Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1522102 (Melanoma)
 7,698 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Peptides from the three type I repeats of human endothelial cell thrombospondin, containing the consensus sequence-Trp-Ser-Xaa-Trp-, bind to sulfated glycoconjugates including heparin and sulfatide. The peptides are potent inhibitors for the binding of thrombospondin, laminin, or apolipoprotein E to these ligands. The thrombospondin peptides that inhibit heparin binding, but not adjacent peptides from the thrombospondin sequence containing the previously identified adhesive motif Val-Thr-Cys-Gly, promote melanoma cell adhesion when immobilized on plastic. Melanoma cell adhesion to the immobilized peptides is inhibited by soluble recombinant heparin-binding fragment of thrombospondin. The peptides also inhibit heparin-dependent binding of thrombospondin or laminin to human melanoma cells. The active peptides lack any previously identified heparin-binding consensus sequences and most do not contain any basic amino acids. Studies with homologous peptides showed that the tryptophan residues are required for binding. Adjacent basic residues in the second type I repeat enhance binding to heparin but not to sulfatide. Thus the type I peptides of thrombospondin define a distinct class of heparin-binding peptides.
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PMID:Heparin- and sulfatide-binding peptides from the type I repeats of human thrombospondin promote melanoma cell adhesion. 155 10

The large subunit of herpes simplex virus type 2 ribonucleotide reductase (ICP10) is a multifunctional protein that contains a serine-threonine protein kinase (PK) activity (Nelson, J. W., Zhu, J. , Smith, C. C., Kulka, M., and Aurelian, L. (1996) J. Biol. Chem. 271, 17021-17027). Phylogenetic analyses indicated that ICP10 PK belongs to a distinct subfamily of growth factor receptor serine-threonine PKs that are characterized by their ability to function with a limited number of conserved catalytic motifs (Hunter, J. C. R., Smith, C. C., and Aurelian, L. (1995) Int. J. Onc. 7, 515-522). Here, we report the isolation and characterization of a novel gene, designated H11, that contains an open reading frame of 588 nucleotides, which encodes a protein similar to ICP10 PK. The H11 protein has Mn(2+)-dependent serine-threonine-specific PK activity as determined with a GST-H11 fusion protein and by immununocomplex PK/immunoblotting assays of 293 cells transfected with a H11 eukaryotic expression vector. PK activity is ablated by mutation of Lys(113) within the presumtive catalytic motif II (invariant Lys). 293 cells stably transfected with H11 acquire anchorage-independent growth. Endogenous H11 RNA and the H11 phosphoprotein are expressed in melanoma cell lines and primary melanoma tissues at levels higher than in normal melanocytes and in benign nevi. Melanoma cell proliferation is inhibited by treatment with antisense oligonucleotides that inhibit H11 translation, suggesting that H11 expression is associated with cell growth.
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PMID:A novel human gene similar to the protein kinase (PK) coding domain of the large subunit of herpes simplex virus type 2 ribonucleotide reductase (ICP10) codes for a serine-threonine PK and is expressed in melanoma cells. 1083 16

Melanoma is a form of skin cancer that has a poor prognosis and which is on the rise in Western populations. If detected early, it is easily treated by surgical excision. However, once melanoma metastasises it is notoriously resistant to existing therapies and for many patients the outlook is dismal. Thus a full description of melanoma etiology and a full understanding of the genetic lesions that underlie this disease is required to allow us to develop new and effective therapeutic strategies for its treatment. RAF proteins are a family of serine/threonine-specific protein kinases that form part of a signalling module that regulates cell proliferation, differentiation and survival. In mammals there are three isoforms, A-RAF, B-RAF and C-RAF, and recently it was shown that the B-RAF isoform is mutated in a high proportion of melanomas. In light of these exciting findings, we review what we have learned about B-RAF and its role in cutaneous melanoma.
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PMID:The role of B-RAF in melanoma. 1578 79

The androgen receptor (AR) is a ligand-activated transcription factor that interacts with coregulatory proteins during androgen-dependent gene regulation. Melanoma antigen gene protein 11 (MAGE-11) is an AR coregulator that specifically binds the AR NH(2)-terminal FXXLF motif and modulates the AR NH(2)- and carboxyl-terminal N/C interaction to increase AR transcriptional activity. Here we demonstrate that epidermal growth factor (EGF) signaling increases androgen-dependent AR transcriptional activity through the posttranslational modification of MAGE-11. EGF in the presence of dihydrotestosterone stabilizes the AR-MAGE complex through the site-specific phosphorylation of MAGE-11 at Thr-360 and ubiquitinylation at Lys-240 and Lys-245. The time-dependent EGF-induced increase in AR transcriptional activity by MAGE-11 is mediated through AR activation functions 1 and 2 in association with the increased turnover of AR and MAGE-11. The results reveal a dynamic mechanism whereby growth factor signaling increases AR transcriptional activity through the covalent modification of an AR-specific coregulatory protein. Sequence conservation of the MAGE-11 phosphorylation and ubiquitinylation sites throughout the MAGE gene family suggests common regulatory mechanisms for this group of cancer-testis antigens.
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PMID:Epidermal-growth-factor-dependent phosphorylation and ubiquitinylation of MAGE-11 regulates its interaction with the androgen receptor. 1821 60

Stem cell factor (SCF) activates a variety of signals associated with stimulation of proliferation, differentiation, migration, and survival in melanocytes. However, the molecular mechanisms by which SCF and its receptor Kit activates these signaling pathways simultaneously and independently are still poorly defined. Here, we examined whether SCF induces ezrin/radixin/moesin (ERM) proteins phosphorylation as a downstream target of PI3K in melanocytes. ERM proteins are cross-linkers between the plasma membrane and the actin cytoskeleton and are activated by phosphorylation of a C-terminal threonine residue. Our results demonstrated that SCF-induced ERM proteins phosphorylation on threonine residue and Rac1 activation in cultured normal human melanocytes through the activation of PI3K. The functional role of phosphorylated-ERM proteins was examined using melanocytes infected with adenovirus carrying a dominant negative mutant (Ala-558, TA) or wild type of moesin. In the TA moesin-overexpressing melanocytes, SCF-induced cell proliferation and migration were inhibited. Thus, our results indicate that phosphorylation of ERM proteins plays an important role in the regulation of SCF-induced melanocyte proliferation and migration.
Pigment Cell Melanoma Res 2009 Feb
PMID:Stem cell factor induces ERM proteins phosphorylation through PI3K activation to mediate melanocyte proliferation and migration. 1898 38

Protein kinase C (PKC) is a heterogeneous family of serine/threonine protein kinases that have different biological effects in normal and neoplastic melanocytes (MCs). To explore the mechanism behind their differential response to PKC activation, we analyzed the expression profile of all nine PKC isoforms in normal human MCs, HPV16 E6/E7 immortalized MCs, and a panel of melanoma cell lines. We found reduced PKCbeta and increased PKCzeta and PKCiota expression at both the protein and mRNA levels in immortalized MCs and melanoma lines. We focused on PKCbeta as it has been functionally linked to melanin production and oxidative stress response. Re-expression of PKCbeta in melanoma cells inhibited colony formation in soft agar, indicating that PKCbeta loss in melanoma is important for melanoma growth. PKCbetaII, but not PKCbetaI, was localized to the mitochondria, and inhibition of PKCbeta significantly reduced UV-induced reactive oxygen species (ROS) in MCs with high PKCbeta expression. Thus alterations in PKCbeta expression in melanoma contribute to their neoplastic phenotype, possibly by reducing oxidative stress, and may constitute a selective therapeutic target.
Pigment Cell Melanoma Res 2010 Apr
PMID:Functional alterations in protein kinase C beta II expression in melanoma. 2001 21

Protein kinase C (PKC) is a multigene family of serine/threonine protein kinases involved in cell signaling pathways of proliferation and motility. PKC interacts with Rho GTPases in the regulation of the actin cytoskeleton. The PKC-alpha isozyme binds the Rho GTPase cdc42, and both are coordinated with the Rac-phosphatidylinositol-3 kinase (PI3K) signaling pathway in melanoma cell invasion and migration on extracellular matrix proteins. To further define the role of PKC-alpha in melanoma cell migration, we tested the effect of PDBu and Ca dependent activation of PKC-alpha as well as treatment with the PKC-alpha inhibitors calphostin C and Go6976. Furthermore, we transfected siRNA targeted against PKC-alpha into human melanoma cells and performed time-lapse analysis of cell migration followed by western immunoblotting. We found that significant enhancement of cell migration at 0.5 h after PDBu treatment directly correlated with Ca dependent activation of PKC-alpha and was inhibited by the PKC-alpha inhibitor calphostin C. PKC-alpha siRNA transfection nearly abrogated PKC-alpha expression and significantly reduced melanoma cell migration compared with siRNA controls. These findings provide further evidence that PKC-alpha plays an important role in melanoma cell migration and may have implications in therapies designed to disrupt melanoma cell motility by alteration of PKC-alpha signaling.
Melanoma Res 2010 Jun
PMID:RNAi-mediated knockdown of protein kinase C-alpha inhibits cell migration in MM-RU human metastatic melanoma cell line. 2021 3

MicroRNAs-221 and -222 are highly upregulated in several solid tumors, including melanomas. We demonstrate that the proto-oncogene ETS-1, involved in the pathogenesis of cancers of different origin, is a transcriptional regulator of miR-222 by direct binding to its promoter region. Differently from 293FT cells or early stage melanomas, where unphosphorylated ETS-1 represses miR-222 transcription, in metastatic melanoma the constitutively Thr-38 phosphorylated fraction of ETS-1 induces miR-222. Despite its stepwise decreased expression along with melanoma progression, the oncogenic activity of ETS-1 relies on its RAS/RAF/ERK-dependent phosphorylation status more than on its total amount. To close the loop, we demonstrate ETS-1 as a direct target of miR-222, but not miR-221, showing the novel option of their uncoupled functions. In addition, a spatial redistribution of ETS-1 protein from the nucleus to the cytoplasm is also evidenced in advanced melanoma cells. Finally, in vivo studies confirmed the contribution of miR-222 to the increased invasive potential obtained by ETS- silencing.
Pigment Cell Melanoma Res 2011 Oct
PMID:Constitutive activation of the ETS-1-miR-222 circuitry in metastatic melanoma. 2171 53

The protein kinase C (PKC) family of serine/threonine protein kinases is a heterogeneous group of enzymes receiving and integrating signals involved in both normal melanocyte biology and melanoma pathology. Alterations in PKC enzyme expression and activation contribute to the malignant phenotype of melanoma in both oncogenic and tumor suppressive roles. Delineating the diverse and often context-dependent functions of PKC enzymes in melanocyte/melanoma biology is key to capitalize on these kinases as drug targets. This review summarizes several of the diverse functions of PKC in melanocyte and melanoma biology with a focus on PKC enzyme regulation and function.
Pigment Cell Melanoma Res 2012 Jul
PMID:Specifying protein kinase C functions in melanoma. 2257 92

Melanoma is the fatal form of skin cancer. Herein, a three-dimensional quantitative structure-activity relationship study on a series of 105 colchicine binding site-targeted 2-arylthiazolidine-4-carboxylic acid amides (ATCAA) derivatives as melanoma antagonists was conducted. The optimal CoMSIA model yields a Q(2) of 0.556, R(2)(ncv) of 0.833 and R(2)(pred) of 0.757, while the CoMFA yields a Q(2) of 0.569, R(2)(ncv) of 0.812 and R(2)(pred) of 0.589. In addition, molecular docking was also carried out. The study results demonstrated that: (1) Bulky substituents in Rings C and D significantly increase the biological activity of compounds while decrease the activity at Rings A and B; (2) Electropositive groups at Rings A and B as well as electronegative groups at Ring C help to increase the activity; (3) HB donor favors Rings A and D while HB acceptor favors Rings B and C. Besides, a statistical analysis of the key amino acids as well as the ones forming HB with various antagonists of the colchicine binding site was conducted based on 34 essays and found HB to be the key interaction that MTAs have with the colchicine binding site and that Ala 250, Asn 258, Thr 179, Lys 254 and Lys 352 are vital in the composition of the site and the formation of HB. The results of this study provide useful information on designing antagonists with improved activity and insight on the composition of the colchicine binding site.
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PMID:Structural analysis for colchicine binding site-targeted ATCAA derivatives as melanoma antagonists. 2362 86


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