Mutational analysis of v-rel, the oncogene of reticuloendotheliosis virus strain T.

Reticuloendotheliosis virus strain T (Rev-T) is a highly oncogenic retrovirus that induces a lethal lymphoma in young galliform birds and also transforms and immortalizes avian lymphoid cells in vitro. Rev-T presumably arose when a reticuloendotheliosis virus (Rev) incorporated a portion of the turkey c-rel gene into its genome, forming the v-rel oncogene. The predicted v-rel protein (p59v-rel) has 14 amino acid substitutions and 3 amino acid deletions relative to the predicted turkey c-rel protein. The 5' Rev env-derived amino-terminus of p59v-rel also has amino acid substitutions in codons 3, 6, and 9 relative to wild-type Rev-A env. To distinguish the critical alterations from the neutral ones, we made a mutation that resulted in a substitution of the 5' Rev env-derived amino-terminus by a single methionine, as well as several back-mutations, in the context of an otherwise wild-type v-rel and tested the transforming, immortalizing, and tumorigenic properties of the resulting proteins. All proteins tested retained the transforming, immortalizing, and tumorigenic functions of v-rel. Absence of the 5' Rev env-derived amino-terminus, as well as back-mutations of six of the amino acid changes present in the rel-derived amino-terminal and central regions of v-rel, reduced transformation efficiency. The mutations present in codons 3, 6, and 9 of p59v-rel showed complicated interactions in their activating effects on transformation efficiency. We also showed that loss of the immortalizing function did not abolish tumorigenesis by v-rel. We further showed that the primary transduction event involving the turkey c-rel gene could have occurred with a replication-competent Rev having v-rel-specific mutations in codons 3, 6, and 9 of the env gene.