Linking Myb to the cell cycle: cyclin-dependent phosphorylation and regulation of A-Myb activity.
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.
Ziebold
U
U
Hans-Spemann-Laboratory, Max-Planck-Institute for Immunobiology, Freiburg, Germany.
Klempnauer
K H
KH
D016475:3T3 Cells; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D016213:Cyclins / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology*; D020598:Proto-Oncogene Proteins c-myb; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology*
D016213:Cyclins; D004268:DNA-Binding Proteins; C000715470:MAS1 protein, human; C088831:MYBL1 protein, human; C490283:Mybl1 protein, mouse; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D020598:Proto-Oncogene Proteins c-myb; D015534:Trans-Activators