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

Interferons (IFNs) induce growth arrest and terminal differentiation through regulation of proliferative genes in a variety of cell types including tumor cells. Growth of melanoma cells is believed to be controlled by the cyclin-dependent kinase inhibitor, mda-6/WAF1/CIP1 gene. IFNs affect the expression of WAF1 in several cell types, including human melanomas. In our earlier reports we demonstrated the antitumor and anticellular activities of different IFN-types on B16 murine melanoma cells. The present study aimed to demonstrate the involvement of mda-6/WAF1 and related cyclin-dependent kinases in antitumor action of different IFN-types in B16 melanoma cells. IFN-alpha has been proven to be a potent inducer of mda-6/WAF1, also inhibiting cyclin-dependent kinases, such as cdc2- and cdk2-kinase. This induction is p53-independent. However, IFN-gamma affects B16 cells differently, it induces p53 activity without inducing WAF1. The combination of IFN-alpha plus IFN-gamma is additive rather than synergistic. Our data demonstrate differential effects of different IFNs on murine B16 melanoma cells which may have relevance in nonsurgical treatment of melanomas.
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PMID:Interferon regulates expression of mda-6/WAF1/CIP1 and cyclin-dependent kinases independently from p53 in B16 murine melanoma cells. 916 13

Tyr-Phe and Met limitation in vitro inhibited cell proliferation and proliferating cell nuclear antigen (PCNA) expression to a greater extent than serum limitation. Tyr-Phe and serum limitation arrested cells in the G0/G1 phase; Met limitation blocked cells in the G0/G1 and S phases. Tyr-Phe limitation progressively decreased cyclin D1 expression to 30% of control within four days and did not affect expression of cyclin D3 or cyclin-dependent kinase (CDK2, CDK4, and CDK5) expression, Met limitation decreased cyclin D3 expression to 25% of control and CDK2 expression to 32% of control by Day 4 and did not affect expression of cyclin D1, CDK4, and CDK5. Serum limitation inhibited cyclin D1 and cyclin D3 expression to 24% of control after four days and did not effect CDK expression. Expression of two CDK inhibitors, p21WAF1/Cip1 and p27Kip1, was not changed by amino acid or serum limitation. Dietary restriction of Tyr-Phe in mice bearing subcutaneous B16BL6 melanoma tumors decreased tumor growth rate compared with mice fed a normal diet. Tumors from Tyr-Phe-restricted mice exhibited decreased PCNA expression, G0/G1 phase cell cycle arrest, and reduced cyclin D1 expression. These data indicate that decreased tumor growth in vivo associated with dietary restriction of Tyr and Phe is cell cycle specific.
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PMID:Tyrosine and phenylalanine restriction induces G0/G1 cell cycle arrest in murine melanoma in vitro and in vivo. 942 72

We have investigated the effect of the flavonoid derivative LY 294002, a potent and selective phosphatidylinositol 3-kinase inhibitor, on cell cycle progression in human choroidal melanoma cells. We demonstrate that LY 294002 induces a specific G1 block in asynchronously growing cells leading to an almost complete inhibition of cell proliferation after three days of treatment. When melanoma cells are released from a nocodazole-induced G2/M block, LY 294002 is shown to delay and greatly restrain the G1/S transition. The inhibitor is able to exert its action as long as it is added during the G1 progression and before the cells enter in S phase. We report that the LY 294002-induced G1 arrest is closely correlated to inhibition of CDK4 and CDK2 activities leading to the impairment of pRb phosphorylation which normally occurs during G1 progression. While the inhibition of CDK4 may be attributed at least in part to the decline in CDK4 protein level, CDK2 activity reduction is rather due to the up-regulation of the CDK inhibitor p27Kip1 and to its increased association to CDK2.
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PMID:G1 phase arrest by the phosphatidylinositol 3-kinase inhibitor LY 294002 is correlated to up-regulation of p27Kip1 and inhibition of G1 CDKs in choroidal melanoma cells. 949 22

Chromosome 9p21 is frequently deleted in malignant melanoma, and one familial malignant melanoma gene has been linked to 9p21-22. Recently, the cyclin D-dependent kinase inhibitors (CDKIs) p16INK4a and p15INK4b have been localized within chromosome 9p21, and the presence of p16INK4a point mutations has been demonstrated in familial melanoma and melanoma cell lines in vitro. To analyse the role of these CDKIs in sporadic human cutaneous non-metastatic malignant melanoma, we examined 36 primary tumour specimens representing different stages of melanoma progression and their corresponding normal skin samples for the three mechanisms of CDKI inactivation described so far. Homozygous codeletion of the p16INK4a and the p15INK4b gene was detected by Southern blot analysis in two tumour samples. By direct sequencing of polymerase chain reaction (PCR)-amplified microdissected genomic DNA; no somatic or germline p16INK4a point mutations or small deletions were detected in the remaining 34 tumour samples; one individual exhibited the previously described germline codon 148 (Ala-->Thr) polymorphism. In these tumour specimens, comparative semiquantitative reverse PCR analysis of p16INK4a transcript levels revealed no evidence for repression of p16INK4a gene transcription and thus for p16INK4a promoter inactivation by DNA methylation. These results indicate homozygous p16INK4a and p15INK4b loss to occur in a subset of cutaneous melanomas and suggest, in view of the frequent loss of heterozygosity on chromosome 9p21, the presence of another tumour suppressor gene within this chromosomal region.
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PMID:Homozygous deletion of the p16INK4a and the p15INK4b tumour suppressor genes in a subset of human sporadic cutaneous malignant melanoma. 953 18

Reduced expression of the myristoylated alanine-rich C kinase substrate (MARCKS) has been described in various cell lines after oncogenic or chemical transformation, leading to the question of whether this protein may be involved in cell proliferation. Here we compare the expression of MARCKS in human tumor-derived choroidal melanoma cells (OCM-1) and in primary cultures of normal choroidal melanocytes. We found an important down-regulation of the protein in the melanoma cell line. Stable transfection of these cells with the cDNA coding for MARCKS led to the selection of several clones expressing variable levels of the protein. Proliferation experiments performed with four of these clones revealed that cell growth was reduced by 35-40% when compared with control cells. Upon serum starvation, cell proliferation was almost abolished when the expression level of MARCKS was high, whereas it was only partially reduced in the controls. MARCKS overexpression induced a higher percentage of cells in the G0-G1 phase of the cell cycle upon serum starvation, as well as the inhibition of colony formation in soft agar. Finally, the expression of the CDK inhibitor p27 was increased in the cells presenting a high level of MARCKS protein. Altogether, these data suggest that the expression of this protein kinase C substrate affects the proliferation and partially reverts the transformed phenotype of the OCM-1 cells.
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PMID:Overexpression of the myristoylated alanine-rich C kinase substrate in human choroidal melanoma cells affects cell proliferation. 953 44

The anti-tumor effect and its mechanism of the herbal medicine sho-saiko-to were investigated on a murine malignant melanoma cell line (Mel-ret). Sho-saiko-to induced apoptotic cell death of Mel-ret cells with a definite increase of cell surface Fas antigen and Fas ligand (FasL). Sho-saiko-to arrested Mel-ret cells in G1 phase by decreasing the expression of cyclin-dependent kinase (cdk) 4 and its homologue cdk6. Kinase activities of cdk4 and cdk6 were identified to be downregulated by sho-saiko-to. Ingredient analysis revealed that baicalin is likely the main active constituent in the upregulation of Fas antigen and Fas ligand, while glycyrrhizin is the main constituent in the inhibition of cdks.
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PMID:The herbal medicine sho-saiko-to inhibits the growth of malignant melanoma cells by upregulating Fas-mediated apoptosis and arresting cell cycle through downregulation of cyclin dependent kinases. 959 93

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

Genistein, the principal isoflavonoid in soybeans, is reported to inhibit cell cycle progression, but the molecular basis for this event is unknown. Here we show that genistein inhibits DNA synthesis and suppresses cyclin E-associated cyclin-dependent kinase-2 (CDK2) activity when quiescent BALB/c 3T3 fibroblasts are stimulated with serum. In these cells, a CDK2 inhibitor, p21(Cip1/WAF1), is markedly increased by genistein, but another CDK2 inhibitor, p27(Kip1), is not increased. In exponentially growing BALB/c 3T3 cells, genistein inhibits proliferation of the cells in a dose-dependent manner. Flow cytometric analysis and measurement of DNA synthesis indicate that genistein blocks the G1 to S phase transition of these cells, which is concomitant with G2-M arrest. In mouse B16-F1 melanoma cells, genistein also blocks the transition of G1 to S phase without arresting at G2-M at low doses. In both cell lines, genistein suppresses cyclin E/CDK2 activity and induces p21(Cip1/WAF1) expression. These results suggest that genistein affects the restriction point control of the cell cycle by inducing p21(Cip1/WAF1) expression in mouse fibroblast and melanoma cells.
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PMID:Genistein induces p21(Cip1/WAF1) expression and blocks the G1 to S phase transition in mouse fibroblast and melanoma cells. 979 Sep 49

Approximately 8-12% of melanoma is inherited in an autosomal dominant fashion with variable penetrance. A chromosome 9p21 locus has been linked to this disease in 50-80% of affected families. CDKN2A (also known as P16, INK4, p16INK4A and MTS1) is allelic to this locus and encodes a cdk4/cdk6 kinase inhibitor that constrains cells from progressing through the G1 restriction point. Although germline CDKN2A coding mutations cosegregate with melanoma in 25-60% of families predisposed to the disease, there remains a number of mutation-negative families that demonstrate linkage of inherited melanoma to 9p21 markers. We show here that a subset of these kindreds possess a G-->T transversion at base -34 of CDKN2A, designated G-34T. This mutation gives rise to a novel AUG translation initiation codon that decreases translation from the wild-type AUG. The G-34T mutation is not seen in controls, segregates with melanoma in families and, on the basis of haplotyping studies, probably arose from a common founder in the United Kingdom. Characterization of this and other CDKN2A non-coding mutations should have an impact on current efforts to identify susceptible melanoma-prone families and individuals.
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PMID:Mutation of the CDKN2A 5' UTR creates an aberrant initiation codon and predisposes to melanoma. 991 6

Human melanoma cell lines derived from early stage primary tumors are particularly sensitive to growth arrest induced by interleukin-6 (IL-6). This response is lost in cell lines derived from advanced lesions, a phenomenon which may contribute to tumor aggressiveness. We sought to determine whether resistance to growth inhibition by IL-6 can be explained by oncogenic alterations in cell cycle regulators or relevant components of intracellular signaling. Our results show that IL-6 treatment of early stage melanoma cell lines caused G1 arrest, which could not be explained by changes in levels of G1 cyclins (D1, E), cdks (cdk4, cdk2) or by loss of cyclin/cdk complex formation. Instead, IL-6 caused a marked induction of the cdk inhibitor p21WAF1/CIP1 in three different IL-6 sensitive cell lines, two of which also showed a marked accumulation of the cdk inhibitor p27Kip1. In contrast, IL-6 failed to induce p21WAF1/CIP1 transcript and did not increase p21WAF1/CIP1 or p27kip1 proteins in any of the resistant lines. In fact, of five IL-6 resistant cell lines, only two expressed detectable levels of p21WAF1/CIP1 mRNA and protein, while in three other lines, p21WAF1/CIP1 was undetectable. IL-6 dependent upregulation of p21WAF1/CIP1 was associated with binding of both STAT3 and STAT1 to the p21WAF1/CIP1 promoter. Surprisingly, however, IL-6 stimulated STAT binding to this promoter in both sensitive and resistant cell lines (with one exception), suggesting that gross deregulation of this event is not the unifying cause of the defect in p21WAF1/CIP1 induction in IL-6 resistant cells. In somatic cell hybrids of IL-6 sensitive and resistant cell lines, the resistant phenotype was dominant and IL-6 failed to induce p21WAF1/CIP1. Thus, our results suggest that in early stage human melanoma cells, IL-6 induced growth inhibition involves induction of p21WAF1/CIP1 which is lost in the course of tumor progression presumably as a result of a dominant oncogenic event.
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PMID:Interleukin-6 dependent induction of the cyclin dependent kinase inhibitor p21WAF1/CIP1 is lost during progression of human malignant melanoma. 1002 78


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