Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The WAF1 gene, located on chromosome 6p, encodes a M(r) 21,000 protein (p21) that can arrest cell growth by associating with and inhibiting cyclin-dependent kinase complexes that are necessary for cells to exit Gr. Transcriptional activation of WAF1 can be accomplished by increasing levels of p53 protein induced by various cellular stresses, including DNA damage. Metastatic melanomas are paradoxical in that most overexpress wild-type p53 protein, yet cell growth is not inhibited. Thus, it is possible that lack of growth suppression in melanomas is due, in part, to mutations in the WAF1 gene. Therefore, we examined the entire coding region of the WAF1 gene in 24 metastatic melanoma cell lines and three normal melanocyte lines by single-strand conformation polymorphism (SSCP) analysis and direct DNA sequencing. We similarly examined the DNA from lymphoblastoid cell lines, derived from nine individuals belonging to seven melanoma-prone families, in which haplotypes of markers on 6p cosegregate with melanoma for germline mutations in the WAF1 gene. Results indicate that (i) mutation of the WAF1 gene is an infrequent event in individuals with sporadic melanoma or predisposed to familial melanoma and (ii) the uncontrolled growth of melanoma cells is not due to mutation of the WAF1 gene. However, expression studies found a wide variation in the level of p21 protein in melanoma cells, suggesting that aberrant regulation of p21 may play a role in melanoma development. Moreover, there was no predictable relationship between p21 expression and p53 expression, indicating that other, p53-independent, pathways may be important for the regulation of p21 in melanoma cells.
Melanoma Res 1995 Aug
PMID:Mutations and defective expression of the WAF1 p21 tumour-suppressor gene in malignant melanomas. 749 59

Sinonasal melanoma is a rare malignancy. We present the clinicopathologic review of 18 cases seen at the British Columbia Cancer Agency between 1976 and 1992: 13 men and five women, mean age 66 years (range 32-88). Patients presented with nasal obstruction and bleeding (n = 8), obstruction alone (n = 4), bleeding alone (n = 5) or pain (n = 1). Those with bleeding presented with a shorter duration of symptoms than those with obstruction alone. All patients with obstruction alone died of their disease, while all patients with bleeding alone are alive or have died of an unrelated cause; four out of eight patients with both obstruction and bleeding are alive. There was no significant relationship between treatment modality and outcome. Histologic subtypes included epithelioid (n = 10), spindle-cell (n = 4), small-cell (n = 3) and pleomorphic (n = 1). Eight out of 11 cases from whom samples of paraffin-embedded tissue were available showed more prominent staining for HMB-45 than for S-100. In two cases, only rare (< 0.1%) cells stained for S-100. Cell type, mitotic rate and P53 expression were unrelated to disease outcome. Six out of seven patients with < or = 10% of cells showing intense staining for PCNA were alive or had died of an unrelated cause, while three out of four with > 10% staining died of their disease.(ABSTRACT TRUNCATED AT 250 WORDS)
Melanoma Res 1995 Aug
PMID:Sinonasal malignant melanoma--a clinicopathologic analysis of 18 cases. 749 62

UV radiation has been shown to play a role in the initiation of human cutaneous melanoma, but its role in the development of malignant melanoma to the metastatic state is not very well defined. Although previous studies have concentrated on the effect of UV-B on the host immune response, the effect of UV-B on the tumor cells was not elucidated. Here we show that UV-B can induce interleukin 8 (IL-8) mRNA and protein secretion in human cutaneous melanoma with negligible expression of IL-8. UV-B-induced IL-8 was constitutively expressed 60 days after irradiation in tumors implanted in mice. Induction of IL-8 was UV-B dose dependent and blocked by cyclohexamide, indicating that de novo protein synthesis is required for its expression. The UV-irradiated cells demonstrated enhanced tumorigenicity and metastatic potential in nude mice. The increase in tumorigenicity and metastatic ability could be explained by the increase in Mr 72,000 type IV collagenase activity and angiogenesis attributed to the induction of IL-8 after irradiation. The acquisition of the metastatic phenotype induced by UV-B could not be attributed to abnormalities in the p53 or MTS-1 (p16INK4) genes. To the best of our knowledge, this is the first report to show that UV-B can increase the aggressiveness of human cutaneous melanoma for growth and metastasis.
 ...
PMID:Ultraviolet B irradiation promotes tumorigenic and metastatic properties in primary cutaneous melanoma via induction of interleukin 8. 754 20

Defects in cellular differentiation are a common occurrence in human cancers. The combination of recombinant human fibroblast interferon (IFN-beta) and the antileukemic compound mezerein (MEZ) results in an irreversible loss of proliferative capacity and terminal cell differentiation in H0-1 human melanoma cells. In contrast, either agent alone induces reversible growth arrest and/or specific components of the differentiation process without inducing terminal differentiation. The current study investigates changes in cell cycle, cell cycle gene expression and E2F transcription factor complex formation during the processes of reversible and irreversible (terminal) differentiation. Induction of both terminal differentiation and reversible differentiation (MEZ treatment) results in a temporal decrease in DNA synthesis and the percentage of cells in S phase and a decrease in the expression of cell cycle and growth regulated genes, including cdc2, cyclin A, cyclin B, histone H1, histone H4, nm23-H1, p53 and c-myc. Persistent gene expression changes occur in terminally differentiated cells, but not in reversibly differentiated cells. H0-1 cells contain several E2F binding activities, including uncomplexed E2F, an E2F-p107-cyclin A-cdk2 kinase complex and an Rb-E2F complex. Induction of growth arrest by MEZ results in a slow migrating gelshift band that contains E2F associated with the pRb2/p130 protein. There is also a loss of the Rb-E2F complex. Induction of terminal differentiation after treatment with IFN-beta + MEZ generates a second pRb2/p130-E2F complex that migrates considerably faster than the pRb2/p130-E2F complex resulting from growth arrest. The slower migrating complex may contribute to growth arrest, whereas the faster migrating complex may play a role in terminal differentiation. Our results demonstrate that terminal cell differentiation involves a co-ordinate and continuous suppression of a number of cell cycle and growth related genes and results in the development of a novel E2F transcription factor complex not apparent in growth arrested and reversibly differentiated human melanoma cells.
 ...
PMID:Cell cycle gene expression and E2F transcription factor complexes in human melanoma cells induced to terminally differentiate. 756 79

Gene transfer techniques may provide efficient treatment for a variety of malignant neoplasms. A replication-deficient adenovirus (Ad) vector which carries the cDNA for wild-type p53 (AdCMV.p53) was tested for its in vitro and in vivo effects on the growth of murine melanoma cell line B16-G3.26 and human melanoma cell line SK-MEL-24. The growth of B16-G3.26 cells infected with AdCMV.p53 was inhibited when compared to the uninfected cells or cells infected with the control vector AdCMV.NLS beta gal. Similarly, the growth of SK-MEL-24 cells infected with AdCMV.p53 was also below that of AdCMV.NLS beta gal-infected and uninfected controls. DNA laddering using agarose gel electrophoresis and in situ labeling of DNA fragmentation (TUNEL) showed that AdCMV.p53-infected murine and human melanoma cells underwent apoptosis. Nude mice injected s.c. either with B16-G3.26 cells or with SK-MEL-24 cells developed localized tumors. These tumors were subsequently infiltrated with either AdCMV.p53, AdCMV.NLS beta gal or saline alone. One week after infection, B16-G3.26 tumors exposed to AdCMV.p53 were 2.5 times smaller than control tumors and exhibited DNA fragmentation. A similar growth-inhibitory effect of AdCMV.p53 was observed with SK-MEL-24 tumors. Thus, Ad-mediated wild-type p53 overexpression resulted in melanoma cell apoptosis and inhibition of melanoma growth in vitro and in vivo. These gene therapy approaches may be useful in targeting rapidly growing, malignant melanomas in a clinical setting.
 ...
PMID:Adenovirus-mediated gene transfer of wild-type p53 results in melanoma cell apoptosis in vitro and in vivo. 759 Dec 84

It is often difficult to predict the outcome of melanoma in patients with Clark level III-IV disease. We sought to identify markers of cell proliferation which may be useful in predicting prognosis. Patients with Clark's level III-IV malignant melanoma who had no local recurrences or metastases were matched with patients of comparable level and thickness who did experience recurrences of metastases. Cell proliferation markers p53, proliferating cell nuclear antigen (PCNA), and Ki-67 were assessed by immunohistochemistry. DNA ploidy was determined by flow cytometry. There was no difference in the expression of p53, PCNA, and Ki-67 between patients with metastases and patients without metastases. However, patients with metastases were more likely to have an aneuploid tumor cell population than were patients without metastases (p < 0.03). Expression of cell proliferation markers do not appear to help predict prognosis in advanced level melanoma; however, aneuploidy may be associated with a greater probability of metastasis.
 ...
PMID:Cell proliferation markers in predicting metastases in malignant melanoma. 759 19

Mutations of the TP53 gene are the most common genetic alterations in human malignancies. Overexpression of the p53 protein has been reported in high frequencies in all types of skin cancer. To determine the role of TP53 in the pathogenesis of malignant melanoma, we investigated the expression of p53 in 12 cell lines and 145 primary and metastatic lesions by immunohistochemistry. Overexpression of p53 was predominantly detected in the cytoplasm of the cells in 96 (66%) tumor and 12 (93%) cell lines. In contrast to findings in other tumor types, in melanomas immunoreactive cells were found in clusters or as scattered single cells. In primary melanomas, the frequency of p53 overexpression did not correlate with tumor thickness. Nucleotide sequencing of TP53 genes of 24 melanoma tumors/cell lines demonstrated point mutations in seven samples, all coding for mutant p53 protein species. The frequency of TP53 alterations of 20%-30% is lower than in other skin tumor types. Notably, immunohistochemistry was not a suitable method to distinguish overexpression of wild-type p53 from mutant species, since cell lines/tumors with TP53 mutations did not show distinctive staining patterns. The mutation pattern in six out of seven lesions was similar to that caused by ultraviolet light damage. This finding may be regarded a further indication for a pathogenetic role of UV light damage in at least a subgroup of malignant melanomas.
 ...
PMID:Mutation and expression of TP53 in malignant melanomas. 759 86

Immunohistochemical analysis of the N-ras p21 and the p53 proteins was carried out on formalin-fixed sections of naevi, primary melanomas and metastases from patients with sporadic melanoma (SCMM) and with hereditary melanoma (HCMM)/dysplastic naevus syndrome (DNS). Seven out of 11 (64%) common naevi and three out of nine (33%) dysplastic naevi showed increased cytoplasmic N-ras expression. No p53 immunopositivity could be recognized in any of the naevus samples. However, strong N-ras expression as well as immunopositivity for p53 was recognized among primary melanomas and metastases with significantly higher frequency among samples from patients with HCMM compared with samples from SCMM cases (for N-ras, 40% vs 10%, P < 0.01; and for p53 43% vs 17%, P < 0.05). We have earlier registered N-ras codon 61 mutations among metastases from 59% of patients with HCMM and from 24% of subjects with SCMM. A comparison of the genetic data with the immunohistochemical results showed occurrence of increased N-ras p21 expression in the presence and absence of detectable N-ras mutant alleles. Increased expression of wildtype N-ras p21 may contribute to tumorigenicity in the absence of mutational activation, at least in a subset of melanomas. Altogether, N-ras p21 alterations are registered at earlier stages than p53 alterations in melanoma development and may be of aetiological importance, whereas p53 alterations may be associated with tumour progression in the late stages.(ABSTRACT TRUNCATED AT 250 WORDS)
Melanoma Res 1995 Apr
PMID:Immunohistochemical analysis of the N-ras p21 and the p53 proteins in naevi, primary tumours and metastases of human cutaneous malignant melanoma: increased immunopositivity in hereditary melanoma. 762 Mar 36

Mutations of the p53 tumour suppressor gene are common to many human malignancies. Although increased p53 expression has been observed in cutaneous malignant melanoma, mutations of the p53 gene appear to be infrequent. We examined 140 benign and malignant paraffin-embedded melanocytic lesions for p53 protein expression by immunohistochemistry, using the monoclonal anti-p53 antibody DO-7 and a microwave method of antigen retrieval. Fifteen naevi and 25 melanomas were further analysed for p53 mutations within exons 5-8 of the p53 gene. DNA was extracted from paraffin sections and screening for mutations was carried out using PCR-SSCP. We demonstrated p53 protein expression in 33% of naevi (17 out of 51), 35% of primary melanomas (20 out of 58), and 70% of metastatic lesions (15 out of 21). p53 expression in benign lesions was weaker than in malignant lesions in intensity and percentage of cells staining. p53 protein expression in melanomas increased in intensity and percentage of cells staining with tumour progression. In 25% (three out of 12) of metastatic melanomas p53 mutations were detected by PCR-SSCP and increased expression of p53 protein was observed in these tumours. p53 gene mutations were not detected in any benign melanocytic lesions. We demonstrate that antigen retrieval techniques increase p53 immunoreactivity in paraffin embedded melanocytic tissues. p53 protein expression in melanomas increases with depth of tumour invasion. As p53 gene mutations occur infrequently in malignant melanoma, other mechanisms are proposed to influence p53 protein expression in melanocytic lesions.
Melanoma Res 1995 Apr
PMID:p53 gene mutation and expression in naevi and melanomas. 762 Mar 45

Paraffin-embedded tissue from the primary tumours of 116 patients with malignant melanoma, and in 40 cases also from corresponding metastases, were examined for accumulation of p53 protein. The fraction of tumours with positive p53 immunostaining was 13% in the least invasive and 36% in the most invasive primary lesions and 48% in the metastases. Where comparisons could be made, both the level and pattern of p53 immunoreactivity were the same in the primary and metastatic tumours. Nine (50%) patients with p53-positive and 34 (39%) with p53-negative primaries relapsed during the first 5 years, but no difference in disease-free period was observed between the two groups. However, an overall longer survival time was observed among patients with p53-positive primaries, especially for those with tumours less invasive than 3.0 mm. Notably, all 11 patients in this group were alive 5 years after diagnosis of the disease, whereas 15 out of 70 (21%) patients with p53-negative tumours died in same period. The results show that an increased level of p53 protein does not indicate increased degree of malignancy in melanoma, but rather suggests a more favourable disease progression.
Melanoma Res 1995 Jun
PMID:Accumulation of p53 protein in human malignant melanoma. Relationship to clinical outcome. 764 May 20


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