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Transcriptional control analyses of the Xiphophorus melanoma oncogene.

ABSTRACT: Melanoma development in interspecific hybrids of Xiphophorus is induced by the overexpression of the mutationally activated receptor tyrosine kinase Xmrk in pigment cells. Based on the melanocyte specificity of the transcriptional upregulation, a pigment cell-specific promoter region was postulated for xmrk, the activity of which is controlled in healthy purebred fish by the molecularly still unidentified regulator locus R. However, as yet the xmrk promoter region is still poorly characterized. In order to contribute to a better understanding of xmrk expression regulation, we performed a functional analysis of the entire putative gene regulatory region of the oncogene using conventional plasmid-based reporter systems as well as a newly established method employing BAC-derived luciferase reporter constructs in melanoma and non-melanoma cell lines. Using the melanocyte-specific mitfa promoter as control, we could demonstrate that our in vitro system is able to reliably monitor regulation of transcription through cell type-specific regulatory sequences. We found that sequences within 200kb flanking the xmrk oncogene do not lead to any specific transcriptional activation in melanoma compared to control cells. Hence, xmrk reporter constructs fail to faithfully reproduce the endogenous transcriptional regulation of the oncogene. Our data therefore strongly indicate that the melanocyte-specific transcription of xmrk is not the consequence of pigment cell-specific cis-regulatory elements in the promoter region. This hints at additional regulatory mechanisms involved in transcriptional control of the oncogene, thereby suggesting a key role for epigenetic mechanisms in oncogenic xmrk overexpression and thereby in tumor development in Xiphophorus.

SUBMITTER: Regneri J

PROVIDER: S-EPMC4662873 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Transcriptional control analyses of the Xiphophorus melanoma oncogene.

Regneri Janine J Volff Jean-Nicolas JN Schartl Manfred M

Comparative biochemistry and physiology. Toxicology & pharmacology : CBP 20150905

Melanoma development in interspecific hybrids of Xiphophorus is induced by the overexpression of the mutationally activated receptor tyrosine kinase Xmrk in pigment cells. Based on the melanocyte specificity of the transcriptional upregulation, a pigment cell-specific promoter region was postulated for xmrk, the activity of which is controlled in healthy purebred fish by the molecularly still unidentified regulator locus R. However, as yet the xmrk promoter region is still poorly characterized. ...[more]

PMID: 26348392

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Project description:BACKGROUND:Evolution occurred exclusively under the full spectrum of sunlight. Conscription of narrow regions of the solar spectrum by specific photoreceptors suggests a common strategy for regulation of genetic pathways. Fluorescent light (FL) does not possess the complexity of the solar spectrum and has only been in service for about 60 years. If vertebrates evolved specific genetic responses regulated by light wavelengths representing the entire solar spectrum, there may be genetic consequences to reducing the spectral complexity of light. RESULTS:We utilized RNA-Seq to assess changes in the transcriptional profiles of Xiphophorus maculatus skin after exposure to FL ("cool white"), or narrow wavelength regions of light between 350 and 600 nm (i.e., 50 nm or 10 nm regions, herein termed "wavebands"). Exposure to each 50 nm waveband identified sets of genes representing discrete pathways that showed waveband specific transcriptional modulation. For example, 350-400 or 450-500 nm waveband exposures resulted in opposite regulation of gene sets marking necrosis and apoptosis (i.e., 350-400 nm; necrosis suppression, apoptosis activation, while 450-500 nm; apoptosis suppression, necrosis activation). Further investigation of specific transcriptional modulation employing successive 10 nm waveband exposures between 500 and 550 nm showed; (a) greater numbers of genes may be transcriptionally modulated after 10 nm exposures, than observed for 50 nm or FL exposures, (b) the 10 nm wavebands induced gene sets showing greater functional specificity than 50 nm or FL exposures, and (c) the genetic effects of FL are primarily due to 30 nm between 500 and 530 nm. Interestingly, many genetic pathways exhibited completely opposite transcriptional effects after different waveband exposures. For example, the epidermal growth factor (EGF) pathway exhibits transcriptional suppression after FL exposure, becomes highly active after 450-500 nm waveband exposure, and again, exhibits strong transcriptional suppression after exposure to the 520-530 nm waveband. CONCLUSIONS:Collectively, these results suggest one may manipulate transcription of specific genetic pathways in skin by exposure of the intact animal to specific wavebands of light. In addition, we identify genes transcriptionally modulated in a predictable manner by specific waveband exposures. Such genes, and their regulatory elements, may represent valuable tools for genetic engineering and gene therapy protocols.

Dataset Information

Transcriptional control analyses of the Xiphophorus melanoma oncogene.

Publications

Transcriptional control analyses of the Xiphophorus melanoma oncogene.

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