Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0278883 (metastatic melanoma)
 6,224 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To determine whether loss or inactivation of the putative tumor-suppressor gene, p16, represents an initiating or a secondary event in the progression of human melanoma, we evaluated the status of this gene in early and advanced-stage melanomas of sporadic origin. The results of this analysis revealed p16 deletions in 4/6 primary and 6/14 metastatic melanoma cell lines but not in 3/3 metastatic melanoma specimens. Surprisingly, p16 deletions were also detected in 8/8 benign compound nevi and in 1/3 normal human melanocyte isolates. To investigate whether these deletions in benign and malignant stages of the human melanocytic system were specific for p16, we analysed the same specimens and cell lines for expression of p21, another cyclin-dependent kinase inhibitor and potential tumor suppressor. In contrast to p16, expression of p21 was detected in 3/3 melanocytes, in 3/3 benign nevi, and in greater than 50% of malignant melanoma cell lines and specimens. Finally, because of the recently documented inverse relationship between expression of p16 and pRb protein in a variety of tumor cell lines, we analysed some of the p16-positive and negative melanoma cell lines for the presence of pRb protein. The results demonstrated pRb protein in each of these cell lines. Taken together, although this study revealed deletions of the p16 gene in a significant number of sporadic primary and metastatic melanoma cell lines, they were also detected in benign nevus specimens and in some normal human melanocyte isolates. Thus, these findings cast some doubt on the role of this gene as being causal to the onset and progression of human melanoma, in particular, sporadic melanoma.
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PMID:Differential expression of the cyclin-dependent kinase inhibitors p16 and p21 in the human melanocytic system. 864 98

Although homozygous deletions of the cyclin-dependent kinase inhibitor 2 gene p16INK4a on 9p21 have been reported frequently in metastatic melanoma cell lines, and intragenic mutations within the p16INK4a gene have been detected in familial melanoma kindreds, specific targeting of this gene in the development of sporadic melanoma in vivo remains controversial. Southern analyses were performed in this study to initially assess the frequency of hemi- or homozygous losses of p16INK4a, as well as its neighboring family member, p15INK4b, and other candidate regions within 9p21, in sporadic melanoma. Overall, 22 of 40 (55%) uncultured sporadic melanoma DNAs were determined to harbor deletions of 1-11 markers/genes located on 9p21. This included 10 tumors (25%; 10 of 40) with homozygous deletions limited to either the p16INK4a gene only (20%; 2 of 10), both the p16INK4a and p15INK4b genes (10%; 1 of 10), another novel 9p21 gene, FB19 (10%; 1 of 10), or all three of these genes plus surrounding markers (60%; 6 of 10). In subsequent single-strand conformation polymorphism and sequencing analyses, intragenic mutations in the p16INK4a gene were also revealed in two (10%; 2 of 21) melanoma DNAs that retained one copy of this locus. By comparison, the frequency of pl6INK4a and p15INK4b homozygous deletions, as well as p16INK4a mutations, in melanoma cell lines (analyzed in parallel) was 2-3-fold higher at 61 (23 of 38) and 24% (9 of 38), respectively. These findings indicate that (a) p16INK4a is inactivated in vivo in over one-fourth (27.5%; 11 of 40) of sporadic melanomas; (b) mutation/deletion of p16INK4a may confer a selective growth advantage in vitro; and (c) other 9p21 tumor suppressor genes could be targeted during the development of melanoma.
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PMID:Loss of the p16INK4a and p15INK4b genes, as well as neighboring 9p21 markers, in sporadic melanoma. 889 59

12-O-Tetradecanoyl phorbol-13-acetate (TPA) inhibits the growth of most malignant melanoma cells but stimulates the growth of normal human melanocytes. We previously showed that addition of TPA inhibits the growth of the human metastatic melanoma cell line, Demel, by blocking cells at both the G1/S and G2/M cell cycle transitions (D. L. Coppock et al., 1992, Cell Growth Differ. 3, 485-494). To examine the G2/M transition, we developed a method to synchronize the cells in early S phase using Lovastatin and mevalonate, followed by treatment with hydroxyurea (HU). TPA (30 nM) was effective in blocking cells from entering mitosis and reentering G1 when added up to the end of G2. These cells arrested in G2. Examination of the levels of cyclins A and B1 demonstrated that the levels of these cyclins were not limiting for entrance into M. However, the addition of TPA blocked the increase in p34(cdc2)/cyclin B1 kinase activity. In cells treated with TPA, most p34(cdc2) was found in the slowly migrating forms on Western blots, which contained increased levels of phosphotyrosine. In addition, the level of the cyclin-dependent kinase inhibitor p21(Cip1/Waf1), but not of p27(Kip1), was increased. We examined the expression of protein kinase C (PKC) isoforms in Demel cells using Western blots to understand which types were involved in the G2 arrest. Demel cells expressed the PKC alpha, betaI, betaII, delta, epsilon, iota/lambda, zeta, and mu isozymes. PKC eta and PKC theta were not detected. Addition of TPA did not completely down regulate any PKC isozymes over a 12-h period in these synchronized cells. PKC alpha, betaI, betaII, delta, and epsilon isozymes were translocated to the membrane fraction from the cytosolic fraction when treated with TPA. PKC delta appeared as a doublet and the addition of TPA shifted a majority to the slower migrating form. The level of PKC mu was constant; however, a slow mobility form was observed in TPA-treated cells. This reduced mobility was at least partially due to phosphorylation. Thus, the arrest of growth in G2 appears to be due to the inhibition of the p34(cdc2) kinase activity which is associated with the increased expression of p21(Cip1/Waf1) and increased phosphorylation on tyrosine of p34(cdc2). This arrest, in turn, is associated with a shift of PKC isozymes PKC alpha, PKC betaI, PKC betaII, PKC delta, PKC epsilon, and PKC mu to the membrane fraction which is induced by addition of TPA.
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PMID:Regulation of the cell cycle at the G2/M boundary in metastatic melanoma cells by 12-O-tetradecanoyl phorbol-13-acetate (TPA) by blocking p34cdc2 kinase activity. 968 25

Malignant melanoma is a notoriously aggressive disease that can affect relatively young individuals and whose incidence is rising at an alarming rate. Unlike many cancers, metastatic melanoma is poorly responsive to current therapies and mutations affecting p53, the retinoblastoma gene product or Ras which occur frequently in many other cancer types, appear to be rare or at least relatively late events in the progression of the disease. Recent advances in our understanding of the disease at the molecular level have indicated that in addition to the loss of cell cycle checkpoints which may be common to all cancers, malignant melanoma shares many characteristics in common with developmental precursors to melanocytes, the mature pigment producing cells of the skin and hair follicles which are responsible for skin and hair colour. This review therefore focuses on the signalling pathways that play a crucial role in the development of the melanocyte lineage which are subject to deregulation in malignant melanoma namely signalling by receptor tyrosine kinases, the Wnt signalling pathway, as well as loss of the p16INK4a cyclin-dependent kinase inhibitor. Intriguingly all three pathways impact on the expression or function of the microphthalmia-associated transcription factor which plays an essential role in melanocyte development.
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PMID:Melanocyte development and malignant melanoma. 1100 28

Decreased expression of p27 (a cyclin-dependent kinase inhibitor) is an adverse prognostic marker in a diverse array of human cancers. The purpose of this study was to investigate the expression of p27 and Jab1 (a protein involved in p27 degradation) in melanocytic lesions, and to identify their possible participation in melanoma progression. A tissue microarray was constructed using formalin-fixed, paraffin-embedded archival tissue blocks of 94 melanocytic lesions including 19 benign nevi, 21 dysplastic nevi, 23 melanomas, and 31 metastatic melanomas. The expression of p27 and Jab1 was evaluated by immunohistochemistry. The association between p27, Jab1, and clinicopathological parameters was analyzed using chi2 and Fisher's exact tests. Nonparametric Pearson's rank correlation was applied to evaluate the relationship between p27 and Jab1 expression. p27 was expressed in 15 (88%) nevi, 18 (95%) dysplastic nevi, 11 (50%) melanomas, and only in four (13%) of the metastatic melanomas (P<0.001). Jab1 was expressed in 14 (82%) standard nevi, 18 (95%) dysplastic nevi, 17 (77%) melanomas, and 16 (53%) of the metastatic melanomas (P<0.01). In metastatic melanomas, there was a negative correlation between p27 and Jab1 expression (r=-0.166). The low levels of p27 in primary and metastatic melanoma cases may explain the high proliferation rate of such lesions. Also, the relative high expression of Jab1 in metastatic melanoma, associated with low levels of p27, suggests that Jab1 may be involved in survival and proliferation of metastatic melanoma cells.
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PMID:Expression of cell cycle inhibitor p27Kip1 and its inactivator Jab1 in melanocytic lesions. 1515 4

The aim of this study was to investigate the therapeutic potential of a cyclin-dependent kinase inhibitor, roscovitine, in cultured melanoma cells and a three-dimensional skin reconstruction model of metastatic melanoma. The modulatory effects of roscovitine on the growth and survival of normal melanocytes and cultured melanoma cell lines were tested. Additionally, we investigated the potential of roscovitine to regulate the growth and differentiation of a metastatic melanoma cell line (A375) in a three-dimensional skin reconstruction culture consisting of A375 cells admixed with normal human keratinocytes embedded within a collagen-constricted fibroblast matrix. We show that roscovitine is able to induce apoptosis in the melanoma cell lines A375, 888, and 624 but not in normal human cultured epithelial melanocytes. The degree of apoptosis within these cell lines correlated with the accumulation of p53 protein and concomitant reduction of X-linked inhibitor of apoptosis protein, with no change in the proteins Bcl-2 and survivin. We also found that roscovitine inhibited the growth and differentiation of A375 melanoma cells within the dermal layer of the skin. The results of this study show that roscovitine has the potential to inhibit the differentiation and invasion of metastatic melanoma and may be useful as a therapy for the treatment of patients with metastatic melanoma.
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PMID:Roscovitine inhibits differentiation and invasion in a three-dimensional skin reconstruction model of metastatic melanoma. 1731 72

A major focus of melanoma research continues to be the search for genes/proteins that may be suitable targets for molecular therapy of primary and metastatic melanoma. In line with this effort, the objective of the study presented herein was to determine whether interfering with cell cycle progression and in particular, the expression and function of select cyclin-dependent kinases, would impair the biological features of advanced melanoma. We provide data, which document that unlike nevi and melanoma in situ, primary and metastatic melanomas express high levels of CDK2, CDK1, and CDK5. Furthermore, we present the results of in vitro and preclinical in vivo studies, which demonstrate that treatment with a small-molecule cyclin-dependent kinase inhibitor that selectively blocks the function of CDK2, CDK5, CDK1, and CDK9, leads not only to inhibition of melanoma cell proliferation and apoptosis of melanoma cells, but also impairs the growth of human melanoma xenografts.
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PMID:Expression analysis and molecular targeting of cyclin-dependent kinases in advanced melanoma. 2146 16

Dermatologic toxicities associated with anticancer-targeted therapy include hand-foot skin reactions, vasculitis, cutaneous epithelial proliferations, such as keratosis, keratoacanthoma, and invasive squamous cell carcinoma. In this case report, we describe alterations of tumor morphology and patterns of cyclin-dependent kinase inhibitor (CDKI) expression in a patient who received GSK2118436, a second-generation RAF inhibitor, for stage IV (M1c) metastatic melanoma. To explore the effects of GSK2118436 on the expression patterns of CDKI (p16, p21, p27, p57), we immunohistochemically evaluated in vivo melanoma cells pre- and posttreated with GSK2118436. After GSK2118436 treatment, the melanoma cells decreased in size and demonstrated hyperchromatic nuclei and indistinct nucleoli. p16 was strongly expressed in the cytoplasm of pretreated melanoma cells and in the nucleus and cytoplasm in posttreated melanoma cells. Expression of both p27 (nucleus) and p57 (cytoplasm) was increased in posttreated melanoma cells and no significant difference in p21 expression was noted in either pre- or posttreated tumor cells. These findings may help explain the molecular mechanisms by which tumor cells retain the ability to proliferate. The persistent activation of pro-oncogenic activities of CDKI (eg, p27 and p57) and/or compartmentalization of p16 in cytoplasm or nucleus may allow tumor cells to bypass BRAF-induced senescence mechanisms. Furthermore, awareness of changes in tumor morphology after treatment with RAF inhibitors may be helpful in histologic evaluation of the spectrum of dermatologic toxicity, which may occur on targeted therapy.
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PMID:Changes in tumor morphology and cyclin-dependent kinase inhibitor expression in metastatic melanoma treated with selective second-generation BRAF inhibitor. 2287 67