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)

In the present study we analyzed, by immunohistochemistry, a panel of human melanomas for protein expression of the cyclin-dependent kinase (cdk) inhibitor p27Kip1 and evaluated whether deregulated expression correlates with clinical outcome for this type of cancer. We found that p27Kip1 was strongly expressed by normal melanocytes and benign nevi, whereas in malignant melanoma, a heterogeneous expression pattern was observed. In the case of nodular melanomas, the level of p27Kip1 was found to correlate significantly with the thickness of the tumor, with less protein expressed in thicker lesions. We also found that patients having tumors with fewer than 5% p27Kip1-staining cells had a significantly higher risk of early relapse of their disease compared with those expressing moderate or high levels. In contrast, the level of p27Kip1 did not correlate with tumor thickness or disease-free survival in patients with superficial spreading melanomas, suggesting that p27Kip1 may play different roles in these two major pathological subgroups of malignant melanoma. Furthermore, p27Kip1 did not appear to have an influence on overall survival for either subgroup. When we examined the combined effect of p21WAF1/CIP1 (another cdk inhibitor) and p27Kip1 on clinical outcome, we found that analysis of these two cdk inhibitors together may have greater prognostic potential than either alone. In conclusion, our results suggest that virtually complete loss of p27Kip1 protein expression has potential importance as a prognostic indicator of early relapse in patients with nodular melanoma The results, furthermore, underscore the value of analyzing multiple cell cycle regulatory proteins to obtain the most reliable indication of prognosis.
 ...
PMID:Protein expression of the cell-cycle inhibitor p27Kip1 in malignant melanoma: inverse correlation with disease-free survival. 966 92

Thrombospondin 1 (TSP1) is an angiogenesis inhibitor that decreases tumor growth. We now report that TSP1 directly inhibits the proliferation of human melanoma cells. TSP1, peptides, and a recombinant fragment from the type I repeats, but not peptides that bind CD36 or CD47, inhibit the proliferation of A2058 melanoma cells. In contrast, chemotaxis is mediated by peptides or recombinant fragments from the procollagen, type I, type II, and cell-binding domains. The antiproliferative activity of TSP1 is mediated by a different signal transduction pathway than those mediating motility responses to the same protein. Activators of protein kinase A and protein kinase C inhibit chemotaxis but not the antiproliferative activity of TSP1, whereas the antiproliferative activity is reversed by inhibiting the tyrosine kinase or phosphatase activities. TSP1-mediated chemotaxis is partially dependent on a pertussis toxin (PT)-sensitive G-binding protein, whereas haptotaxis is not. Chemotaxis stimulated by the procollagen domain and the CD47-binding sequences from the COOH-terminal domain are also sensitive to PT, but responses to the type I and type III domains are not sensitive to PT. Residual chemotaxis to TSP1 in the presence of PT may therefore be mediated by the activities of the type I or type III repeats. Thus, TSP1 elicits several intracellular signals in melanoma cells that result from interactions with several domains of this protein and differentially affect growth and motility.
 ...
PMID:Differential roles of protein kinase C and pertussis toxin-sensitive G-binding proteins in modulation of melanoma cell proliferation and motility by thrombospondin 1. 967 84

Varicella-zoster virus (VZV) encodes five gene products that do not have homologs in herpes simplex virus. One of these genes, VZV open reading frame 32 (ORF32), is predicted to encode a protein of 16 kDa. VZV ORF32 protein was shown to be phosphorylated and located in the cytosol of virus-infected cells. Antibody to ORF32 protein immunoprecipitated 16- and 18-kDa phosphoproteins from VZV-infected cells. Since VZV encodes two protein kinases that might phosphorylate ORF32 protein, immunoprecipitations were performed with cells infected with VZV mutants unable to express either of the viral protein kinases. Cells infected with VZV unable to express the ORF66 protein kinase contained both the 16- and 18-kDa ORF32 phosphoproteins; however, cells infected with the VZV ORF47 protein kinase mutant showed only the 16-kDa ORF32 phosphoprotein. Treatment of [35S]methionine-labeled proteins with calf intestine alkaline phosphatase resulted in a decrease in size of the ORF32 proteins from 16 and 18 kDa to 15 and 17 kDa, respectively. VZV unable to express ORF32 protein replicated in human melanoma cells to titers similar to those seen with parental virus; however, VZV unable to express ORF32 was impaired for replication in U20S osteosarcoma cells. Thus, VZV ORF32 protein is posttranslationally modified by the ORF47 protein kinase. Since the VZV ORF47 protein kinase has recently been shown to be critical for replication in human fetal skin and lymphocytes, its ability to modify the ORF32 protein suggests that the latter protein may have a role for VZV replication in human tissues.
 ...
PMID:Varicella-zoster virus (VZV) ORF32 encodes a phosphoprotein that is posttranslationally modified by the VZV ORF47 protein kinase. 973 48

The cAMP-dependent pathway has been long presumed to play a critical role in mediating alpha-melanocyte-stimulating hormone (alpha-MSH)-induced pigmentation, but it has never been demonstrated that this pathway is obligatory. In order to determine whether the cAMP-dependent pathway is required for a alpha-MSH-induced pigmentation, we inhibited the activity of cAMP-dependent protein kinase (PKA), the main kinase mediating in this pathway, by introducing a physiologic cAMP-dependent protein kinase inhibitor (PKI) into S91 murine melanoma cells and then measuring pigment response after alpha-MSH stimulation. Cells were stably transfected either with the pMXX-PKI expression vector that encodes the active part of PKI (the amino terminal 1-31 amino acids) under a metallothionein-inducible promoter and the pSV2-Neo expression vector alone. As expected, treatment of transfected cells with 1 microM CdCl2 for 24 h induced the expression of PKI mRNA in cells transfected with both vectors, but not in cells transfected with the pSV2-Neo expression vector alone. Subsequent treatment of these transfected cells with alpha-MSH for 5-6 days in the continual presence of 1 microM CdCl2 resulted in inhibition of PKA activity by 30-40% in cells expressing PKI. Parallel measurements revealed that alpha-MSH-increased melanin content five- to six-fold in control cells transfected with pSV2-Neo alone, while there was only a two-fold increase in PKI-expressing cells, a 40-50% inhibition in alpha-MSH-induced total melanin content. alpha-MSH-induced tyrosinase activity and tyrosinase mRNA and protein levels measured in parallel were also inhibited by 40-50% in PKI-expressing cells compared to control cells transfected with pSV2-Neo alone. Together, these results demonstrate for the first time that activation of PKA through the cAMP-dependent pathway is required for optimal alpha-MSH-induced pigmentation.
 ...
PMID:Activation of cAMP-dependent protein kinase is required for optimal alpha-melanocyte-stimulating hormone-induced pigmentation. 977 Mar 55

Recent evidence has implicated cyclins and cyclin-dependent kinases in the evolution and progression of various malignancies. We studied the immunohistochemical expression of cyclin A, cyclin B, and cyclin-dependent kinase p34cdc2 in a broad spectrum of benign and malignant melanocytic lesions. Formalin-embedded, parrafin-fixed tissue sections from 66 malignant melanomas (MM) and 60 benign nevi were examined for the expression of these cell-cycle proteins. The results were compared with the standard proliferative marker Ki-67 and mitotic index. MM showed significantly higher immunoreactivity for cyclin A, cyclin B, p34cdc2, and Ki-67 compared with benign nevi. Cyclin A, p34cdc2, and Ki-67 displayed strong co-expression in MM. Overexpression of cyclin A and p34cdc2 correlated with histological type, mitotic activity, Ki-67 index, tumor thickness, Clark's level, and clinical outcome in MM. In invasive MM, increased immunostaining of cyclin A and Ki-67 were associated with decreased patient survival. These findings indicate potential roles of mitotic cyclins and cyclin-dependent kinases in the pathogenesis and progression of malignant melanoma.
 ...
PMID:Mitotic cyclins and cyclin-dependent kinases in melanocytic lesions. 978 46

The cyclin-dependent kinase (CDK) inhibitor p21WAF1/CIP1 is a multidomain, multifunctional protein and a candidate tumor suppressor. Here, we show that, among rationally designed and tumor-associated mutants of human p21 ectopically expressed in U-2-OS cells, those that are selectively deficient in binding to either cyclin or CDK are partially impaired in inhibiting endogenous CDK activities but efficiently promote assembly of active cyclin D/CDK4(6) complexes. These results provide mechanistic insights into the p21-cyclin/CDK interplay in vivo and suggest a functional subclassification of tumor-specific aberrations of p21. Intriguingly, the subclass exemplified by the melanoma-derived N50S mutant may promote tumorigenesis, by both attenuating CDK-inhibitory function and concomitantly activating the proto-oncogenic cyclin D-dependent kinases.
 ...
PMID:p21WAF1/CIP1 mutants deficient in inhibiting cyclin-dependent kinases (CDKs) can promote assembly of active cyclin D/CDK4(6) complexes in human tumor cells. 982 9

B16 murine melanoma cells selected in vivo for enhanced liver metastatic ability (B16-LS9) show on the one hand an increased expression and constitutive activation of the proto-oncogene c-met (the receptor for hepatocyte growth factor/scatter factor), and on the other hand a more differentiated phenotype, when compared to the parental cell line, B16-F1. Following this observation, we have tried to establish whether there is a direct relationship between differentiation and c-met expression in B16 melanoma cells. Treatment of these cells with differentiating agents indicated that c-met expression was strongly induced by melanocyte stimulating hormone, while retinoic acid had almost no influence. c-met induction was triggered by engagement of the melanocortin receptor, cAMP elevation and PKA/PKC(&agr;) activation, as respectively shown by the effects of ACTH, cAMP elevating agents and specific PK inhibitors. Regulation of c-met expression via the melanocortin receptor and cAMP raises the intriguing possibility that autocrine and/or paracrine mechanisms acting in vivo on this circuit might influence (through c-met expression and activation) the metastatic behavior of these tumor cells, which we have shown to be dependent on their c-met expression.
 ...
PMID:Regulation of c-met expression in B16 murine melanoma cells by melanocyte stimulating hormone. 997 97

The two genes encoding the PITSLRE protein kinase isoforms, CDC2L1 and CDC2L2, are localized to human chromosome band 1p36. The PITSLRE protein kinases are a part of the p34cdc2 supergene family. Several protein products of the CDC2L locus may be effector(s) in apoptotic signaling. The larger PITSLRE p110 isoforms appear to regulate some aspect of RNA splicing/transcription during the cell cycle. One or more of these genes may function as tumor suppressor genes in melanoma. Using fluorescence in situ hybridization, one allele of the CDC2L gene complex on chromosome 1 was either deleted or translocated in 8 of 14 different melanoma cell lines. We also observed mutations in the 5' promoter region of the CDC2L1 gene in four different cell lines relative to normal melanocytes using PCR-SSCP analysis and direct DNA sequencing. Western blot analysis revealed decreased level of PITSLRE protein expression in several cell lines, as well as in four surgical malignant melanoma specimens relative to normal melanocytes. Thus, the decreased PITSLRE protein expression appears to result from deletion of the CDC2L alleles and possibly by mutations within the 5' promoter region. We propose that aberrations in the CDC2L genes may contribute to the pathogenesis or progression of melanoma.
 ...
PMID:Abnormalities in the p34cdc2-related PITSLRE protein kinase gene complex (CDC2L) on chromosome band 1p36 in melanoma. 1147 3

Beta-Catenin has a critical role in E-cadherin-mediated cell-cell adhesion, and it also functions as a downstream signaling molecule in the wnt pathway. Mutations in the putative glycogen synthase kinase 3beta phosphorylation sites near the beta-catenin amino terminus have been found in some cancers and cancer cell lines. The mutations render beta-catenin resistant to regulation by a complex containing the glycogen synthase kinase 3beta, adenomatous polyposis coli, and axin proteins. As a result, beta-catenin accumulates in the cytosol and nucleus and activates T-cell factor/ lymphoid enhancing factor transcription factors. Previously, 6 of 27 melanoma cell lines were found to have beta-catenin exon 3 mutations affecting the N-terminal phosphorylation sites (Rubinfeld B, Robbins P, Elgamil M, Albert I, Porfiri E, Polakis P: Stabilization of beta-catenin by genetic defects in melanoma cell lines. Science 1997, 275:1790-1792). To assess the role of beta-catenin defects in primary melanomas, we undertook immunohistochemical and DNA sequencing studies in 65 melanoma specimens. Nuclear and/or cytoplasmic localization of beta-catenin, a potential indicator of wnt pathway activation, was seen focally within roughly one third of the tumors, though a clonal somatic mutation in beta-catenin was found in only one case (codon 45 Ser-->Pro). Our findings demonstrate that beta-catenin mutations are rare in primary melanoma, in contrast to the situation in melanoma cell lines. Nonetheless, activation of beta-catenin, as indicated by its nuclear and/or cytoplasmic localization, appears to be frequent in melanoma, and in some cases, it may reflect focal and transient activation of the wnt pathway within the tumor.
 ...
PMID:Frequent nuclear/cytoplasmic localization of beta-catenin without exon 3 mutations in malignant melanoma. 1002 90

Since tumor promoter benzoyl peroxide (BPO) mimics phorbol esters in some aspects, its effects on protein kinase C (PKC) were previously studied. However, in those studies due to the presence of thiol agents in the PKC preparations, the sensitive reaction of BPO with redox-active cysteine residues in PKC was not observed. In this study, by excluding thiol agents present in the purified PKC preparation, low concentrations of BPO modified PKC, resulting in the loss of both kinase activity and phorbol ester binding (IC50 = 0. 2 to 0.5 microM). This modification, which was not dependent on transition metals, was totally blocked by a variety of thiol agents including GSH, which directly reacted with BPO. Substoichiometric amounts of BPO (0.4 mol/mol of PKC) oxidized two sulfhydryls in PKC and inactivated the enzyme which was readily reversed by dithiothreitol. The regulatory domain having zinc thiolate structures supporting the membrane-inserting region provided the specificity for PKC reaction with BPO, which partitioned into the membrane. Unlike H2O2, BPO did not induce the generation of the Ca2+/lipid-independent activated form of PKC. Other redox-sensitive enzymes such as protein kinase A, phosphorylase kinase, and protein phosphatase 2A required nearly 25- to 100-fold higher concentrations of BPO for inactivation. BPO also inactivated PKC in a variety of cell types. In the JB6 (30 P-) nonpromotable cell line and other normal cell lines, where BPO was more cytotoxic, it readily inactivated PKC due to a slow reversibility of this inactivation by the cell. However, in the JB6 (41 P+) promotable cell line, C3H10T1/2 and B16 melanoma cells, where BPO was less cytotoxic, it did not readily inactivate PKC due to a rapid reversibility of this inactivation by an endogenous mechanism. Nevertheless, BPO inactivated PKC at an equal rate in the homogenates prepared from all these cell types. Inclusion of NADPH reversed this inactivation in the homogenates to a different extent, presumably due to a difference in distribution of a protein disulfide reductase, which reverses this oxidative modification. BPO-induced modification of PKC occurred independent of the cellular status of GSH. However, externally added GSH and cell-impermeable thiol agents prevented the BPO-induced modification of PKC. Since BPO readily partitions into membranes, its reaction with redox-cycling thiols of membrane proteins such as PKC may trigger epigenetic events to prevent cytotoxicity, but favor tumor promotion.
 ...
PMID:Tumor promoter benzoyl peroxide induces sulfhydryl oxidation in protein kinase C: its reversibility is related to the cellular resistance to peroxide-induced cytotoxicity. 1006 46


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