Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:B6E4X6 (mutant p53)
 3,342 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previously, we have shown that the chicken anemia virus-derived VP3 ("apoptin") protein induces apoptosis in chicken mononuclear cells. Here, we report that apoptin also induces apoptosis in human osteosarcoma cells, regardless of whether they expressed wild-type, mutant p53, or no p53 at all. Moreover, the nuclear location of apoptin appears to be important for its optimal induction of apoptosis. The fact that apoptin can induce p53-independent apoptosis in human tumor cells makes apoptin a potential candidate for treatment of frequently occurring types of cancer cells that do not contain functional p53.
Cancer Res 1995 Feb 01
PMID:Apoptin, a protein derived from chicken anemia virus, induces p53-independent apoptosis in human osteosarcoma cells. 783 13

Human astrocytomas frequently overexpress wild-type p53, which suggests that gliomas have evolved a mechanism to subvert p53-mediated apoptosis. bcl-2 inhibits apoptosis mediated by p53, and it is expressed in several human cancers. We therefore examined a series of human gliomas to determine whether bcl-2 is expressed and whether this expression is associated with tumors which have wild-type p53. Twenty-eight paraffin-embedded gliomas (3 WHO grade II, 13 grade III, 12 grade IV) were immunohistochemically stained for bcl-2 and p53. p53 mutations were identified with single strand conformation polymorphism and DNA sequencing. Sixteen of 28 (57%) tumors expressed bcl-2, and bcl-2 expression was associated with wild-type p53 (P < 0.01). Among gliomas which overexpressed p53, bcl-2 was positive in 7 of 7 tumors with wild-type p53 but in only 1 of 7 with mutant p53 (P < 0.01). We conclude that bcl-2 is frequently expressed in human gliomas and that expression is more common in tumors with wild-type p53.
Cancer Res 1995 Mar 01
PMID:Human gliomas with wild-type p53 express bcl-2. 786 12

Antisense oligonucleotides targeting p53 have been hailed as a potentially new technique for treating patients with cancer, and there have been encouraging reports of good patient tolerance in vivo and of antiproliferative effects in vitro. However, evidence is lacking that these oligonucleotides are acting via an antisense interaction to modulate p53 expression. We examined a phosphorothioate antisense oligonucleotide, directed against exon 10 of the TP53 gene, and a chimaeric phosphorothioate-phosphodiester oligonucleotide directed against the p53 translation initiation codon. Both failed to specifically suppress p53 protein production in a cell-free assay system or to have any effect on mutant p53 expression by human pancreatic cancer cell lines. Antiproliferative effects were apparent, especially with the phosphorothioate antisense oligonucleotide, but this was independent of the p53 status of the cells (mutant, wild-type or absent) and also occurred with the control (sense and randomised) oligonucleotides. The most dramatic antiproliferative effects were seen with the 'control' phosphorothioate oligonucleotides. These findings suggest that the antiproliferative effects of some antisense oligonucleotides may be unrelated to expression of the gene they have been designed to target.
Br J Cancer 1995 Mar
PMID:Antisense oligonucleotides directed against p53 have antiproliferative effects unrelated to effects on p53 expression. 788 Jul 19

p21WAF/CIP1/SDI1 is a recently identified gene expressed in cells harboring wild-type but not mutant p53 gene. It encodes a nuclear protein of 21 kD which inhibits cyclin-dependent kinase activity. Constitutive p21WAF1/CIP1/SDI1 mRNA expression was detected in neoplastic cells from patients with various hematological malignancies as well as in normal bone marrow mononuclear cells and in myeloid and lymphoid cell lines independent of their p53 status. Induced differentiation of the p53-deficient promyelocytic HL-60 cells along the monocytic lineage by phorbol ester or 1a,25 dihydroxyvitamin D3 resulted in a marked increase of both p21WAF1/CIP1/SDI1 mRNA and protein expression due to enhanced mRNA stability. Differentiation towards the granulocytic lineage by all-trans retinoic acid or dimethylsulfoxide failed to produce this effect. p21WAF1/CIP1/SDI1 is an immediate early gene since its upregulation occurred independently of de novo protein synthesis. The induction of p21WAF1/CIP1/SDI1 expression and its regulation in p53-deficient differentiating leukemic cells support the idea of an additional, p53-independent role of p21WAF1/CIP1/SDI1 in human hematopoiesis.
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PMID:Posttranscriptional stabilization underlies p53-independent induction of p21WAF1/CIP1/SDI1 in differentiating human leukemic cells. 788 98

Mutation in the p53 tumor suppressor gene is the most common genetic alteration in human cancer. As in mutant p53 the protein is stabilised and the half-life is extended, it becomes detectable by immunohistological staining. p53 immunoreactivity thus seems to be a potential biomarker for the assessment of the oncogenic potential of malignant melanomas. In 103 tissue sections of primary and metastatic malignant melanomas of the head and neck detectable levels of p53 were only found in 3 of the primary tumors and in none of the metastases. At the same time the proliferation status of the malignant melanoma lesions was determined using the cell cycle specific antibody PCNA. 55 primary and metastatic tumors were stained with a PCNA-MAb to determine the proliferation activity of the tumors. The results of our immunohistochemical investigation suggest that immunoreactivity of p53 cannot be used to determine the malignant potential of melanomas in the head and neck. PCNA staining showed that the majority of the tumors and metastases were proliferating rapidly.
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PMID:p53 and PCNA expression in malignant melanomas of the head and neck. 788 8

The wild-type (wt) p53 tumor suppressor gene is commonly inactivated in human malignancies, either by mutations or by loss of expression. An additional proposed mechanism for inactivation of wt-p53 is amplification of the murine double minute 2 (MDM2) gene and overexpression of the MDM2 protein, which binds to p53 and eliminates its tumor suppressor function. To investigate a potential role for MDM2 in the inactivation of wt-p53 in pediatric acute lymphoblastic leukemia (ALL), we examined the expression of MDM2 and p53, as well as the occurrence of p53 mutations and possible amplification of the MDM2 gene, in 19 pediatric ALL cell lines and one pediatric acute myelogenous leukemia (AML) line. Although we did not find significant amplification of the MDM2 gene in any of the leukemic lines, we detected overexpression of MDM2 in all 10 lines that expressed wt-p53. Of the 10 lines without overexpression of the MDM2 gene, six (including the AML line) did not express p53, and four expressed mutant p53 with single point mutations in exons 7 and 8. To determine whether primary leukemic cells showed a similar correlation, we analyzed the original cryopreserved leukemic bone marrow cells from seven patients from whom cell lines were established. We obtained similar results from both the primary leukemic cells and the corresponding cell lines: overexpression of MDM2 was present in primary cells that expressed wt-p53 but not in cells that lacked expression of wt-p53. These findings suggest an important role for MDM2 in the pathogenesis of pediatric ALL in which leukemic cells express wt-p53.
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PMID:Overexpression of the MDM2 gene by childhood acute lymphoblastic leukemia cells expressing the wild-type p53 gene. 788 79

Mutation of the p53 gene is one of the most common genetic lesions observed in human cancer. The p53 protein functions as a transcription factor, however it is still unresolved to what extend this property is related to its tumour suppressor activity. Since there is evidence that protein modifications as well as protein-protein interactions may regulate p53 function, we have studied p53 protein-DNA complex formation in nuclear extracts prepared from human tumour cell lines. In 13 different cell lines PAb421-induced DNA binding activity was compared to the level and conformation of the endogenous p53 protein. Surprisingly, sequence-specific p53 DNA binding activity was detected not only in cell lines that express wild-type p53, but also in seven cell lines which contain only mutant protein. Oligonucleotide competition analyses with various p53 target sequences and methylation interference experiments establish that wild-type and mutant p53 differ significantly in their sequence-specific interactions. Our analysis also provides evidence that the PAb1620 conformation is neither sufficient nor essential for DNA binding of endogenous p53 and that the cellular environment in addition to the specific point mutation may influence p53 DNA binding activity.
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PMID:p53 derived from human tumour cell lines and containing distinct point mutations can be activated to bind its consensus target sequence. 789 29

There is accumulating evidence that the p53 protein contributes to tumor suppression by stimulating the transcription of specific cellular genes, such as the cell cycle control gene WAF1/ClP1. p53-mediated transcriptional activation is inhibited in cotransfection assays by overexpressed E6 protein from cancer-associated human papillomavirus (HPV) types, pointing at a possible molecular mechanism by which these viruses contribute to malignant cell transformation. Here we analysed the transcriptional transactivation function of endogenous p53 protein in a series of cervical cancer cell lines, which express the E6 gene from integrated viral sequences. Transient and stable transfection analyses employing p53-responsive reporter constructs indicated that HPV-positive cervical cancer cells contained transactivating p53 protein. Treatment of HPV-positive cells with genotoxic agents, such as mitomycin C, cisplatin, or u.v. irradiation, resulted in an increase of nuclear p53 protein levels and enhanced binding of p53 to a p53-recognition site. These effects were accompanied by an increase of WAF1/ClP1 mRNA levels. In several HPV-positive cell lines, these molecular events were linked to a cell cycle arrest in G1. In contrast, cancer cells containing mutant p53 genes did not contain transactivating endogenous p53 protein and lacked the p53-mediated response to DNA damaging agents. These results indicate that the tumorigenic phenotype of HPV-positive cancer cell lines does not necessarily correlate with a lack of basal or DNA damage induced p53 activities and that therefore the presence of high risk HPV sequences is not functionally equivalent to the loss of p53 function through somatic mutations of the p53 gene.
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PMID:Functional p53 protein in human papillomavirus-positive cancer cells. 789 34

Fine needle aspirates (FNA) from 106 high-risk women and 25 low-risk women were evaluated for overexpression of estrogen receptor (ER), epidermal growth factor receptor (EGFR), mutant p53, and HER-2/neu by immunocytochemistry, and for aneuploidy by image analysis. Aspirates were also classified cytologically as normal, apocrine metaplasia, epithelial hyperplasia (EH), or dysplasia. High-risk women were those with a first-degree relative with breast cancer (76%), precancerous breast disease (26%), prior cancer of the contralateral breast (9%), or multiple abnormalities (11%). Low-risk women had none of the above risk factors, nor a prior breast biopsy or clinical evidence of fibrocystic disease. The median 10-year Gail risk for the high-risk group was 4%, compared to 0.7% for the low-risk group. There were significant differences (p < 0.01) between high- and low-risk women in the prevalences of hyperplasia (55% versus 12%), dysplasia (19% versus 0%), aneuploidy (32% versus 0%), overexpressed EGFR (32% versus 4%), and overexpressed p53 (29% versus 4%). The prevalence of multiple biomarker abnormalities was also greater in high-risk than in low-risk women (28% versus 0%; p < 0.01). Four percent (4%) of FNAs from high-risk women with normal cytology, 29% of aspirates with hyperplastic cytology, and 60% of those with dysplasia were associated with two or more biomarker abnormalities. The differences in the prevalence of multiple biomarker abnormalities among various cytologic categories were statistically significant (p = 0.02, normal versus EH; p = 0.02, EH versus dysplasia; p < 0.01, normal versus dysplasia).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Biomarker and cytologic abnormalities in women at high and low risk for breast cancer. 791 61

Around 60% of oral squamous cell carcinomas (SCCs) have been shown to harbour p53 mutations, and other studies have demonstrated mutant p53 genes in normal and dysplastic squamous epithelium adjacent to these SCCs. In line with these earlier studies we show here that DOK, a keratinocyte cell line derived from a dysplasia, displays elevated levels of p53 protein and harbours a 12 bp in-frame deletion of the p53 gene spanning codons 188-191. In contrast, the coding region of the p53 gene was normal in a series of six benign recurrent laryngeal papillomas and a series of four premalignant oral erythroplakia biopsies and their cell cultures. All but one of these lesions were free of malignancy at the time of biopsy, in contrast to the premalignant lesions studied by previous investigators, but keratinocytes cultured from these lesions all displayed a partially transformed phenotype that was less pronounced than that of DOK. Since three out of four of the erythroplakia patients developed SCC within 1 year of biopsy, these lesions were by definition premalignant. The availability of strains of partially transformed keratinocytes from premalignant erythroplakias which possess normal p53 genes should enable us to test the role of mutant p53 in the progression of erythroplakia to SCC. The premalignant tissues and cultures were also tested for the presence of human papillomavirus (HPV), which is known to inactivate p53 function in some cases. Only the benign papillomas were shown to contain high levels of either HPV 6 or HPV 11 E6 DNA, but not both, and none of the samples contained detectable levels of HPV 16, HPV 18 or HPV 33 E6 DNA or L1 DNA of several other HPV types. There was therefore no evidence to suggest that p53 was being inactivated by a highly oncogenic HPV in these samples.
Br J Cancer 1994 Oct
PMID:The p53 status of cultured human premalignant oral keratinocytes. 791 2


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