Linking Myb to the cell cycle: cyclin-dependent phosphorylation and regulation of A-Myb activity.

Abstract

A-myb, a conserved member of the Myb proto-oncogene family, encodes a sequence-specific DNA binding protein (A-Myb) that binds to and transactivates promoters containing myb-binding sites. Previous work has suggested that the C-terminus of A-Myb functions as a regulatory domain, however, the physiological signals that control the activity of A-Myb have not yet been identified. The presence of potential phosphorylation sites for cyclin-dependent kinases in the C-terminus of A-Myb has prompted us to examine the possibility that the function of A-Myb is controlled by the cell cycle. We here show that the transactivation potential of A-Myb is repressed by the C-terminal domain and that phosphorylation of A-Myb, induced by cyclins A and E, relieves this inhibitory effect. Our work provides the first evidence that the function of A-Myb is regulated by the cell cycle machinery and that the carboxy-terminal domain of A-Myb acts as a cell cycle sensor. In addition, we show that A-myb mRNA expression is also cell cycle regulated and attains maximal levels during the late G1- and early S-phase. Thus, A-Myb appears to be controlled by two different mechanisms resulting in maximal A-Myb activity during the G1/S-transition and the S-phase of the cell cycle.