Tumor Suppression in
            <i>Xiphophorus</i>
            by an Accidentally Acquired Promoter

Adam, Dieter; Dimitrijevic, Nicola; Schartl, Manfred

doi:10.1126/science.8430335

Cited by 91 publications

(67 citation statements)

References 13 publications

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“…If genome duplications occurred a long time ago their traces might be obliterated by the loss of genes, fusion of chromosomes and lineagespecific gene amplifications, rendering the distinction between the two competing explanations for the observation of more genes in fishes much more difficult. There are clear examples in fish of individual duplications that are, as expected, mapped onto chromosomes in tandem arrays and in closely linked gene clusters [21,22]. Although humans and zebrafish last shared a common ancestor about 380 million years ago, there are a growing number of studies [15 •• ,23] that show extensive conserved synteny between zebrafish and human chromosomes.…”

Section: Even More Genes In Fish?mentioning

confidence: 76%

Gene and genome duplications in vertebrates: the one-to-four (-to-eight in fish) rule and the evolution of novel gene functions

Meyer¹,

Schartl²

1999

Current Opinion in Cell Biology

747

532

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Section: Even More Genes In Fish?mentioning

confidence: 76%

Gene and genome duplications in vertebrates: the one-to-four (-to-eight in fish) rule and the evolution of novel gene functions

Meyer¹,

Schartl²

1999

Current Opinion in Cell Biology

747

532

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“…For the RTK Xmrk a role in tumor development is suggested by the fact that overexpression of Xmrk leads to the formation of malignant melanoma in Xiphophorus hybrids (Adam et al, 1991(Adam et al, , 1993. We therefore addressed the question which intracellular mechanisms are underlying Xmrk oncogenicity.…”

Section: Discussionmentioning

confidence: 99%

Signalling by the oncogenic receptor tyrosine kinase Xmrk leads to activation of STAT5 in Xiphophorus melanoma

et al. 1998

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Overexpression of the mutationally activated Xmrk receptor initiates the formation of hereditary malignant melanoma in the ®sh Xiphophorus. In addition to transcriptional overexpression a cell-type speci®c signal transduction is essential for Xmrk mediated tumor formation. To elucidate the consequence of Xmrk signalling and to identify target proteins that characterize the tumor phenotype, we analysed proteins that are strongly tyrosine phosphorylated in the ®sh melanoma cell line PSM. One of the most prominent phosphotyrosine proteins was found to be the signal transducer and activator of transcription STAT5. In a heterologous cell system (murine pro B-cells), activation of the Xmrk kinase in a chimeric receptor induced tyrosine phosphorylation, nuclear translocation and DNA binding of STAT5. Following receptor stimulation, expression of the STAT5 speci®c target genes cis, osm and pim-1 was induced. In Xiphophorus PSM cells STAT5 was found to be preferentially localized in the nucleus, but treatment with tyrphostin AG555, a speci®c Xmrk kinase-inhibitor, blocked nuclear localization. In these cells as well as in Xiphophorus melanoma expression of pim-1 and constitutive DNA-binding activity of STAT5 was detectable. This constitutive activity was higher in malignant than in benign melanomas, indicating that STAT5 activation is correlated with the malignancy of these tumors.

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“…In an earlier study, it was shown that ONC-Xmrk was generated by a recombination event between INVXmrk and the D-locus (Adam et al, 1993). To analyse the genomic organisation in the region of the genomic breakpoint, PCR was performed with primers that bridge the breakpoint in the oncogene.…”

Section: Genomic Organization Of the Xmrk Proto-oncogenementioning

confidence: 99%

“…It was suggested that, due to a recombination event between INV-Xmrk and another unrelated locus (referred to as the D-locus), a new regulatory sequence was translocated to the 5' end of the transcribed portion of the proto-oncogene, thus generating ONCXmrk (Adam et al, 1993, FoÈ rnzler et al, 1996. Therefore, melanoma formation in Xiphophorus can be explained by deregulation of this new promoter in the absence of the R-locus.…”

Section: Introductionmentioning

confidence: 99%

Activation of the Xmrk proto-oncogene of Xiphophorus by overexpression and mutational alterations

et al. 1998

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Xmrk is a receptor tyrosine kinase closely related to the human EGF receptor. In the teleost ®sh Xiphophorus two versions of the Xmrk gene exist, an oncogene (ONC) and a proto-oncogene (INV). While ONC-Xmrk is the melanoma-inducing gene, INV-Xmrk appears not to be involved in transformation of pigment cells. To elucidate the mechanism that converts the proto-oncogene into a transforming oncogene a comparative analysis of the structure, expression and function of both versions of the gene was performed. In contrast to ONC-Xmrk which is expressed at high levels in melanoma cells, the protooncogene INV-Xmrk is ubiquitously expressed at very low levels indicating overexpression as one possible reason for tumorigenicity by ONC-Xmrk. As sequence comparison of the proto-oncogene and the oncogene revealed a number of amino acid changes, a possible eect of these mutations on the activation of the ONCXmrk receptor was determined. A constitutive activation of the oncogenic receptor was found and ectopic expression of INV-Xmrk after microinjection into medaka®sh embryos did not lead to the high tumour rate in transgenic ®sh as observed for the oncogene. Our data therefore suggest that overexpression of the receptor alone is not sucient for melanoma induction, but that in addition activating mutations in ONC-Xmrk are responsible for its full tumorigenic potential.

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Tumor Suppression in Xiphophorus by an Accidentally Acquired Promoter

Cited by 91 publications

References 13 publications

Gene and genome duplications in vertebrates: the one-to-four (-to-eight in fish) rule and the evolution of novel gene functions

Gene and genome duplications in vertebrates: the one-to-four (-to-eight in fish) rule and the evolution of novel gene functions

Signalling by the oncogenic receptor tyrosine kinase Xmrk leads to activation of STAT5 in Xiphophorus melanoma

Activation of the Xmrk proto-oncogene of Xiphophorus by overexpression and mutational alterations

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