Fig. 6. Mechanistic model of the coactivator function of MSK1 in p53-dependent p21 transcription.

p38 MAPK phosphorylates two downstream targets, p53 and MSK1/2, which act cooperatively to stimulate transcription of the p53-responsive p21 gene as follows: (i) p38 phosphorylates p53 and increases its protein stability and transcription activity; (ii) p38-dependent phosphorylation triggers autophosphorylation of the NKD, which is stimulated by negative charges acquired by phosphorylation events in the hydrophobic motif (HM) and in turn activates the histone kinase activity of MSK1; (iii) activated MSK1 phosphorylates nucleosome phosphorylation through direct interactions with p53, which increases p21 transcription