Search for genes critical for the early and/or late events in carcinogenesis: studies in Xiphophorus (Pisces, Teleostei).

Southern blot analyses of the xiphophorine genome with probes specific for 15 viral and cellular oncogenes revealed that only three v-erbB related EcoRI fragments comprising 4.9 kb of a certain X, 11.5 kb of another X, and 6.7 kb of both a Y and a Z chromosome are inherited in parallel with the Tu complex and melanoma formation. They are accessory in the genome, and are highly homologous with each other and with an ubiquitous autosomal 7.5-kb fragment. The latter one is probably linked to the indispensable Tu complex that is postulated to be present in all individuals of Xiphophorus irrespective of whether they possess or lack the capacity to form melanoma in interspecific hybrids. Three restriction fragments, the X-chromosomal 4.9-kb, the Y-chromosomal 6.7-kb and the ubiquitous Tu-nonlinked 5.5-kb EcoRI fragments were cloned and sequenced. The X- and the Y-chromosomal fragments show perfect identity in the regions of the putative exons C and D of the EGF receptor gene and minor but significant differences to the putative exon C (exon D not identified) of the Tu-nonlinked fragment of 5.5 kb, indicating that at least two different types of x-erb B genes coding for slightly different EGF-receptors exist in the fish. Northern blot analyses revealed expression of the Tu-linked x-erbB genes (x-gfrB genes) in both transformed and nontransformed tissue, suggesting their essential role in regulation of normal cell proliferation and in carcinogenesis. We conclude that the indispensable x-egfrB genes remain unchanged and strictly regulated, while the sex chromosomal accessory x-egfrB genes possibly undergo dramatic changes in structure and/or function (e.g., unscheduled expression, ectopic expression, point mutations, truncation) leading to activation of the oncogenic potential of these genes, which in turn could induce several cellular events involved in the switch from the normal to the transformed state of the cell. In contrast, none of the x-erbA restriction fragments could be assigned to the Tu-complex or to any regulatory gene (R or S). These results, however, do not exclude the existence of a structural and/or functional relation between x-erbA genes and R and S genes. We therefore analyzed x-erbA genes by cloning, sequencing, and expression studies.(ABSTRACT TRUNCATED AT 400 WORDS)