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)

Defects in neural tube formation are among the most common malformations leading to infant mortality. Although numerous genetic loci appear to contribute to the defects observed in humans and in animal model systems, few of the genes involved have been characterized at the molecular level. Mice lacking the p53 tumour suppressor gene are predisposed to tumours, but the viability of these animals indicates that p53 function is not essential for embryonic development. Here, we demonstrate that a fraction of p53-deficient embryos in fact do not develop normally. These animals display defects in neural tube closure resulting in an overgrowth of neural tissue in the region of the mid-brain, a condition known as exencephaly.
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PMID:A subset of p53-deficient embryos exhibit exencephaly. 766 12

DNA damage may mediate birth defects caused by many drugs and environmental chemicals, therefore p53, a tumour suppressor gene that facilitates DNA repair, may be critically embryoprotective. We have studied the effects of the environmental teratogen, benzo[a]pyrene, on pregnant heterozygous p53-deficient mice. Such mice exhibited between 2- to 4-fold higher embryotoxicity and teratogenicity than normal p53-controls. Fetal resorptions reflecting in utero death were genotyped using the polymerase chain reaction and found to be increased 2.6-fold and 3.6-fold respectively with heterozygous and homozygous p53-deficient embryos. These results provide the first direct evidence that p53 may be an important teratological suppressor gene which protects the embryo from DNA-damaging chemicals and developmental oxidative stress.
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PMID:A teratologic suppressor role for p53 in benzo[a]pyrene-treated transgenic p53-deficient mice. 766 13

Experiments were done to show whether a G to T mis-sense mutation at the third base of codon 249 of the p53 tumour suppressor gene is a 'hot spot' of aflatoxin attack as suggested by the results of epidemiological studies. Liver tissue from liver cancer patients in Taiwan and Japan was analysed for the presence of aflatoxin-DNA adducts (ADA) as a marker for aflatoxin exposure and an AGG to AGT transversion at codon 249 of the p53 gene. Ten per cent of samples containing ADA, indicating definite exposure of the subjects to aflatoxin, was found to harbour the codon 249 mutation, whereas 18% of the samples with no detectable adducts also contained the mutation. Our data do not support the hypothesis that codon 249 of the p53 gene DNA is a hot spot for aflatoxin mutagenesis as a 'late stage event' in human hepatocellular carcinogenesis.
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PMID:Recent aflatoxin exposure and mutation at codon 249 of the human p53 gene: lack of association. 766 37

In the present study, we investigated the expression of the tumour suppressor protein p53 in 113 primary and 43 metastatic malignant melanomas by immunohistochemistry, and correlated the findings with clinicopathological parameters such as histological melanoma subtype, thickness of primary melanomas (Breslow thickness) and patient outcome. In primary melanomas, the polyclonal anti-p53 antibody CM-1 detected immunoreactivity in 70% of the lesions, predominantly in the cytoplasm. Signals were observed in this cellular compartment in 57% of the melanomas, whereas in 32% nuclear p53 over-expression was detected. Immunohistochemistry, using the monoclonal antibody DO-1, revealed lower staining frequencies. However, both antibodies showed congruent results in approximately 80% of the cases. Overall, immunoreactivity was observed in 73% of superficial spreading melanomas, but only in 52% of lentigo maligna melanomas. This difference (P < 0.001) was mainly due to a lower frequency of cytoplasmic immunoreactivity (P < 0.002). There was no difference with respect to cytoplasmic and nuclear immunoreactivity between thin (< 1 mm thickness) and thicker primary melanomas. Staining frequencies detected in metastatic lesions seemed to be lower than in primary tumours. In 103 primary melanomas, follow-up data for at least 5 years were available. In 71% (54 of 76) of the primary melanomas which did not recur, and in 78% (21 of 27) of tumours with subsequent metastases, p53 over-expression was detected by CM-1. However, this difference was not statistically significant. The results of the present study indicate that immunoreactivity to anti-p53 antibodies is a common observation in malignant melanomas, with staining signals predominantly found in the cytoplasm of cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Expression of p53 protein in malignant melanoma: clinicopathological and prognostic implications. 766 36

Tumour-suppressor genes are negative regulators of cell division and growth. Over the past decade, multiple, distinct tumour-suppressor genes have been identified and cloned. In recent years, the ability to specifically manipulate the mouse genome via overexpression, underexpression or deletion of genes using transgenic expression systems and embryonic stem cell (ES) technology has led to the identification and definition of the precise function of several tumour suppressor genes in vivo. Included in this group are mice with mutations in the p53 and retinoblastoma (Rb) genes. p53 Mutant mice are highly susceptible to tumour development and will serve as excellent models to understand the aetiology and pathology of several human cancers. In contrast to the role of the Rb gene in human retinoblastomas, mice heterozygous for a mutant Rb allele do not develop retinoblastoma, but develop pituitary tumours instead. Similar ES cell technology has been used to generate alpha-inhibin deficient mice. Inhibin-deficient mice develop gonadal and adrenal tumours with nearly 100% penetrance. These studies have identified inhibin as a novel secreted tumour suppressor. In the future, many of the unidentified functions of tumour-suppressor genes can be tested using this powerful in vivo assay system.
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PMID:Transgenic mouse models for tumour-suppressor genes. 767 52

Multiple endocrine neoplasia type 2 (MEN 2) is a familial cancer syndrome arising from mutation at a locus or loci in chromosome region 10p11.2-q11.2. The disease is characterized by medullary thyroid carcinoma (MTC) and pheochromocytoma (Pheo). To assess the genetic events in tumour initiation and progression in this disease, we have compiled an allelotype for MTC and Pheo tumours using polymorphic marker loci from each chromosome arm. Using a panel of 58 tumours, we found frequent allele losses on chromosome arms 1p (42%), 3p (30%), 3q (38%), 11p (11%), 13q (10%), 17p (8%), and 22q (29%). Loss of heterozygosity (LOH) for loci on chromosome 10 was detected in a single tumour where one whole chromosome copy was lost. We used a panel of polymorphic markers for each of chromosomes 1, 3, 11, and 17 to define a shortest region of overlap for these regions. The most frequent allele losses were on chromosome 1, spanning the entire short arm of the chromosome but not loci on 1q. LOH on chromosome 3 encompassed a minimal common region of 3q12-qter. The regions of allelic deletion on chromosome 11 (11pter-p13), 17 (17pter-p11.2), and 13 (13q) encompass known tumour suppressor loci (WTI, TP53, RBI) which must therefore be candidates for genes contributing to MTC and Pheo development. Our data suggest allele loss on chromosome 11, 13, or 17 occurs predominantly in tumours with losses on chromosome 3, potentially reflecting the accumulation of genetic change in tumour progression. These events may be associated with more advanced disease in MTC. We suggest that at least 7 genes contribute to tumour development in MEN 2, including an initiating locus on chromosome 10 and loci on chromosomes 1, 3, 11, 13, 17, and 22 which have a progressional role in these tumours.
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PMID:Genetic events in tumour initiation and progression in multiple endocrine neoplasia type 2. 768 2

The expression of 6 different oncoproteins and 2 tumour suppressor gene products in the plasma cells of 63 bone marrow samples was used to determine a profile of the oncogenic phenotype of patients with multiple myeloma. Dual label flow cytometry after periodatelysine paraformaldehyde fixation was used to detect cell surface phenotype and intracellular protein expression simultaneously. The normal range for both the incidence and intensity of expression was determined for each protein by analysing plasma cells (high CD38 intensity) in 22 normal bone marrow samples. The percentage of myeloma patients with a greater than normal incidence of plasma cells expressing these proteins was 53% for c-myc, 28% for Rb, 28% for bcl-2, 27% for c-fos, 24% for p53 wild, 22% for p53 mutant, 13% for c-neu and 13% for pan-ras. When a panel of 8 antibodies was used, 82% of the samples (n = 28) had an increased incidence of expression by at least one oncoprotein or tumour suppressor gene product. The 5 patients with a normal incidence of expression of all 8 proteins were in plateau stage and 4 had not received chemotherapy for more than 12 months. The number of patients with an increased incidence of expression by 2 or more oncoproteins was significantly greater (X2 = 9.0; p < 0.005) in progressive disease (55%) than in stable disease (14%) but there was no specific phenotype pattern associated with progressive disease. All 6 oncoproteins and both tumour suppressor gene products had a greater incidence and intensity of expression in progressive than in stable disease. The expression of c-myc oncoprotein correlated with c-myc mRNA expression in the same samples (n = 10) but c-myc did not correlate with either the plasma cell labelling index (r = -0.15) nor serum thymidine kinase (r = 0.10). Our results suggest that there is a heterogeneous, non-systematic but almost universal presence of activated oncogenes and tumour suppressor genes in the plasma cells of patients with multiple myeloma and that disease progression is associated with the accumulation of a variety of secondary genetic changes which confer increased malignant behaviour.
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PMID:The oncoprotein phenotype of plasma cells from patients with multiple myeloma. 769 21

Mutations of the tumour suppressor p53 gene have been reported in a variety of human malignant tumours, and are frequently associated with overexpression of p53 protein. To examine the significance of p53 gene alteration in malignant epithelial tumours of the ovary, we studied the immunohistochemical reactivity with a monoclonal antibody against p53 (PAb 1801) in 6 ovarian tumours of low malignant potential (LMP) and 32 ovarian carcinomas. The existence of any correlation of p53 overexpression with the clinicopathological features and with the immunohistochemical expression of 72 kDa heat shock protein (HSP72) and sex steroid receptors (oestrogen receptors; ER, progesterone receptors; PR) was also analysed. Expression of p53 was found in 2 of the 6 (33.3%) LMP tumours and in 15 of the 32 (46.9%) carcinomas. Strong expression of HSP72 was observed in 11 of the 17 (64.7%) p53-positive tumours, but only in 2 of the 21 (9.5%) p53-negative ones. Histologically, p53-positivity was observed in 7 of the 10 (70%) serous carcinomas, 4 of the 6 (66.7%) mucinous, 4 of the 10 (40%) endometrioid, and none of the 4 clear cell and 2 transitional cell carcinomas. Distribution of p53-positive cells in the tumour sections was homogenous in serous tumours, but heterogenous in mucinous lesions. All of the 4 carcinomas arising in endometriotic cysts were p53-negative. These differences support the thesis of heterogeneity in ovarian carcinogenesis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Immunohistochemical analysis of p53 protein and 72 kDa heat shock protein (HSP72) expression in ovarian carcinomas. Correlation with clinicopathology and sex steroid receptor status. 769 17

The occurrence of mutations within the coding sequence of the p53 tumour suppressor gene is now well documented for squamous cell carcinomas of the head and neck region. However, evidence that these mutations are required for the maintenance and progression of squamous tumours is still formally lacking. To test this we have examined whether p53 mutations detected in primary squamous cell carcinomas of the tongue are also detected in the corresponding lymph node metastases. Three different p53 mutations were detected in each of three primary tongue squamous cell carcinomas (SCC), and in each case the same mutation was detected in a lymph node metastasis excised from the same patient. Although the sample number is small, the chance of obtaining the same p53 mutation independently in both the primary and metastatic tumour of each patient is at least 10(-4), therefore the results indicate that keratinocytes harbouring these p53 mutations possess a selective advantage throughout SCC progression.
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PMID:Maintenance of identical p53 mutations throughout progression of squamous cell carcinomas of the tongue. 770 3

The state of p53 tumour suppressor and the frequency of high-risk human papillomavirus (HPV) infections were studied in nine human oral cancer cell lines. Three cancer cell lines (SCC-4, Tu-177 and FaDu) had similar amounts of p53 transcripts to normal cells, but contained significantly higher levels of p53 protein than the normal control cells. Sequencing highly conserved open reading frames of the p53 gene of these cancer cells showed point mutations in the SCC-4 and Tu-177 cell lines, a base transition from CCC to TCC occurred at codon 151; and in the line FaDu, a mutation of CGG to CTG occurred at codon 248. The HEp-2 and 1483 cancer lines contained significantly lower levels of p53 protein compared to the normal counterpart. Sequencing of p53 cDNA for HEp-2 and 1483 lines showed no mutations, but northern analysis revealed that these cell lines expressed HPV-18 E6/E7 messages. Four cell lines (SCC-9, SCC-15, SCC-25, and Tu-139) expressed negligible amounts of p53 transcripts compared to the normal counterpart and undetectable levels of p53 protein. These cell lines contained mutations in the highly conserved open reading frames of the p53 gene as follows: the SCC-9 had a deletion of 32 base pairs between codons 274 and 285; the line SCC-15 had an insertion of five base pairs between codons 224 and 225; the line SCC-25 had a deletion of two base pairs in codon 209; and the Tu-139 line had a deletion of 46 base pairs between codons 171 and 186.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inactivation of the p53 gene by either mutation or HPV infection is extremely frequent in human oral squamous cell carcinoma cell lines. 770 4


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