Expression regulation triggers oncogenicity of xmrk alleles in the Xiphophorus melanoma system

Abstract

The Xiphophorus melanoma model has gained attention in biomedical research as a genetic model for tumor formation. Melanoma development in interspecific hybrids of Xiphophorus is connected to pigment cell specific overexpression of the mutationally activated receptor tyrosine kinase Xmrk. In purebred fish the oncogenic function of xmrk is suppressed by a so far unknown regulator locus R. To test the hypothesis that R is involved in transcriptional regulation of xmrk and consequently acts upstream of the xmrk signal, we performed a quantitative analysis of xmrk transcript levels in normal and melanoma tissues of different Xiphophorus genotypes carrying either a highly tumorigenic or a non-tumorigenic xmrk allele. Our results demonstrate that expression of the tumorigenic xmrk allele is highly increased in malignant melanomas compared to benign lesions, macromelanophore spots, and healthy skin. Transcription of the non-tumorigenic xmrk allele in pigment cells, in contrast, is not influenced by the presence or absence of R. These findings strongly indicate that differential transcriptional regulation of the xmrk promoter determines the tumorigenic potential of xmrk alleles in the Xiphophorus melanoma system, thereby supporting the hypothesis that R suppresses the oncogenic function of xmrk on the level of transcriptional control.