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)

The effects of all-trans retinoic acid on the differentiation and proliferation of immature melanocyte precursors were studied. NCC-melb4 cells are an immortal cloned cell line established from mouse neural crest cells using a single-cell cloning method. These cells were positive for tyrosinase-related protein 1, tyrosinase-related protein 2 and KIT, but were negative for tyrosinase and had no dihydroxyphenylalanine reaction. They contained only stage I melanosomes without any melanosomes in more advanced stages. After treatment with all-trans retinoic acid, many of the cells became tyrosinase- and dihydroxyphenylalanine-reaction-positive, changed from polygonal to dendritic in shape, and had stage III to IV melanosomes. These findings indicate that treatment with all-trans retinoic acid induced the differentiation of NCC-melb4 cells. Reverse transcription polymerase chain reaction analysis revealed a marked increase in expression of microphthalmia-associated transcription factor mRNA after all-trans retinoic acid treatment, suggesting that microphthalmia-associated transcription factor may be the key molecule in this event. Enhanced expression of protein kinase Calpha following treatment with all-trans retinoic acid was also demonstrated. The proliferation of NCC-melb4 cells was inhibited by all-trans retinoic acid in a dose-dependent manner. Increased apoptosis after all-trans retinoic acid treatment was observed by electron microscopy, the TUNEL method, DNA fragmentation assay, and flow cytometry. All-trans retinoic acid upregulated caspase-3 and downregulated bcl-2. Electron microscopy showed that apoptotic cells contained melanosomes of advanced stages, suggesting that mature melanocytes may tend to undergo apoptosis after all-trans retinoic acid treatment. This study provides important clues towards understanding the roles and working mechanisms of retinoic acids in melanocyte development and melanogenesis.
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PMID:All-trans retinoic acid induces differentiation and apoptosis of murine melanocyte precursors with induction of the microphthalmia-associated transcription factor. 1185 73

Clear cell sarcoma of soft tissue (CCSST), also known as malignant melanoma of soft parts, represents a rare lesion of the musculoskeletal system usually affecting adolescents and young adults. CCSST is typified by a chromosomal t(12;22)(q13;q12) translocation resulting in a fusion between the Ewing sarcoma gene (EWSR1) and activating transcription factor 1 (ATF1), of which the activity in nontransformed cells is regulated by cyclic AMP. Our aim was to identify critical differentially expressed genes in CCSST tumor cells in comparison with other solid tumors affecting children and young adults to better understand signaling pathways regulating specific features of the development and progression of this tumor entity. We applied Affymetrix Human Genome U95Av2 oligonucleotide microarrays representing approximately 12,000 genes to generate the expression profiles of the CCSST cell lines GG-62, DTC-1, KAO, MST2, MST3, and Su-CC-S1 in comparison with 8 neuroblastoma, 7 Ewing tumor, and 6 osteosarcoma cell lines. Subsequent hierarchical clustering of microarray data clearly separated all four of the tumor types from each other and identified differentially expressed transcripts, which are characteristically up-regulated in CCSST. Statistical analysis revealed a group of 331 probe sets, representing approximately 300 significant (P < 0.001) differentially regulated genes, which clearly discriminated between the CCSST and other tumor samples. Besides genes that were already known to be highly expressed in CCSST, like S100A11 (S100 protein) or MITF (microphthalmia-associated transcription factor), this group shows an obvious portion of genes that are involved in cyclic AMP response or regulation, in pigmentation processes, or in neuronal structure and signaling. Comparison with other expression profile analyses on neuroectodermal childhood tumors confirms the high robustness of this strategy to characterize tumor entities based on their gene expression. We found the avian erythroblastic leukemia viral oncogene homologue 3 (ERBB3) to be one of the most dramatically up-regulated genes in CCSST. Quantitative real-time PCR and Northern blot analysis verified the mRNA abundance and confirmed the absence of the inhibitory transcript variant of this gene. The protein product of the member of the epidermal growth factor receptor family ERBB3 could be shown to be highly present in all of the CCSST cell lines investigated, as well as in 18 of 20 primary tumor biopsies. In conclusion, our data demonstrate new aspects of the phenotype and the biological behavior of CCSST and reveal ERBB3 to be a useful diagnostic marker.
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PMID:Expression profiling of t(12;22) positive clear cell sarcoma of soft tissue cell lines reveals characteristic up-regulation of potential new marker genes including ERBB3. 1515 91

Efficient and specific signaling by mitogen-activated protein kinases (MAPKs) is enhanced by docking sites found on many MAPK substrates and regulators. Here we show that the MAPKs ERK1 and ERK2 form a stable complex (Kd approximately 6 microm) with their substrate the microphthalmia-associated transcription factor (MITF). Complex formation requires a domain of MITF of approximately 100 residues that is nearby, but C-terminal to, the MAPK phosphorylation site at Ser73. MITF derivatives lacking this ERK-binding domain do not bind ERK2 and are phosphorylated less efficiently by ERK2. The ERK-binding domain of MITF bears no obvious resemblance to previously characterized MAPK docking motifs; in particular, it does not contain a consensus D-site. Consistent with this, ERK2-MITF binding does not require the integrity of the CD/sevenmaker region of ERK2. Furthermore, D-site peptides, which are able to potently inhibit ERK2-mediated phosphorylation of the Elk-1 transcription factor (IC50= 3 microm), are relatively poor inhibitors of ERK2-mediated phosphorylation of MITF, exhibiting >15-fold selectivity for inhibition of Elk-1 versus MITF. These observations demonstrate substrate-selective kinase inhibition: the possibility that small molecules that target docking interactions may be used to selectively inhibit the phosphorylation of a subset of the substrates of a kinase.
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PMID:Characterization of an ERK-binding domain in microphthalmia-associated transcription factor and differential inhibition of ERK2-mediated substrate phosphorylation. 1624 39

The activity of NADPH oxidase is increased in malignant skin keratinocytes. We demonstrated that inhibition of NADPH oxidase activity by diphenyleneiodonium (DPI) suppressed free radical production, inhibited cell growth and promoted cell differentiation of B16 melanoma cells, as indicated by cell morphology, increased production of melanin, and increased expression of microphthalmia-associated transcription factor (MITF). siRNA to NADPH oxidase subunit Rac1 or p47 induced the expression of MITF, verifying that the pro-differentiation effects are due to the inhibition of NADPH oxidase. Biochemical studies suggest that ERK plays a positive role whereas PKCalpha plays a negative role during this differentiation event. In addition, the protein levels of the tumor suppressor p53 were suppressed by DPI, suggesting that p53 is activated by oxidative stress and may negatively regulate differentiation in melanoma cells. Taken together, these results suggest that inhibiting NADPH oxidase activity promotes cell differentiation of B16 melanoma cells.
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PMID:Inhibition of NADPH oxidase activity promotes differentiation of B16 melanoma cells. 1842 80

The Microphthalmia-associated transcription factor (MITF) is an important regulator of cell-type specific functions in melanocytic cells. MITF is essential for the survival of pigmented cells, but whereas high levels of MITF drive melanocyte differentiation, lower levels are required to permit proliferation and survival of melanoma cells. MITF is phosphorylated by ERK, and this stimulates its activation, but also targets it for degradation through the ubiquitin-proteosome pathway, coupling MITF degradation to its activation. We have previously shown that because ERK is hyper-activated in melanoma cells in which BRAF is mutated, the MITF protein is constitutively down-regulated. Here we describe another intriguing aspect of MITF regulation by oncogenic BRAF in melanoma cells. We show oncogenic BRAF up-regulates MITF transcription through ERK and the transcription factor BRN2 (N-Oct3). In contrast, we show that in melanocytes this pathway does not exist because BRN2 is not expressed, demonstrating that MITF regulation is a newly acquired function of oncogenic BRAF that is not performed by the wild-type protein. Critically, in melanoma cells MITF is required downstream of oncogenic BRAF because it regulates expression of key cell cycle regulatory proteins such as CDK2 and CDK4. Wild-type BRAF does not regulate this pathway in melanocytes. Thus, we show that oncogenic BRAF exerts exquisite control over MITF on two levels. It downregulates the protein by stimulating its degradation, but then counteracts this by increasing transcription through BRN2. Our data suggest that oncogenic BRAF plays a critical role in regulating MITF expression to ensure that its protein levels are compatible with proliferation and survival of melanoma cells. We propose that its ability to appropriate the regulation of this critical factor explains in part why BRAF is such a potent oncogene in melanoma.
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PMID:Oncogenic BRAF regulates melanoma proliferation through the lineage specific factor MITF. 1862 67

The hypo-pigmentation of human skin on the palms and the soles compared with other areas of the body has recently been reported to be due to mesenchymal-epithelial interactions via a fibroblast-derived factor, dickkopf 1, an inhibitor of the canonical Wnt signaling pathway. Recently, it has been reported that keratinocytes play a significant role in skin color determination by producing cytokines involved in melanogenesis. Thus, we hypothesized that the downregulated expression of keratinocyte- or fibroblast-derived melanogenic cytokines may also be responsible for the decreased function of palmoplantar (PP) melanocytes in addition to the suppressive effects of dickkopf 1 on melanogenic function in epidermal melanocytes. Immunohistochemistry revealed that the number of tyrosinase, S100alpha, c-KIT, endothelin B receptor (ETBR), SOX10, and microphthalmia-associated transcription factor (MITF) immuno-positive melanocytes is significantly reduced in PP epidermis. In contrast, dopa-histochemistry demonstrated no substantial reduction in melanocyte populations in PP epidermis. Real-time RT-PCR revealed that the expression of stem cell factor (SCF) and endothelin (ET)-1 mRNAs in PP skin was significantly downregulated. In parallel, immunohistochemistry revealed that SCF and ET-1 immuno-staining was markedly attenuated in PP skin. Western blotting revealed that the expression of SCF, c-KIT, and MITF-M proteins was significantly decreased in PP skin. These findings suggest the possibility that downregulation of ET-1/SCF/receptor linkages is also associated with the decreased function of melanocytes in PP skin.
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PMID:Downregulated melanogenic paracrine cytokine linkages in hypopigmented palmoplantar skin. 1908 31

In this study, the essential oil from lotus flower extract, including petals and stamens, was assessed with regard to its effects on melanogenesis in human melanocytes. The lotus flower essential oil was shown to stimulate melanin synthesis and tyrosinase activity in a dose-dependent manner. The lotus flower essential oil induced the expression of tyrosinase, microphthalmia-associated transcription factor M (MITF-M), and tyrosinase-related proten-2 (TRP-2) proteins, but not tyrosinase mRNA. Moreover, it increased the phosphorylation of ERK and cAMP response element binding protein (CREB). In order to verify the effective components of the lotus flower oil, its lipid composition was assessed. It was found to be comprised of palmitic acid methyl ester (22.66%), linoleic acid methyl ester (11.16%), palmitoleic acid methyl ester (7.55%) and linolenic acid methyl ester (5.16%). Among these components, palmitic acid methyl ester clearly induced melanogenesis as the result of increased tyrosinase expression, thereby indicating that it may play a role in the regulation of melanin content. Thus, our results indicate that lotus flower oil may prove useful in the development of gray hair prevention agents or tanning reagents.
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PMID:Lotus (Nelumbo nuficera) flower essential oil increased melanogenesis in normal human melanocytes. 1932 28

White spotting is one of the most distinguishing visual characters in dairy cattle. There is considerable variation within and between breeds of cattle. The objective of this study was to map quantitative trait loci (QTL) affecting the degree of white spotting in dairy cattle based on an F(2) experimental design using Holstein-Friesian and Jersey crossbred cows. The genome scan was implemented using half-sib and line-of-descent approaches with high density markers. Significant QTL were found on chromosomes 6, 18 and 22. The mapped region on BTA6 confirmed the widely conserved KIT locus affecting mammalian pigmentation. Haplotype information linked the highly significant QTL on BTA22 to the Microphthalmia-associated transcription factor (MITF) gene, which has been reported to be associated with pigmentation traits in some other mammals.
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PMID:Genome scan for the degree of white spotting in dairy cattle. 1953 Nov 14

The microphthalmia-associated transcription factor (Mitf) has emerged as an important model for gene regulation in eukaryotic organisms. In vertebrates, it regulates the development of several cell types including melanocytes and has also been shown to play an important role in melanoma. In vitro, the activity of MITF is regulated by multiple signaling pathways, including the KITL/KIT/B-Raf pathway, which results in phosphorylation of MITF on serine residues 73 and 409. However, the precise role of signaling to MITF in vivo remains largely unknown. Here, we use a BAC transgene rescue approach to introduce specific mutations in MITF to study the importance of specific phospho-acceptor sites and protein domains. We show that mice that carry a BAC transgene where single-amino-acid substitutions have been made in the Mitf gene rescue the phenotype of the loss-of-function mutations in Mitf. This may indicate that signaling from KIT to MITF affects other phospho-acceptor sites in MITF or that alternative sites can be phosphorylated when Ser73 and Ser409 have been mutated. Our results have implications for understanding signaling to transcription factors. Furthermore, as MITF and signaling mechanisms have been shown to play an important role in melanomas, our findings may lead to novel insights into this resilient disease.
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PMID:The role of MITF phosphorylation sites during coat color and eye development in mice analyzed by bacterial artificial chromosome transgene rescue. 1963 38

Malignant melanoma is the most aggressive form of cutaneous carcinoma, accounting for 75% of all deaths caused by skin cancers. Microphthalmia-associated transcription factor (MITF) is a master gene regulating melanocyte development and functions as a "lineage addiction" oncogene in malignant melanoma. We have identified the receptor protein tyrosine kinase TYRO3 as an upstream regulator of MITF expression by a genome-wide gain-of-function cDNA screen and show that TYRO3 induces MITF-M expression in a SOX10-dependent manner in melanoma cells. Expression of TYRO3 is significantly elevated in human primary melanoma tissue samples and melanoma cell lines and correlates with MITF-M mRNA levels. TYRO3 overexpression bypasses BRAF(V600E)-induced senescence in primary melanocytes, inducing transformation of non-tumorigenic cell lines. Furthermore, TYRO3 knockdown represses cellular proliferation and colony formation in melanoma cells, and sensitizes them to chemotherapeutic agent-induced apoptosis; TYRO3 knockdown in melanoma cells also inhibits tumorigenesis in vivo. Taken together, these data indicate that TYRO3 may serve as a target for the development of therapeutic agents for melanoma.
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PMID:A genomic screen identifies TYRO3 as a MITF regulator in melanoma. 1980 17


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