The 70kDa ribosomal protein S6 kinases (S6K1 and S6K2) play important roles in 
the regulation of protein synthesis, cell growth and survival. S6Ks are 
activated in response to mitogen stimulation and nutrient sufficiency by the 
phosphorylation of conserved serine and threonine residues. Here we show for the 
first time, that in addition to phosphorylation, S6Ks are also targeted by 
lysine acetylation. Following mitogen stimulation, S6Ks interact with the p300 
and p300/CBP-associated factor (PCAF) acetyltransferases. S6Ks can be acetylated 
by p300 and PCAF in vitro and S6K acetylation is detected in cells expressing 
p300. Furthermore, it appears that the acetylation sites targeted by p300 lie 
within the divergent C-terminal regulatory domains of both S6K1 and S6K2. 
Acetylation of S6K1 and 2 is increased upon the inhibition of class I/II histone 
deacetylases (HDACs) by trichostatin-A, while the enhancement of S6K1 
acetylation by nicotinamide suggests the additional involvement of sirtuin 
deacetylases in S6K deacetylation. Both expression of p300 and HDAC inhibition 
cause increases in S6K protein levels, and we have shown that S6K2 is stabilized 
in cells treated with HDAC inhibitors. The finding that S6Ks are targeted by 
histone acetyltransferases uncovers a novel mode of crosstalk between mitogenic 
signalling pathways and the transcriptional machinery and reveals additional 
complexity in the regulation of S6K function.