Regulation of cell fate by phosphorylation : a tale of two transcription factors

Abstract

As transcription factors are the nuclear effectors of signaling cascades, mechanisms must exist to specifically regulate their activities in response to signaling events. Regulation can occur at the DNA, RNA, or protein level. Many transcription factors are present in cells and tissues before they are needed, allowing quick response to extracellular stimuli. In these cases the activity of the transcription factor is regulated at the protein level. A wide variety of post-translational modifications are known to play critical roles in regulating transcription factors, and are capable of altering the localization, stability, interactions, other post-translational modifications, and activity of a protein. The combinations of modifications that can occur on an individual protein yield immense regulatory possibilities. Aside from analyses of the effects of serine/threonine (S/T) phosphorylation, studies on post-translational modifications of transcription factors are only in the beginning stages. The current paradigm that an enzyme activated in response to upstream signaling will localize to the nucleus and modify specific transcription factors is an over-simplification. Intriguingly, there appears to be an emerging theme in which the transcription factor itself possesses a second, enzymatic function. This creates an entirely new set of regulatory mechanisms that emanate locally from the transcriptional complexes themselves. Thus transcription factors are not passive on/off switches controlled by signaling pathways, but are active players in determining the activity, output, and regulation of transcriptional complexes. Here I will review the various post-translational modifications that are mediated by such dual function transcription factors and other signaling regulated enzymes, and provide specific examples of how such modifications regulate the activities of ETS transcription factors. Then I will review the enzymatic functions of the transcriptional regulators EYA, DBP1, ERK5, p300, and TAFII250.