Oncogenic activation of c-Myb correlates with a loss of negative regulation by TIF1beta and Ski.
The c-myb proto-oncogene product (c-Myb) regulates proliferation of hematopoietic cells by inducing the transcription of a group of target genes. Removal or mutations of the negative regulatory domain (NRD) in the C-terminal half of c-Myb leads to increased transactivating capacity and oncogenic activation. Here we report that TIF1beta directly binds to the NRD and negatively regulates the c-Myb-dependent trans-activation. In addition, three corepressors (Ski, N-CoR, and mSin3A) bind to the DNA-binding domain of c-Myb together with TIF1beta and recruit the histone deacetylase complex to c-Myb. Furthermore, the Drosophila TIF1beta homolog, Bonus, negatively regulates Drosophila Myb activity. The Ski corepressor competes with the coactivator CBP for binding to c-Myb, indicating that the selection of coactivators and corepressors is a key event for c-Myb-dependent transcription. Mutations or deletion of the NRD of c-Myb and the mutations found in the DNA-binding domain of v-Myb decrease the interaction with these corepressors and weaken the corepressor-induced negative regulation of Myb activity. These observations have conceptual implications for understanding how the nuclear oncogene is activated.
Nomura
Teruaki
T
Laboratory of Molecular Genetics, RIKEN Tsukuba Institute, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan.
Tanikawa
Jun
J
Akimaru
Hiroshi
H
Kanei-Ishii
Chie
C
Ichikawa-Iwata
Emi
E
Khan
Md Matiullah
MM
Ito
Hiroki
H
Ishii
Shunsuke
S
D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics*; D004330:Drosophila; D015972:Gene Expression Regulation, Neoplastic; D020570:Genes, myb / Q000235:genetics*; D051379:Mice; D009154:Mutation; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors; D015533:Transcriptional Activation; D000076183:Tripartite Motif-Containing Protein 28
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C512653:Ski protein, mouse; D014157:Transcription Factors; C103190:Trim28 protein, mouse; D000076183:Tripartite Motif-Containing Protein 28