Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

MCAM/MUC18 is a cell-surface glycoprotein of 113 kDa, originally identified as a melanoma antigen, whose expression is associated with tumor progression and the development of metastatic potential. We have previously shown that enforced expression of MCAM/MUC18 in primary cutaneous melanoma led to increased tumor growth and metastatic potential in nude mice. The mechanism for up-regulation of MCAM/MUC18 during melanoma progression is unknown. Here we show that up-regulation of MCAM/MUC18 expression in highly metastatic cells correlates with loss of expression of the transcription factor AP-2. The MCAM/MUC18 promoter contains four binding sites for AP-2, and electrophoretic mobility shift assay gels demonstrated that the AP-2 protein bound directly to the MCAM/MUC18 promoter. Transfection of AP-2 into highly metastatic A375SM melanoma cells (AP-2-negative and MCAM/MUC18-positive) inhibited MCAM/MUC18 promoter-driven chloramphenicol acetyltransferase reporter gene in a dose-dependent manner. MCAM/MUC18 mRNA and protein expression were down-regulated in AP-2-transfected but not in control cells. In addition, re-expression of AP-2 in A375SM cells inhibited their tumorigenicity and metastatic potential in nude mice. These results indicate that the expression of MCAM/MUC18 is regulated by AP-2 and that enforced AP-2 expression suppresses tumorigenicity and metastatic potential of human melanoma cells, possibly by down-regulating MCAM/MUC18 gene expression. Since AP-2 also regulates other genes that are involved in the progression of human melanoma such as c-KIT, E-cadherin, MMP-2, and p21(WAF-1), we propose that loss of AP-2 is a crucial event in the development of malignant melanoma.
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PMID:Loss of AP-2 results in up-regulation of MCAM/MUC18 and an increase in tumor growth and metastasis of human melanoma cells. 963 18

The molecular changes associated with the transition of melanoma cells from radial growth phase to vertical growth phase (metastatic phenotype) are not well defined. Our recent studies have demonstrated that the two tumor suppressor genes, p53 and p16/CDKN2, do not play a major role in the acquisition of the metastatic phenotype in human melanoma. Mutations in p53 are infrequent and do not correlate with the metastatic potential of human melanoma cells while p16/CDKN2 abnormalities are frequent, but are not pre-requisite for the acquisition of the metastatic phenotype. On the other hand, the tyrosine-kinase receptor c-KIT and the cell adhesion molecule MCAM/MUC-18 play active roles in the progression of human melanoma. Metastatic melanoma cells overexpress MCAM and do not express the c-KIT receptor. Enforced c-KIT expression in metastatic cells significantly inhibited their growth and metastatic potential in nude mice. Furthermore, exposure of c-KIT-positive melanoma cells in vitro and in vivo to stem cell factor (SCF), the ligand for c-KIT, triggered apoptosis of these cells but not of normal melanocytes. Ectopic expression of MCAM into primary cutaneous melanoma cells enhanced their tumorigenicity and metastatic ability in vivo. We found that both genes, c-KIT and MCAM, are regulated by the transcription factor AP-2 and that metastatic melanoma cells do not express AP-2. We therefore propose that loss of AP-2 might be a crucial event in the progression of human melanoma.
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PMID:Molecular changes in human melanoma metastasis. 981 May 13

Cutaneous malignant melanoma (CMM) is a common skin cancer. About 50% of CMM sporadic tumours have lost one copy of the chromosome 9p21 region. To identify genes involved in the initiation and/or progression of CMM we have characterised the 9p21 melanoma deleted region and screened the human expressed sequence tag (EST) databases (dbEST) to search for expressed genes. We have identified the gene that encodes the human orthologue of the rat phospholipase A2 activating protein (PLAP). PLAP was considered a potential candidate to be involved in malignant melanoma because it maps to the critical region for CMM and because the PLA2 gene has been identified as a modifier of the APC gene, responsible for the adenomatous polyposis phenotype in the mouse. PLAP encodes a protein of 738 amino acids and has a high DNA (90%) and protein (97%) sequence similarity with the rat and mouse PLAP protein. PLAP has a region of WD40 repeats in the amino-terminus, which allows us to include this protein in the superfamily of beta-transducin proteins. Northern blot hybridisation gave a fragment of 4.5 kb, with higher expression in heart compared to other tissues. PLAP was localised at chromosome 9p21, between marker AFM218xg11 and TEK. SSCP analysis of the coding region of PLAP revealed no variants in the studied samples, but one of six CMM samples analysed by RT-PCR showed specific inactivation of PLAP. Despite PLAP's important role in mediating several cellular responses and its localisation to the chromosome 9p21 region deleted in CMM, it is unlikely that point mutations or deletions in the coding region of PLAP are responsible for the initiation or progression of CMM. Further studies on PLAP inactivation should be performed to clarify its potential involvement in CMM.
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PMID:Cloning of the human phospholipase A2 activating protein (hPLAP) gene on the chromosome 9p21 melanoma deleted region. 1057 Oct 45

The molecular changes associated with the transition of melanoma cells from radial growth phase (RGP) to vertical growth phase [(VGP), metastatic phenotype] are not very well defined. We previously demonstrated that expression of the cell-surface adhesion molecule MCAM/MUC18 correlates directly with the metastatic potential of human melanoma cells. In addition, the progression of human melanoma towards the metastatic phenotype is associated with loss of expression of the tyrosine-kinase receptor c-KIT. In this review, I will summarize our recent studies demonstrating that the expression of both genes is regulated by the AP-2 transcription factor. Moreover, we have observed a loss of AP-2 expression in metastatic melanoma cells. Re-expression of AP-2 in the highly metastatic A375SM cells decreased their tumorigenicity and inhibited their metastatic potential in nude mice. MCAM/MUC18 mRNA and protein expression was significantly down-regulated while c-KIT expression was up-regulated in the AP-2-transfected cells. To further investigate the role of AP-2 in the progression of human melanoma, we attempted to inactivate AP-2 in primary cutaneous melanoma by using a dominant-negative AP-2, or the AP-2B gene. Expression of AP-2B in SB-2 cells augmented their tumorigenicity in nude mice, and upregulated MMP-2 expression and activity. As AP-2 also regulates other genes that are involved in the progression of human melanoma such as E-cadherin, p21/WAF-1, HER2/neu, Bcl-2, FAS/APO-1, IGF-R-1, VEGF and the thrombin receptor (PAR-1), we therefore propose that loss of AP-2 is a crucial event in the development of malignant melanoma. In addition, the transition of melanoma cells from RGP to VGP is also associated with over-expression of the transcription factors CREB and ATF-1. The notion that the balance between AP-2 and CREB/ATF-1 expression determines the progression of melanoma cells towards the metastatic phenotype will be discussed.
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PMID:Gene regulation in melanoma progression by the AP-2 transcription factor. 1131 Jul 95

We recently have introduced the term vasculogenic mimicry to describe the unique ability of aggressive melanoma tumor cells to form tubular structures and patterned networks in three-dimensional culture, which "mimics" embryonic vasculogenic networks formed by differentiating endothelial cells. In the current study, we address the biological significance of several endothelial-associated molecules (revealed by microarray analysis) with respect to expression and function in highly aggressive and poorly aggressive human cutaneous melanoma cell lines (established from the same patient). In a comparative analysis, CD31 was not expressed by any of the melanoma cell lines, whereas TIE-1 (tyrosine kinase with Ig and epidermal growth factor homology domains-1) was strongly expressed in the highly aggressive tumor cells with a low level of expression in one of the poorly aggressive cell lines. Vascular endothelial (VE)-cadherin was exclusively expressed by highly aggressive melanoma cells and was undetectable in the poorly aggressive tumor cells, suggesting the possibility of a vasculogenic switch. Down-regulation of VE-cadherin expression in the aggressive melanoma cells abrogated their ability to form vasculogenic networks and directly tested the hypothesis that VE-cadherin is critical in melanoma vasculogenic mimicry. These results highlight the plasticity of aggressive melanoma cells and call into question their possible genetic reversion to an embryonic phenotype. This finding could pose a significant clinical challenge in targeting tumor cells that may masquerade as circulating endothelial cells or other embryonic-like stem cells.
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PMID:Expression and functional significance of VE-cadherin in aggressive human melanoma cells: role in vasculogenic mimicry. 1141 60

Melanoma begins with benign nevi and progresses to radial growth phase (RGP) and to vertical growth phase [(VGP), metastatic phenotype]. The molecular changes associated with these transitions are not yet well defined. However, transcriptional regulation of some genes that are critical in melanoma progression is beginning to be elucidated. The first part of this review will focus on our recent studies demonstrating that progression of human melanoma is associated with loss of expression of the transcription factor AP-2. In metastatic melanoma cells, this loss resulted in overexpression of MCAM/MUC18 and MMP-2, and lack of expression of c-KIT. In further investigations, we inactivated AP-2 in SB-2 primary cutaneous melanoma cells by using a dominant-negative AP-2, the AP-2B gene. Expression of AP-2B in SB-2 cells augmented their tumorigenicity in nude mice and upregulated MMP-2 expression and activity. We have also recently demonstrated that loss of AP-2 expression in metastatic melanoma cells resulted in overproduction of the thrombin receptor, PAR-1. Other studies have shown that AP-2 regulates additional genes involved in melanoma development and progression, including E-cadherin, p21/WAF-1, HER2, Bcl-2, FAS/APO-1, IGF-R-1, and VEGF. We propose that loss of AP-2 is crucial in the development of malignant melanoma. Additionally, the transition of melanoma cells from RGP to VGP is associated with overexpression of two transcription factors, CREB and ATF-1, both of which may act as survival factors for human melanoma cells. The second part of the review will briefly discuss the role of other transcription factors, including ATF-2, SNAIL, MITF, and NFkappaB in the progression of human melanoma and will summarize recent knowledge on how changes in the expression of these transcription factors contribute to acquisition of the metastatic phenotype in human melanoma.
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PMID:Transcriptional regulation of metastasis-related genes in human melanoma. 1274 83

The BRAF gene, encoding a mitogen-activated protein kinase kinase kinase, is mutated in several human cancers, with the highest incidence occurring in cutaneous melanoma. The activating V599E mutation accounted for 80% of all mutations detected in cutaneous melanoma cell lines. Reconstitution experiments have shown that this mutation increases ectopically expressed B-Raf kinase activity and induces NIH3T3 cell transformation. Here we used tumor-derived cell lines to characterize the activity of endogenous mutated B-Raf protein and assess its specific role in transformation. We show that three cell lines (OCM-1, MKT-BR, and SP-6.5) derived from human choroidal melanoma, the most frequent primary ocular neoplasm in humans, express B-Raf containing the V599E mutation. These melanoma cells showed a 10-fold increase in endogenous B-RafV599E kinase activity and a constitutive activation of the MEK/ERK pathway that is independent of Ras. This, as well as melanoma cell proliferation, was strongly diminished by siRNA-mediated depletion of the mutant B-Raf protein. Moreover, blocking B-RafV599E-induced ERK activation by different experimental approaches significantly reduced cell proliferation and anchorage-independent growth of melanoma cells. Finally, quantitative immunoblot analysis allowed us to identify signaling and cell cycle proteins that are differentially expressed between normal melanocytes and melanoma cells. Although the expression of signaling molecules was not sensitive to U0126 in melanoma cells, the expression of a cluster of cell cycle proteins remained regulated by the B-RafV599E/MEK/ERK pathway. Our results pinpoint this pathway as an important component in choroidal melanoma cell lines.
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PMID:Mutation of B-Raf in human choroidal melanoma cells mediates cell proliferation and transformation through the MEK/ERK pathway. 1291 19

The v-raf murine sarcoma viral homolog B1 (BRAF) gene, one of the human isoforms of RAF, is activated by Ras, leading to cooperative effects in cells responsive to growth factor signals. Recently, somatic missense mutations of the BRAF gene have been detected in more than 66% of malignant melanomas of the skin. We analyzed 42 malignant melanomas of the uvea, 3 corresponding liver metastases, and 10 cutaneous melanomas for possible BRAF mutations: after microdissection, mutation analysis of BRAF and KRAS was performed. The expression of extracellular-regulated kinase 1 and 2 (ERK1/2), an important downstream point of convergence in the Ras-RAF-MEK-Erk pathway, was analyzed immunohistochemically. Interestingly, we failed to detect activating BRAF mutations in uvea melanomas and their corresponding liver metastases. There were no mutations of BRAF in corresponding non-neoplastic uvea specimens, although we detected three BRAF mutations in sporadic cutaneous melanoma that led to a substitution of valine by glutamic acid at position 599 (V599E). KRAS mutations were detected in 1 of 10 cutaneous melanoma but not in uveal or metastatic melanoma. Despite the lack of activating mutations in the BRAF gene, we identified constitutively activated ERK in almost all (86%) uveal melanoma tissues tested but not in corresponding normal retina or uveal cells. Our data indicate that BRAF gene mutations are rare to absent events in uveal melanoma. The finding of activated Erk suggests a causative role for MAPK activation in uveal melanoma independent of activating BRAF or RAS mutations.
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PMID:Absence of mutations of the BRAF gene and constitutive activation of extracellular-regulated kinase in malignant melanomas of the uvea. 1469 Dec 95

Both genetic and environmental factors confer a significantly increased risk for cutaneous melanoma. This review discusses hereditary predisposition to the disease, focusing on the high-penetrance candidate genes INK4A/ARF and CDK4, and on pathogenetic mechanisms of mutations in those genes. As known mutations account for approximately 25 to 40% of melanoma families reported to date, it is clear that other melanoma genes and other mechanisms underlying predisposition remain to be discovered. Low penetrance susceptibility genes such as melanocortin 1 receptor and their modifying effect, also in concert with UV radiation, are likely to be implicated. Recent reports on a new candidate locus on chromosome 1p22 and somatic mutations in genes of the RAS-RAF-ERK signalling pathway raise interesting questions for further investigation.
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PMID:Genetics of melanoma susceptibility. 1473 79

Glomeruloid microvascular proliferations (GMPs), which are focal proliferative buddings of endothelial cells resembling a renal glomerulus, can be induced experimentally by adenoviral transfer of VEGF-A(165). We recently found that GMPs were present in 13-23% of various human tumours (melanoma, breast-, endometrial- and prostate cancer), and this vascular signature was significantly associated with an impaired prognosis. In the present study, a series of 202 vertical growth phase melanomas were examined for the expression of various angiogenic factors and their receptors. Presence of GMP was associated with increased expression in tumour endothelium of the VEGF-A receptors KDR, FLT-1 and neuropilin-1, as well as VEGF-D protein. Thrombospondin-1 staining in the tumour stroma showed the same relationship. Endothelial cell expression of VEGF-A was increased in GMP endothelium when compared with other intra-tumoural vessels. In contrast, GMP expression of bFGF was decreased. Our findings suggest an important role of VEGF-A and its receptors in GMP formation in human cutaneous melanoma.
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PMID:Increased expression of VEGF-receptors (FLT-1, KDR, NRP-1) and thrombospondin-1 is associated with glomeruloid microvascular proliferation, an aggressive angiogenic phenotype, in malignant melanoma. 1516 98


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