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Phosphorylation-dependent down-regulation of c-Myb DNA binding is abrogated by a point mutation in the v-myb oncogene

Item Type:Article
Title:Phosphorylation-dependent down-regulation of c-Myb DNA binding is abrogated by a point mutation in the v-myb oncogene
Creators Name:Andersson, K.B. and Kowenz-Leutz, E. and Brendeford, E.M. and Tygsett, A.H.H. and Leutz, A. and Gabrielsen, O.S.
Abstract:The viral Myb (v-Myb) oncoprotein of the avian myeloblastosis virus (AMV) is an activated form of the cellular transcription factor c-Myb causing acute monoblastic leukemia in chicken. Oncogenic v-Myb alterations include N- and C-terminal deletions as well as point mutations. Whereas truncations in Myb cause loss of various protein modifications, none of the point mutations in v-Myb has been directly linked to protein modifications. Here we show that the DNA-binding domain of c-Myb can be phosphorylated on serine 116 by the catalytic subunit of protein kinase A. Phosphorylation of Ser 116 differentially destabilizes a subtype of c-Myb-DNA complexes. The V117D mutation of the AMV v-Myb oncoprotein abolishes phosphorylation of the adjacent Ser 116 residue. Modification of Ser 116 was also detected in live cells in c-Myb, but not in AMV v-Myb. Phosphorylation-mimicking mutants of c-Myb failed to activate the resident mim-1 gene. Our data imply that protein kinase A or a kinase with similar specificity negatively regulates c-Myb function, including collaboration with C/EBP, and that the leukemogenic AMV v-Myb version evades inactivation by a point mutation that abolishes a phosphoacceptor consensus site. This suggests a novel link between Myb, a signal transduction pathway, cooperativity with C/EBP, and a point mutation in the myb oncogene.
Keywords:Amino Acid Sequence, Amino Acid Sequence Homology, Base Sequence, Cell Line, Cyclic AMP-Dependent Protein Kinases, DNA, Down-Regulation, Molecular Sequence Data, Phosphorylation, Point Mutation, Protein Binding, Proto-Oncogene Proteins c-myb, Animals, Chickens, Quail
Source:Journal of Biological Chemistry
Publisher:American Society for Biochemistry and Molecular Biology
Page Range:3816-3824
Date:7 February 2003
Official Publication:https://doi.org/10.1074/jbc.M209404200
PubMed:View item in PubMed

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