MSK1 triggers the expression of the INK4AB/ARF locus in oncogene-induced senescence

The tumor suppressor proteins p15(INK4B), p16(INK4A), and p14(ARF), encoded by the INK4AB/ARF locus, are crucial regulators of cellular senescence. The locus is epigenetically silenced by the repressive Polycomb complexes in growing cells but is activated in response to oncogenic stress. Here we show that the mitogen- and stress-activated kinase (MSK1) is up-regulated after RAF1 oncogenic stress and that the phosphorylated (activated) form of MSK1 is significantly increased in the nucleus and recruited to the INK4AB/ARF locus. We show that MSK1 mediates histone H3S28 phosphorylation at the INK4AB/ARF locus and contributes to the rapid transcriptional activation of p15(INK4B) and p16(INK4A) in human cells despite the presence of the repressive H3K27me3 mark. Furthermore, we show that upon MSK1 depletion in oncogenic RAF1-expressing cells, H3S28ph presence at the INK4 locus and p15(INK4B) and p16(INK4A) expression are reduced. Finally, we show that H3S28-MSK–dependent phosphorylation functions in response to RAF1 signaling and that ERK and p38α contribute to MSK1 activation in oncogene-induced senescence.