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)

Alterations in the function of p53, a tumor suppressor gene, have been postulated as a principal underlying mechanism involved in the loss of cell cycle control in human malignancies. Because p53 dysfunction is generally associated with protein overexpression, immunocytochemistry is a valuable technique for the analysis of p53's functional status. We tested the hypothesis that loss of p53 function is a critical event in the early development and progression of human malignant melanoma and can lead to alterations in cell proliferation. We performed an immunocytochemical study in archival fixed, embedded specimens that included 102 melanocytic lesions ranging from benign nevi to metastatic melanoma. In addition to p53, we assessed the p53-associated protein, mdm-2, and markers of cell cycle status (the MIB-1-defined cell proliferation marker; proliferating cell nuclear antigen; and statin, a 57-kDa nuclear protein expressed preferentially by G0 cells). Tumor expression of all nuclear proteins was scored in a semiquantitative fashion related to the fraction of positive tumor nuclei. The overall incidence of significant p53 overexpression was low (8% of primary and 14% of metastatic melanomas). Analysis demonstrated strong correlation between increasing p53 expression in primary versus metastatic lesions (chi 2 analysis, P = 0.001). Correlation was found between increased MIB-1-defined cell proliferation and p53 overexpression in primary melanomas (P = 0.02). Detectable mdm-2 expression was significantly correlated with p53 overexpression (P = 0.02). Comparison of statin and proliferating cell nuclear antigen indices demonstrated inverse correlation (chi 2 , P = 0.03) in the combined groups, but within the metastatic group there was a subset of cases strongly expressing the two markers.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:p53 and mdm-2 expression in malignant melanoma: an immunocytochemical study of expression of p53, mdm-2, and markers of cell proliferation in primary versus metastatic tumors. 767 73

Overexpression of the p53 gene product has been observed in a high percentage of malignant melanomas. To evaluate the role of this protein in the development of melanoma, we examined p53 expression in benign, premalignant, and malignant melanocytic lesions. Using the antibodies DO-7 and 1801, which recognize both wild-type and most mutant forms of the p53 protein, we analyzed by immunohistochemical staining 26 benign nevi, 34 dysplastic nevi from patients at low risk for the development of melanoma, 22 dysplastic nevi from patients at high risk for the development of melanoma, 61 primary melanomas (including 15 that arose from dysplastic nevi), and 10 metastatic melanomas. Expression of the p53 protein was not observed in any of the benign or dysplastic nevi. Of the primary melanomas only 3 (5%) demonstrated nuclear staining, whereas 70% of the metastatic melanomas showed a positive reaction for p53. These data suggest that overexpression of the p53 gene product is a late event in the progression of melanoma and consequently indicate that expression of this protein cannot be used as a marker to identify patients at high risk for the subsequent development of melanoma.
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PMID:Overexpression of p53 is a late event in the development of malignant melanoma. 848 8

p53 Protein immunohistochemical expression is a wide-spread feature of the malignant phenotype; most melanomas are reported as p53 positive, while nevi are reported as p53 negative. We investigate a series of 75 benign nevi and 47 melanomas (40 primary and seven metastatic) to evaluate their pattern of p53 immunoreactivity with a panel of specific antibodies (PAb1801, PAb240, DO7, and CM1) in view of a possible diagnostic role of p53 immunostaining. Our results demonstrate that 15% of nevi show p53 immunoreactive nuclei (usually in less than 1% of the cells) and that 30% of melanomas show p53 immunoreactive nuclei (one case with 20% immunoreactive cells, six cases with 1% to 5% positive cells, and four cases with less than 1% positive nuclei). p53 Positivity was seen also in basal and suprabasal keratinocytes. p53 Positivity in nevi is at variance with literature data supporting that nevi are p53 negative. p53 Positivity in nevi and in epidermis may be related to mechanisms of DNA repair, apoptosis, or to a specific phase of the cell cycle. In our series, p53 expression in melanomas is not as frequent as reported in the literature. Population-based differences or differences in case selection and sample handling may account for the above discrepancies. The demonstration of p53 positivity in benign skin lesions greatly hinders the possibility of a diagnostic use of p53 immunostaining in dermatopathology.
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PMID:p53 Protein expression in nevi and melanomas. 751 47

Immunohistochemical analysis of the expression of the cyclin kinase inhibitor p21WAF1/CIP1 in a panel of primary and metastatic human melanocytic tumors was performed. It was found that, independent of the p53 status, approximately 30% of the primary melanomas and 40% of the metastases completely lacked expression of this cell cycle inhibitor. Some tumors were also analyzed by Northern blotting, and in most of the cases a consistant correlation between mRNA and protein expression was observed. In four benign nevi studied, WAF1/CIP1 mRNA was expressed whereas the protein was not detected, suggesting a post-transcriptional regulation of the inhibitor in these cases. In superficial spreading melanomas, a significant correlation between protein expression and tumor thickness was found, with thin lesions showing low protein levels. Interestingly, by comparing primary and metastatic specimens obtained from the same patient, a reduction in p21WAF1/CIP1 antibody staining was observed in the latter, probably reflecting a more aggressive phenotype of the metastases. In conclusion, our results demonstrate the complexity in the relationship between p21WAF1/CIP1 expression and tumor phenotype and furthermore suggest that aberrant expression of the cyclin-dependent kinase inhibitor may be of importance in the development and progression of sporadic malignant melanoma.
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PMID:Cyclin kinase inhibitor p21WAF1/CIP1 in malignant melanoma: reduced expression in metastatic lesions. 895 18

p21(WAF1/CIP1) (p21) is an inhibitor of cyclin-dependent kinases recently identified as the downstream effector of wild-type p53-mediated cell cycle arrest. The gene coding for p21 may function as a negative regulator of melanoma growth, progression, and metastasis. Using immunohistochemistry and Western blotting, we investigated the expression of p21 in human melanocytic proliferations. Immunohistochemical staining was performed on 13 common acquired nevi, 12 dysplastic nevi, 23 primary malignant melanomas, and 12 metastatic melanomas. Common acquired nevi showed minimal p21 staining (1.8+/-0.3%, mean+/-SEM). The percentage of positive nuclei was slightly elevated in dysplastic nevi (8.9+/-1.7%). Both primary malignant melanoma (29+/-3%) and metastatic melanoma (33+/-5%) demonstrated a significantly increased number of p21-positive nuclei compared to benign lesions (p<0.001). p21 was strongly expressed even in actively proliferating lesions as confirmed by MIB-1 labelling, and although the majority of p21-positive cells likely represent a non-proliferating population, staining was occasionally observed in cells undergoing mitosis, suggesting abnormal function of this cell cycle inhibitor in malignant melanoma. Overexpression of p21 in metastatic melanoma compared to common acquired nevi was confirmed by Western blot analysis of human tumor samples. These findings suggest that increased p21 expression relative to benign nevi is not sufficient to control melanoma growth in vivo.
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PMID:Overexpression of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1) in human cutaneous malignant melanoma. 919 78

Aggregates of benign nevus cells occurring in lymph nodes are a well-described incidental finding. Nevus cell aggregates (NCAs) can mimic foci of metastatic carcinoma or other disease processes, so the surgical pathologist should be familiar with this lesion. The purpose of this report is to describe the potential diagnostic difficulties created by benign NCAs within the thymus of a 32-year-old man with dysplastic nevus syndrome and malignant melanoma involving mediastinal lymph nodes and the right lung. Morphologically, the NCAs in this case elicited the differential diagnoses of metastatic melanoma and thymoma. Immunohistochemical studies helped to establish the correct diagnosis by demonstrating reactivity for S-100 protein and negative staining for keratin and HMB-45. Unlike malignant melanomas, NCAs show no p53 protein immunoreactivity, and low proliferative activity was detected by Ki-67 antigen immunostaining. Although melanocytic cells were rarely reported in thymic neoplasms, we are not aware of any previous reports of NCAs occurring in the normal thymus.
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PMID:Benign nevus cell aggregates in the thymus: a case report. 1010 20

The etiology of malignant melanoma has been intensely studied over the last decade. Much of the recent work focuses on oncongenes and tumour suppressor genes and the role of apoptosis in melanoma. Loss of tumour suppressor proteins such as p16 has been documented in melanoma and correlates with tumour progression. Mutations in the tumour suppressor p53 have also been documented in melanoma. The proto-oncongene Bcl-2 encodes a protein that inhibits apoptosis. Bcl-2 is found in normal melanocytes and benign nevi. However, lower levels are seen in melanoma. To investigate the relationship between melanoma and nevi, in our Basic and Clinical Science section, Dr. Radhi examines the expression of p53, p16, and Bcl in malignant melanoma arriving in benign nevi. P53 immunoreactivity was found only in the malignant component, with no expression being seen in the benign components of the lesion. This suggests that this tumour suppressor gene is involved in the pathogenesis of melanoma.
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PMID:The etiology of malignant melanoma. 1057 55

Microdissection genotyping was performed on 16 cases of melanoma, including two cutaneous and one lymph node metastases. Three benign nevi were used as controls. Where possible, tumor was microdissected at several sites. Genotyping involved assessment of loss of heterozygosity [LOH]), which was accomplished using a panel of nine polymorphic tetranucleotide microsatellites. Polymerase chain reaction was performed on the normal tissue sample to establish microsatellite heterozygous status. Informative markers were then tested on microdissected lesional tissue and scored for the presence and extent of allelic imbalance (AI). Microsatellite informativeness varied from 33% to 66%. Benign nevi were without AI. All invasive melanomas manifested acquired allelic loss, which involved 75% or 100% of the markers shown to be informative for each subject. Eleven of 13 (84%) primary melanomas demonstrated intratumoral heterogeneity of AI consistent with development of tumor subclones with differing genotypic profiles within thin as well as thick melanomas. Although a consistent pattern did not emerge among the markers, LOH of 9p21 (D9S254) occurred in 60% (9/15) of the cases followed by 40% of cases displaying LOH of 1p34, p53, 10q (MXI1), and 10q23 (D10S520) and 25% with 5q21 (D5S 592) abnormalities. A third of the cases including the metastatic foci demonstrated two different patterns of AI affecting alternative alleles of the same genomic marker within different parts of the melanoma. Two melanomas in situ did not display LOH of any markers in the informative cases although the in situ component in the invasive tumors had allelic losses that were in part similar to the invasive areas. The results of this study support the expanded use of microdissection genotyping and explore other markers to define the unique mutational profile for malignant melanoma that may complement other histologic characteristics of melanoma.
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PMID:Genotypic analysis of primary and metastatic cutaneous melanoma. 1255 Jul 56

In the last 2 years, it has become apparent that the p53-family members p53 and p73 play fundamentally different roles in human malignancies. In contrast to p53, many studies on cancer patients failed to detect mutational inactivation of p73 and reported overexpression of wild-type p73 instead. A possible explanation was provided by the recent discovery of N-terminal truncated isoforms of p73 (DeltaTA-p73) that act as dominant-negative inhibitors of wild-type p53 and TA-p73 and result in tumor growth in nude mice. We investigated the role of DeltaTA-p73 in the development and progression of human melanomas, which lack p53 mutations. We analyzed 8 benign melanocytic nevi, 8 primary melanomas and 19 melanoma metastases for alterations of TA-p73 and DeltaTA-p73 expression using isoform-specific real-time RT-PCR. Based on our results, p73Deltaex2 and Deltaex2/3 spliced transcripts derived from the first promoter were significantly up-regulated in melanoma metastases, whereas DeltaN-p73 generated from the second promoter was the predominant isoform in benign nevi. Moreover, increased expression of p73Deltaex2 and p73Deltaex2/3 correlated with high-levels of both TA-p73 and E2F1. Our data suggest a potential function of DeltaTA-p73 splice isoforms in melanoma progression.
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PMID:Alterations of DeltaTA-p 73 splice transcripts during melanoma development and progression. 1461 32

Inactivation of the p53 pathway represents the most common molecular defect of human cancer. But in the setting of melanoma, a highly aggressive and invariably fatal malignancy in its advanced disseminated form, mutation/deletion of p53 is relatively rare, whereas its positive regulator ARF is often lost. Here, we show that genetic deficiency in Arf but not p53 facilitates rapid development of melanoma in a genetically engineered mouse model. This difference is accounted for, at least in part, by the unanticipated observation that, unlike fibroblasts, senescence control in melanocytes is strongly regulated by Arf and not p53. Moreover, oncogenic NRAS collaborates with deficiency in Arf, but not p53, to fully transform melanocytes. Our data demonstrate that ARF and p53, although linked in a common pathway, suppress tumorigenesis through distinct, lineage-dependent mechanisms and suggest that ARF helps restrict melanoma progression by executing the oncogene-induced senescence program in benign nevi. Thus, therapeutics designed to restore wild-type p53 function may be insufficient to counter melanoma and other malignancies in which ARF holds p53-independent tumor suppressor activity.
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PMID:ARF functions as a melanoma tumor suppressor by inducing p53-independent senescence. 1757 30


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