Coordinate regulation of myelomonocytic phenotype by v-myb and v-myc.

Abstract

Both avian myeloblastosis virus (by the action of v-myb) and avian myelocytomatosis virus MC29 (by the action of v-myc) transform cells of the myelomonocytic lineage. Whereas avian myeloblastosis virus elicits a relatively immature phenotype, cells transformed by MC29 resemble mature macrophages. When cells previously transformed by v-myb were superinfected with MC29, their phenotype was rapidly altered to that of a more mature cell. These superinfected cells expressed both v-myb (at a level similar to that found before superinfection) and v-myc. It therefore appears that the expression of v-myc can elicit certain properties of a more differentiated phenotype. In addition, unlike cells transformed by v-myb alone, the cells expressing both v-myb and v-myc could not be induced by the tumor promoter 12-0-tetradecanoylphorbol-13-acetate to differentiate to fully mature macrophages. Cells with a morphology similar to that of the superinfected cells were elicited by simultaneously infecting yolk sac macrophages with avian myeloblastosis virus and MC29. Such cells expressed both v-myb and v-myc. These results indicate that expression of v-myb and v-myc in infected cells coordinately regulates myelomonocytic phenotype and that the two viral oncogenes vary in their ability to interfere with tumor promoter-induced differentiation. Our findings also sustain previous suggestions that the oncogenes v-myb and v-myc may not transform target cells by simply blocking differentiation.

A novel function for Myc: inhibition of C/EBP-dependent gene activation.

“…To identify target genes for v-Myc in myelomonocytic cells, we searched for genes differentially expressed between the avian myeloblastosis virus-transformed chicken myeloblast cell line BM2 (26) and subclones of this line infected with the chicken retrovirus MC29 (27). To our surprise, by simply comparing the expression of known genes in these cells, we identified several genes whose expression was down-regulated by v-Myc.…”

“…BM2 is a line of avian myeloblastosis virustransformed chicken myeloblasts (26). Infection of BM2 cells with MC29 virus has been described (27) (30) and encodes the MC29-specific Gag-Myc fusion protein. pMC29(Q10-4)Notfs is a derivative of pMC29(Q10-4) carrying a frameshift at a unique NotI restriction site in the v-myc-coding region.…”

v-Myc inhibits C/EBPβ activity by preventing C/EBPβ-induced phosphorylation of the co-activator p300

“…One of the hallmarks of v-Myc and c-Myc is the ability to interfere with differentiation processes, particularly of cells, such as myelomonocytic cells or adipocytes, whose differentiation is dependent on C/EBP factors (Symonds et al, 1986;Hoffman-Liebermann and Liebermann, 1991;Freytag and Geddes, 1992;Heath et al, 2000). Earlier, we have shown that v-Myc inhibits the transactivation potential of several C/EBP family members (Mink et al, 1996), suggesting that C/EBPs are crucial targets for Myc in C/EBPdependent differentiation processes.…”

Crosstalk between Myc and activating transcription factor 2 (ATF2): Myc prolongs the half-life and induces phosphorylation of ATF2

“…We were therefore interested to see whether an e ect of v-Myc on ATF2 could also be observed under more physiological conditions. To address this question we analysed the amount and phosphorylation state of (Symonds et al, 1986) and have been used before to demonstrate the inhibitory e ect of Myc on the expression of C/EBP regulated genes (Mink et al, 1996). As shown by Western blotting, both the amount of total ATF2 as well as of phosphorylated ATF2 was increased in the BM2(MC29)cl.4 cells compared to the original BM2 line.…”

“…BM2 is a line of avian myeloblastosis virus transformed chicken myeloblasts (Moscovici et al, 1982). BM2(MC29)cl.4 is a derivative of the BM2 line obtained by infecting BM2 cells MC29 virus (Symonds et al, 1986). BM2 and BM2(MC29) cells were grown in RPMI 1640 medium supplemented with 10% (vol/vol) tryptose phosphate broth, 5% (vol/vol) fetal calf serum and 5% (vol/vol) chicken serum.…”