Avian leukosis virus (ALV) is the prototype of non-acute retroviruses, a group of naturally occurring cancer viruses which do not carry oncogenes and induce cancers by proviral insertional activation of host oncogenes. In the previous grant period, we have established that ALV induces erythroblastosis by insertional activation of the host oncogene c-erbB which has recently been shown to be related, if not identical, to the EGF receptor. We have identified several extraordinary features regarding c-erbB activation; all the proviruses are inserted in the middle of the erbB gene at a point very close to the exon where homology to v-erbB starts, suggesting truncation of the protein at this point maybe important for oncogenesis. The proviruses utilize their 5'LTR (rather than 3' LTR) promoter to transcribe a readthrough message encompassing both the viral genes and the downstream c-erbB sequences. This is followed by a novel splicing scheme to generate the activated c-erbB transcript. The activated c-erbB gene product contains the viral envelope signal sequence, the region related to v-erbB and a 34 amino acid c-terminal domain homologous to EGF-receptor which contains the major autophosphorylation site. These findings provide new leads in our understanding of the viral oncogenesis mechanisms, the oncogenic conversion of a normal cellular receptor gene, and the role of a growth factor receptor in leukemgenesis. We wish to extend these analyses to more clearly define (1) the structure of the chicken c-erbB locus with an emphasis on its possible identity to the EGF-receptor (2) the nature of the multiple transcripts of the normal and activated c-erbB genes (3) the properties of the activated c-erbB protein (4) the oncogenic determinants of the c-erbB (or EGF receptor) gene and (5) the mechanisms involved in the transduction of activated c-erbB to generate an acute oncogenic retrovirus.
Showing the most recent 10 out of 42 publications
