Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0677930 (primary tumor)
 20,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The MITF/TFE subfamily of basic helix-loop-helix leucine-zipper (bHLH-LZ) transcription factors consists of four closely related members, TFE3, TFEB, TFEC and MITF, which can form both homo- and heterodimers. Previously, we demonstrated that in t(X;1)(p11;q21)-positive renal cell carcinomas (RCCs), the TFE3 gene on the X chromosome is disrupted and fused to the PRCC gene on chromosome 1. Here we show that in t(6;11)(p21;q13)-positive RCCs the TFEB gene on chromosome 6 is fused to the Alpha gene on chromosome 11. The AlphaTFEB fusion gene appears to contain all coding exons of the TFEB gene linked to 5' upstream regulatory sequences of the Alpha gene. Quantitative PCR analysis revealed that AlphaTFEB mRNA levels are up to 60-fold upregulated in primary tumor cells as compared with wild-type TFEB mRNA levels in normal kidney samples, resulting in a dramatic upregulation of TFEB protein levels. Additional transfection studies revealed that the TFEB protein encoded by the AlphaTFEB fusion gene is efficiently targeted to the nucleus. Based on these results we conclude that the RCC-associated t(6;11)(p21;q13) translocation leads to a dramatic transcriptional and translational upregulation of TFEB due to promoter substitution, thereby severely unbalancing the nuclear ratios of the MITF/TFE subfamily members. We speculate that this imbalance may lead to changes in the expression of downstream target genes, ultimately resulting in the development of RCC. Moreover, since this is the second MITF/TFE transcription factor that is involved in RCC development, our findings point towards a concept in which this bHLH-LZ subfamily may play a critical role in the regulation of (aberrant) renal cellular growth.
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PMID:Upregulation of the transcription factor TFEB in t(6;11)(p21;q13)-positive renal cell carcinomas due to promoter substitution. 1283 90

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

Melanoma is a cancer with a poorly understood molecular pathobiology. We find the transcription factors PAX3, SOX10, MITF, and the tyrosine kinase receptor MET expressed in melanoma cell lines and primary tumors. Analysis for MET expression in primary tumor specimens showed 27/40 (68%) of the samples displayed an increased expression of MET, and this expression was highly correlated with parallel expression of PAX3, SOX10, and MITF. PAX3 and MITF bind to elements in the MET promoter independently, without evidence of either synergistic activation or inhibition. SOX10 does not directly activate the MET gene alone, but can synergistically activate MET expression with either PAX3 or MITF. In melanoma cells, there was evidence of two pathways for PAX3 mediated MET induction: (i) direct activation of the gene, and (ii) indirect regulation through MITF. SK-MEL23 melanoma cells have both of these pathways intact, while SK-MEL28 melanoma cells only have the first pathway. In summary, we find that PAX3, SOX10 and MITF play an active role in melanoma cells by regulating the MET gene. In consequence, MET promotes the melanoma cancer phenotype by promoting migration, invasion, resistance to apoptosis, and tumor cell growth.
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PMID:PAX3 and SOX10 activate MET receptor expression in melanoma. 2006 53

Malignant melanoma of the skin is the most aggressive human cancer given that a primary tumor a few millimeters in diameter frequently has full metastatic competence. In view of that, revealing the genetic background of this potential may also help to better understand tumor dissemination in general. Genomic analyses have established the molecular classification of melanoma based on the most frequent driver oncogenic mutations (BRAF, NRAS, KIT) and have also revealed a long list of rare events, including mutations and amplifications as well as genetic microheterogeneity. At the moment, it is unclear whether any of these rare events have role in the metastasis initiation process since the major drivers do not have such a role. During lymphatic and hematogenous dissemination, the clonal selection process is evidently reflected by differences in oncogenic drivers in the metastases versus the primary tumor. Clonal selection is also evident during lymphatic progression, though the genetic background of this immunoselection is less clear. Genomic analyses of metastases identified further genetic alterations, some of which may correspond to metastasis maintenance genes. The natural genetic progression of melanoma can be modified by targeted (BRAF or MEK inhibitor) or immunotherapies. Some of the rare events in primary tumors may result in primary resistance, while further new genetic lesions develop during the acquired resistance to both targeted and immunotherapies. Only a few genetic lesions of the primary tumor are constant during natural or therapy-modulated progression. EGFR4 and NMDAR2 mutations, MITF and MET amplifications and PTEN loss can be considered as metastasis drivers. Furthermore, BRAF and MITF amplifications as well as PTEN loss are also responsible for resistance to targeted therapies, whereas NRAS mutation is the only founder genetic lesion showing any association with sensitivity to immunotherapies. Unfortunately, there are hardly any data on the possible organ-specific metastatic drivers in melanoma. These observations suggest that clinical management of melanoma patients must rely on the genetic analysis of the metastatic lesions to be able to monitor progression-associated changes and to personalize therapies.
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PMID:Genetic progression of malignant melanoma. 2697 Sep 65