LIGAND-DEPENDENT TUMOR-INDUCTION IN MEDAKAFISH EMBRYOS BY A XMRK RECEPTOR TYROSINE KINASE TRANSGENE

Xmrk encodes a subclass I receptor tyrosine kinase (RTK) which has bee n cloned from the melanoma-inducing locus Tn of the poeciliid fish Xip hophorus. To demonstrate a high oncogenic potential in vivo we transfe rred the gene into early embryos of the closely related medakafish. Ec topic expression of the Xmrk oncogene under the control of a strong, c onstitutive promoter (CMVTk) led to the induction of embryonic tumors with high incidence, after short latency periods, and with a specific pattern of affected tissues. We demonstrate ligand-dependent transform ation in vivo using a chimeric receptor consisting of the extracellula r and transmembrane domains of the human EGF receptor (HER) and the cy toplasmatic domain of Xmrk. Expression of the chimeric receptor alone does not lead to kinase activation or induction of tumors. Coexpressio n of the chimera with its corresponding ligand, human transforming gro wth factor alpha (hTGF alpha), however, results in the activation of t he chimeric RTK. In injected fish embryos the induction of the neoplas tic growth is observed with similar incidence and tissue distribution as in embryos carrying the native Xmrk oncogene suggesting that the li gand as well as factors downstream of the RTK are required for tumor f ormation. In this study we show single-step induction of tumors by ect opic expression of RTKs in vivo substantiating the significance of aut ocrine stimulation in RTK induced tumors in vertebrates.