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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mitogen-activated protein kinases (MAPKs) extracellular signal-regulated protein kinase (ERK)1 and ERK2, involved in regulating cell growth and differentiation, are constitutively active in A375 and WM239 human melanoma cells. Using PD098059, an inhibitor of MAPK kinase (MEK), we investigated the role of persistently activated ERK1/2 in cell growth. The inhibition of MAPK activity induced a dose-dependent growth arrest in G(0)/G(1) phase. Correspondingly, we observed the up-regulation of the cyclin-dependent kinase (Cdk) inhibitor p27/Kip1 and hypophosphorylation of the retinoblastoma protein. Further studies showed that PD098059 treatment significantly decreased Cdk2 kinase activity, most probably owing to an augmented level of p27/Kip1 associated with cyclin E-Cdk2 complexes. The accumulation of p27/Kip1 protein in A375 cells was attributed to its increased stability. Our findings suggest that constitutively active ERK1/2 kinases contribute to the growth of melanoma cells by negative regulation of the p27/Kip1 inhibitor.
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PMID:Mitogen-activated protein kinases control p27/Kip1 expression and growth of human melanoma cells. 1141 63

In recent years, increasing evidence indicated the importance of a deregulated c-myc gene in the melanoma pathogenesis. We have previously demonstrated that treatment of melanoma cells with c-myc antisense oligodeoxynucleotides can inhibit cell proliferation and activate apoptosis. To gain insight into the mechanisms activated by Myc down-regulation, we have now developed an experimental model that allows modulating Myc protein expression in melanoma cells. This was achieved by originating stable melanoma cell clones expressing ecdysone-inducible c-myc antisense RNA. We show that the induction of c-myc antisense RNA in M14 melanoma cells leads to an inhibition of cell proliferation characterized by accumulation of cells in the G(1) phase of the cell cycle (up to 80%) and activation of apoptosis (50%). These data are associated with an increase of p27(kip1) levels and a significant reduction of the cdk2-associated kinase activity. In addition, we show that an ectopic overexpression of p27(kip1) in this experimental model can enhance the apoptotic rate. Our results indicate that down-regulation of Myc protein induces a G(1) arrest and activates apoptosis by increasing p27(kip1) content in melanoma cells, that are known to be defective for the p16-cyclinD/cdk4-pRb G(1) checkpoint. This is particularly relevant for identifying new therapeutic strategies based on the re-establishment of the apoptotic pathways in cancer cells.
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PMID:Myc down-regulation induces apoptosis in M14 melanoma cells by increasing p27(kip1) levels. 1142 Jun 93

Inactivation of p16INK4a and/or activation of cyclin-dependent kinase-4 (CDK4) are strongly associated with both susceptibility and progression in melanoma. Activating CDK4 mutations prevent the binding and inhibition of CDK4 by p16INK4a. A second, more indirect role for CDK4 is in late G1, where it may sequester the inhibitors p27KIP1 or p21CIP1 away from CDK2, and in doing so upregulate the CDK2 activity necessary for cells to proceed completely through G1 into S phase. As the pivotal residues around the most predominant R24C activating CDK4 mutation are invariant between CDK2 and CDK4, we speculated that the pivotal arginine (position 22 in CDK2), or a nearby residue, may be mutated in some melanomas, resulting in the diminution of its binding and inhibition by p27KIP1 or p21CIP1. However, except for a silent polymorphism, we detected no variants within this region of the CDK2 gene in 60 melanoma cell lines. Thus, if CDK2 activity is dysregulated in melanoma it is likely to occur by a means other than mutations causing loss of direct inhibition. We also examined the expression of the CDK2 gene in melanoma cell lines, to assess its possible co-regulation with the gene for the melanocyte-lineage antigen pmel17, which maps less than 1 kb away in head to head orientation with CDK2 and may be transcribed off the same bidirectional promoter. However, expression of the genes is not co-regulated.
Melanoma Res 2001 Aug
PMID:No evidence of a role for activating CDK2 mutations in melanoma. 1147 22

Many studies have attempted to define the state of differentiation of melanoma cells and to correlate it with other critical parameters of malignancy such as the tumorigenic and metastatic nature of the cells. In the present paper we focused on the possible relationships between the novel protein kinase C isoform nPKCdelta, melanin synthesis and proliferative capacity in a primary human melanoma cell line WM115. Cells were transfected to produce overexpression of this isoform and the effects on melanin synthesis, cyclin-E dependent kinase (cdk2) activity and cyclin E expression were studied. It was shown that translocation of nPKCdelta into the nucleus affects melanin synthesis and inhibits cdk2 activity. As a compensatory effect, the level of cyclin E increases. In view of these results we suggest a model for the role of nPKCdelta in melanoma cells that may offer a new therapeutic perspective.
Melanoma Res 2002 Aug
PMID:Higher levels of melanin and inhibition of cdk2 activity in primary human melanoma cells WM115 overexpressing nPKCdelta. 1217 Jan 78

Multi-cellular spheroids (MCS) generated from tumor cells serve as excellent in vitro models for understanding the mechanisms of tumor progression and micro-metastasis. We have compared the expression of molecular markers with reference to their growth as conventional adherent monolayers (2-D) and anchorage independent cultures (3-D) using two mouse melanoma cell lines, B16F10 and Clone M3. The two cell lines differed in their ability to form spheroids with respect to their aggregation potential, with B16F10 forming large clusters compared to Clone M3. A panel of molecular markers comprising cell adhesion molecules, cyclin dependent kinase inhibitors and members of the cadherin-catenin complex were analyzed by flow cytometry in 2-D and 3-D cultures. There was a distinct difference in the patterns of expression of CD44(S) and variant isoforms v3, v10 in spheroids compared to cells grown as monolayers in both cell lines. Also, there was an increase in cells positive for CDK inhibitor p27 in 3-D cultures from the B16F10 cell line. The expression of alpha and gamma catenin was down regulated in spheroids. As these molecules are implicated in the regulation of cell proliferation, alterations in the expression of these molecules in 3-D cultures compared to their 2-D counterparts suggests the importance of spheroids as experimental model for tumorigenesis.
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PMID:Differential expression of CD44(S) and variant isoforms v3, v10 in three-dimensional cultures of mouse melanoma cell lines. 1219 73

Epidemiological studies support a link between melanoma risk and UV exposure early in life, yet the molecular targets of UV's mutagenic actions are not known. By using well characterized murine models of melanoma, we provide genetic and molecular evidence that identifies components of the Rb pathway as the principal targets of UV mutagenesis in murine melanoma development. In a melanoma model driven by H-RAS activation and loss of p19(ARF) function, UV exposure resulted in a marked acceleration in melanoma genesis, with nearly half of these tumors harboring amplification of cyclin-dependent kinase (cdk) 6, whereas none of the melanomas arising in the absence of UV treatment possessed cdk6 amplification. Moreover, UV-induced melanomas showed a strict reciprocal relationship between cdk6 amplification and p16(INK4a) loss, which is consistent with the actions of UV along the Rb pathway. Most significantly, UV exposure had no impact on the kinetics of melanoma driven by H-RAS activation and p16(INK4a) deficiency. Together, these molecular and genetic data identify components of the Rb pathway as critical biological targets of UV-induced mutagenesis in the development of murine melanoma in vivo.
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PMID:Components of the Rb pathway are critical targets of UV mutagenesis in a murine melanoma model. 1253 79

Due to minimal success with non-surgical treatment options for melanoma, it is imperative that other compounds be tested for potential preventive/therapeutic use. We have tested the ability of the endogenous oestrogenic metabolite 2-methoxyestradiol (2-ME) to inhibit the growth of human melanoma cells in culture. 2-ME inhibited the growth of all the melanoma cells tested, without inhibiting the growth of non-tumorigenic cells. Microscopic observations showed that treated cells exhibit the characteristic features of apoptosis. Examination of the molecular mechanism in WM98-1 cells, using biochemical assays such as a modified TUNEL staining and DNA fragmentation, confirmed the induction of apoptosis following 2-ME treatment. Flow cytometry analysis showed that, following treatment, cells are arrested in the G(2)/M phase of the cell cycle. Western blot analysis of the G(2)/M regulatory proteins suggests that cdc2 is involved in the cell cycle block by Myt1 phosphorylation following 2-ME treatment. Furthermore, examination of the levels of apoptosis regulatory proteins showed that, while levels of p53, Bax and p21 are higher, that of anti-apoptotic Bcl-2 is undetectable in cells treated with 2-ME compared with untreated controls. Taken together these results have major implications for the use of 2-ME for melanoma management.
Melanoma Res 2003 Apr
PMID:Cell cycle block and apoptosis induction in a human melanoma cell line following treatment with 2-methoxyoestradiol: therapeutic implications? 1269 Feb 94

Although activated macrophages destroy cancer cells more effectively than normal cells, the facility to escape activated macrophages is a characteristic of tumor cells. One of the mechanisms responsible for the specific killing of tumor cells by macrophages is the production of the cytokine tumor necrosis factor alpha (TNF). Therefore, resistance to TNF may provide such cancer cells a selective advantage against host elimination. In the present work we explore the possibility that cyclin D1 overrides the cytostatic effect of TNF. We show that TNF induces p21(waf1) protein in malignant melanoma A375 cells and its binding to CDK2/4 and 6 proteins, and thereby inhibiting the activity of these complexes. This inhibition leads the cells to a G1 arrest. Overexpression of cyclin D1 in these cells makes them insensitive to TNF treatment with the recovery of CDK activity, however, is unable to overcome the inhibitory action of etoposide blocking the cells on G2/M. The bypass of TNF-induced G1 arrest seems to be related to the increase in the stability of cyclin D bound CDK complexes, increasing the total amount of CDK2/4 and 6 complexes and leading to a functional down titration of the p21(waf1) molecules. In these conditions the TNF-induced increase of p21(waf1) is not sufficient to inhibit the high amount of cyclin D-bound complexes. This hypothesis is supported by the fact that a reduction in the levels of p21(waf1) protein, induced by the expression of a mRNA antisense against p21(waf1), is also able to bypass of TNF-induced arrest. Our results confirm that p21(waf1) has an essential role in TNF-induced arrest and that the deregulation of cyclin D1 may be one of the mechanisms to escape physiological signals to restrict tumoral growth.
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PMID:Overexpression of cyclin D1 inhibits TNF-induced growth arrest. 1276 82

Aberrations of chromosome 9 p21-22 are involved in the genesis of many forms of cancer. The gene p16 and p15 have been assigned to this region. Both p16 and p15 are an inhibitor of cyclin D-cdk4,cyclin D-cdk6 complex and have been implicated in a wide variety of cancer types, including the germline of patients with familial melanoma. In order to investigate and compare the status of p16,p15 gene in primary tumors and cell lines, we examined 357 primary tumors and 29 cell lines derived from diverse tumor types. In addition to analysis of these primary tumors and cell lines, blood specimens from 91 patients either with sporadic multiple cancers or from cancer-prone families were also analyzed. The data showed the following: 1) Homozygous deletions of p16,p15 were comparatively rare and far less common than previously reported, although hemizygous deletions were observed in a significant fraction of many tumor types; 2) the incidence of p16,p15 deletions (either homozygous deletions or heterozygous deletions) varied significantly among different tumor types; 3) most deletions involved in both p16 and p15 genes; 4) sequence variations in the coding sequence of p16,p15 were comparatively rare among these tumor types, though mutations and polymorphisms were identified; 5) some tumors which showed LOH at 9p, containing p16 and p15 gene, did not show deletions or point mutations in the p16,p15 gene. 6) In a subset of retinoblastoma and osteosarcoma where no Rb gene mutations were present a significant fraction was found to contain p16,p15 gene deletions.
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PMID:Deletions and point mutations of p16,p15 gene in primary tumors and tumor cell lines. 1289 91

Chromosomal numerical aberrations (CNAs), particularly regional amplifications and deletions, are a hallmark of solid tumor genomes. These genomic alterations carry the potential to convey etiologic and clinical significance by virtue of their clonality within a tumor cell population, their distinctive patterns in relation to tumor staging, and their recurrence across different tumor types. In this study, we showed that array-based comparative genomic hybridization (CGH) analysis of genome-wide CNAs can classify tumors on the basis of differing etiologies and provide mechanistic insights to specific biological processes. In a RAS-induced p19(Arf-/-) mouse model that experienced accelerated melanoma formation after UV exposure, array-CGH analysis was effective in distinguishing phenotypically identical melanomas that differed solely by previous UV exposure. Moreover, classification by array-CGH identified key CNAs unique to each class, including amplification of cyclin-dependent kinase 6 in UV-treated cohort, a finding consistent with our recent report that UVB targets components of the p16(INK4a)-cyclin-dependent kinase-RB pathway in melanoma genesis (K. Kannan, et al., Proc. Natl. Acad. Sci. USA, 21: 2003). These results are the first to establish the utility of array-CGH as a means of etiology-based tumor classification in genetically defined cancer-prone models.
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PMID:Array comparative genome hybridization for tumor classification and gene discovery in mouse models of malignant melanoma. 1450 Mar 67


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