Two modes of c-myb activation in virus-induced mouse myeloid tumors.

Abstract

Two modes of disruption of the protooncogene c-myb by viral insertional mutagenesis In mouse myeloid tumor cells are described. The first mode was found in six tumors in which a Moloney murine leukemia virus component had inserted in the same transcriptional orientation upstream of the 5'-most exon with v-myb homology (vEl). cDNA sequence data indicate the presence of a truncated c-myb mRNA that is initiated in the upstream 5' long terminal repeat of the integrated provirus and processed via a cryptic splice donor sequence in the gag region to the splice acceptor site in vEl of the c-myb gene, thus removing the remaining downstream viral and myb intronic sequences. Unlike most gag-onc transcripts, the gag and myb sequences in the hybrid transcript were not in the same reading frame. It is presumed that the gag sequence provides a cryptic translation initiation site for the novel amino-truncated c-myb protein. The second mode of disruption was by downstream virus insertion at the 3' side of the c-myb, which results in the synthesis of a small (-2 kilobase) myb transcript. The 5' long terminal repeat of the inserted provirus provides a TGA termination codon that results in the elimination of 240 normal c-myb amino acid residues from the carboxyl terminus of the tumor-specific myb protein. These results suggest that truncated myb proteins play a role in neoplastic transformation of myeloid cells. Avian myeloblastosis virus (AMV) is a replicationdefective retrovirus which induces myeloblastosis in vivo and transforms myelomonocytic cells in vitro (35). The viral genome contains a v-myb sequence that is homologous to the middle portion of the chicken protooncogene c-myb (1,16,22,52,58) and is thought to be essential for its oncogenic properties (11,59). Another avian leukemia virus (ALV), E26, also has been shown to contain most of the v-myb sequences and an additional nucleotide sequence derived from the c-ets protooncogene (27,41). While the target cells of AMV are of the myeloid lineage, cells of the myeloid as well as erythroid lineages are transformed by E26 (36, 37, 50). It appears that the myeloid leukemogenicity shared by AMV and E26 correlates with the common myb sequence. The p75 protein encoded by normal c-myb is 30 kilodaltons (kDa) larger than the p45 protein encoded by the AMVtransduced v-myb (23). Several lines of evidence indicate that a variety of alterations in protooncogenes can render them oncogenic (reviewed in reference 64). It is, however, currently unclear whether truncation of the c-myb protein is the abnormality responsible for the tumors induced by v-myb.The acute transforming retroviruses of mammalian and avian origin have led to the identification of nearly 20 cellular oncogenes. Retroviruses that lack oncogenes can induce a variety of tumors by insertional mutagenesis which affects both known c-onc genes and previously unidentified cellular genes (e.g., int loci) that are now implicated in tumorigenesis (reviewed in reference 3). Two modes of insertional mutagenesis which involve oncoge...

Identification of functional domains in the maize transcriptional activator C1: comparison of wild-type and dominant inhibitor proteins.

“…It is possible that this conservative amino acid change decreases CI DNA binding; however, the Cl-I protein (with Glu^°*) is believed to bind DNA (cited in Paz-Ares et al 1990). This Asp residue is conserved evolutionarily between the various members of the myb oncogene family (Bergmann et al 1981;Klempnauer et al 1982Klempnauer et al , 1986Gonda et al 1985;Boyle et al 1986;Shen-Ong et al 1986;Peter et al 1987) and may occupy a position in the DNA-recognition helix (Ohlendorf et al 1982;Lehming et al 1987;Aggarwal et al 1988;Jordan and Pabo 1988;Otting et al 1988). This conservation suggests that an analogous change in any of the various mammalian or insect myb-homologous domains could also decrease the transcriptional activation function of these proteins dramatically.…”

Functional genomic analysis reveals distinct neoplastic phenotypes associated with c-myb mutation in the bursa of Fabricius

“…Retrovirus-mediated disruption of the c-myb locus is also oncogenic in mice producing myeloid leukemia (Shen-Ong et al, 1986;Gonda et al, 1987;Shen-Ong and Wolff, 1987;Wolff et al, 1988;Nason-Burchenal and Wolff, 1993). A growing number of genes which can be directly regulated by Myb have been described (reviewed in Ness, 1996), but in neither chickens nor mice are the regulatory targets and pathways known through which this transcription factor promotes tumorigenesis.…”

Insertional activation of N-myc by endogenous Moloney-like murine retrovirus sequences in macrophage cell lines derived from myeloma cell line-macrophage hybrids.

“…2b and c). The overall structure was very similar to that of proviral MoMuLV, although several sequences were different (2,45) (Fig. 2f).…”