v-Myb of E26 leukemia virus up-regulates bcl-2 and suppresses apoptosis in myeloid cells.
Many oncogenes have been shown to be deregulated transcription factors, yet direct target genes mediating cell transformation remain elusive. Here we describe such a target for v-Myb by exploiting a temperature-sensitive mutant of the E26 avian leukemia virus encoding Myb-Ets. Myeloblasts transformed by the mutant differentiate into macrophages or die by apoptosis when shifted to the nonpermissive temperature as a result of inactivation of v-Myb. During this process mRNA of the antiapoptotic oncoprotein Bcl-2 is down-regulated with kinetics similar to those of Mim-1, a differentiation-related protein whose expression is directly regulated by Myb. Forced expression of bcl-2 rescues the cells from apoptosis, without preventing either their withdrawal from the cell cycle or their differentiation. v-Myb appears to act directly on the bcl-2 gene, because a bcl-2 promoter-driven reporter is activated by Myb-Ets and v-Myb-VP16 and requires intact Myb binding sites within the promoter. Surprisingly, inactivation of v-Myb in multipotent progenitors transformed by E26 virus does not induce apoptosis, indicating that bcl-2 regulation by the oncoprotein is required for the transformation of some cell types but not others.
Frampton
J
J
European Molecular Biology Laboratory, Heidelberg, Germany.
Ramqvist
T
T
Graf
T
T
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D002645:Chickens; D015536:Down-Regulation; D006098:Granulocytes / Q000166:cytology; D006358:Hot Temperature; D007938:Leukemia / Q000235:genetics; D008264:Macrophages / Q000166:cytology; D020626:Oncogene Proteins v-myb; D009856:Oncogene Proteins, Viral / Q000235:genetics*; D011485:Protein Binding; D015682:Retroviridae Proteins, Oncogenic / Q000378:metabolism / Q000502:physiology*; D015854:Up-Regulation
D020626:Oncogene Proteins v-myb; D009856:Oncogene Proteins, Viral; D015682:Retroviridae Proteins, Oncogenic