hodgkin's disease, and suggest the possibility of undertaking functional studies (E1A adhesion, p16 expression) with the aim of better characterising the status of Rb protein, and correlating these findings with clinical course in Hodgkin's disease patients.
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PMID:Anomalous retinoblastoma protein expression in Sternberg-Reed cells in Hodgkin's disease: a comparative study with p53 and Ki67 expression. 885 74

The cell cycle regulatory proteins p16 and p21 cause cell cycle arrest at the G1 checkpoint by inhibiting activity of cyclin D-CDK4 complexes. The TP53 gene, regulating the p21 protein, is mutated at high frequency in ovarian cancer. The CDKN2 gene, encoding the p16 protein, has been mapped to chromosome 9p21 and encompasses three exons. To establish the frequency of CDKN2 gene abnormalities in ovarian tumour specimens, we have studied this gene in five ovarian cancer cell lines and in 32 primary and five metastatic ovarian adenocarcinomas. Using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and sequencing techniques both exon 1 and 2 of the CDKN2 gene, encompassing 97% of the coding sequence, were analysed. In addition, the TP53 gene was studied for the presence of mutations. The cell line HOC-7 showed a 16 bp deletion in exon 2 of the CDKN2 gene, resulting in a stop codon, whereas in cell line SK-OV-3 this gene was found to be homozygously deleted. Nine primary tumour specimens showed a migration shift on SSCP. Sequencing revealed a common polymorphism (Ala148Thr) in seven of these ovarian tumour specimens. The two other tumour samples were found to contain silent mutations, one at codon 23 (GGT-->GGA) and the other at codon 67 (GGC-->GGT). Mutations in the TP53 gene were observed in 46% of the ovarian tumour specimens. We conclude that CDKN2 gene alterations are rare events in human ovarian cancer. The low prevalence of these alterations do not allow for analysis of an association of this gene with prognosis.
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PMID:Sporadic CDKN2 (MTS1/p16ink4) gene alterations in human ovarian tumours. 885 76

A total of 10 glioma cell lines were examined for alterations of the p16, p15, p53 and p21 genes, which are tumor suppressor genes or candidates with direct or indirect CDK-inhibitory functions. Genetic alterations (deletions or mutations) were frequently seen in the p16, p15 and p53 genes in these cell lines, but not in the p21 gene. When the states of the p16, p15 and p53 genes were compared among cell lines, all the cell lines showed abnormalities in at least 1 gene, often in 2 or 3 genes coincidentally, suggesting that dysfunction of these genes is closely related to glioma cell growth. Although alteration of all 3 genes was most frequent, there were cell lines having either p16/p15 or p53 or pl6 and p53 gene alterations, suggesting that the time order of these genetic alterations was variable depending on the cell line. Among cell lines examined, one with homozygous p53 gene deletion seemed of particular practical value, since such a cell line might be useful in various studies, including investigation of the functions of various mutant p53 genes in the absence of heteromeric protein formation. On examination of the primary tumor tissues, the same alterations of the p16/p15 and p53 genes as detected in the cell lines were demonstrated in all 6 cases examined: p16/p15 gene deletion in 1, p16 gene mutation in 1 and p53 gene mutations in 5 cases. This suggested that the p16/p15 and the p53 gene alterations and their combinations in at least some glioma cell lines reflected those in the primary glioma tissues.
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PMID:A comparative study of glioma cell lines for p16, p15, p53 and p21 gene alterations. 887 51

The frequencies of mutations in the adenomatous polyposis coli (APC). p53, and p16 (MTS1; multiple tumor suppressor 1/CDK4I; cyclin-dependent kinase 4 inhibitor) tumor suppressor genes were investigated in 23 oral squamous cell carcinomas (SCCs). Loss of heterozygosity (LOH) at the retinoblastoma (Rb) gene locus and on chromosomes 3p (VHL; von Hippel-Lindau disease tumor suppressor gene locus), 5q (APC) and 9p (p16), and H-ras oncogene mutations were also studied in the same samples. Techniques employed were polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP), DNA sequencing and PCR-microsatellite analyses. Mutations of the p53 gene were detected in 26% (6/23) of the tumor specimens. APC and p16 were not mutated in any of the 23 oral SCCs studied. LOH was detected in 17% (2/12 informative cases) at the Rb, in 33% (4/12) on 3p, in 17% (4/ 23) on 5q and in 30% (3/10) on 9p. Mutations of the H-ras gene were detected in 9% (2/23). The only correlation between these genetic alterations and clinicopathologic characteristics was that mutations of the p53 gene were detected more frequently in oral SCCs with lymph node metastasis than in those without it (P < 0.05). These results demonstrate that mutations of the p53 gene and LOH on 3p and 9p frequently occur in oral SCC and play important roles in the development and/or progression of this common malignancy.
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PMID:Alterations of tumor suppressor genes and the H-ras oncogene in oral squamous cell carcinoma. 888 73

There have been many new developments in our understanding of esophageal carcinoma biology over the past several years. Information regarding both of the major forms of this disease, adenocarcinoma and squamous cell carcinoma, has accumulated in conjunction with data on precursor conditions such as Barrett's esophagus. Some of the most interesting and promising findings have included aneuploidy (abnormal DNA content), amplification and overexpression of proto-oncogenes, loss of heterozygosity at multiple chromosomal loci, and tumor suppressor gene inactivation. Of particular importance is mutation and deletion involving the tumor suppressor gene p53, but abnormalities in the retinoblastoma, deleted in colon cancer, and adenomatous polyposis coli genes have been described as well. Recently, two important cancer pathways implicated in the genesis of multiple tumor types have also been inculpated in esophageal carcinogenesis: the cyclin kinase inhibitor cascade and the DNA mismatch repair process. Alterations in the p16 and p15 cyclin kinase inhibitors, including point mutation and homozygous deletion, have been reported in primary esophageal tumors and/or tumor-derived cell lines. Microsatellite instability, the hallmark of DNA mismatch repair defects, has been detected in esophageal cancers, particularly those associated with Barrett's metaplasia (where it may represent an early event). Further developments in the field of molecular carcinogenesis of esophageal malignancies promise to yield improvements in the early detection, prognostic categorization, and perhaps eventual gene-based therapy of this deadly disease.
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PMID:The molecular biology of esophageal carcinoma. 889 31

An understanding of the biological significance of the multiple genetic alterations identified in clinical bladder cancers to the stepwise pathogenesis of the disease is evolving. Alterations in p53 and pRb, products of the chromosomes 17p13 TP53 and 13q14 RB tumor suppressor genes, occur in approximately 50% and approximately 33% of bladder cancers respectively, and are associated with later stage, higher grade disease. p53 and pRb alterations are also known to occur in early stage bladder carcinoma in situ where they are thought to represent a poor prognosis for tumor progression. Allelic loss of genes on 9p21 occurs in approximately 50% of bladder cancers, but whether the only critical gene in this region is the CDKN2/p16 cyclin/CDK inhibitor is at present uncertain. Amplification and/or overexpression of the oncogenes epidermal growth factor receptor and erbB2 are associated with later stage disease. Finally, recent findings generated using in vitro transformation systems with human uroepithelial cells provide strong evidence that loss of genes on 3p, which occurs in approximately 20% of bladder cancers, and/or gain of genes on 20q play an important role in blocking HUC cellular senescence. This latter phenotype should represent a critical step in oncogenesis, as cells that do not senesce can survive to accumulate the multiple genetic alterations associated with invasive and metastatic bladder cancers. Further understanding of the biochemical mechanisms underlying these genetic changes will provide the additional information needed to design better strategies for bladder cancer intervention and treatment.
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PMID:A molecular genetic model of human bladder cancer pathogenesis. 889 68


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