p300/cyclic AMP-responsive element binding protein-binding protein (CBP) are 
general coactivators for multiple transcription factors involved in various 
cellular processes. Several highly conserved domains of p300/CBP serve as 
interacting sites for transcription factors and regulatory proteins. 
Particularly, the intrinsic histone acetyltransferase (HAT) activity and 
transactivation domains (TAD) play essential roles for their coactivating 
function. Autoacetylation of p300/CBP is commonly observed in cell-free HAT 
assays and has been implicated in the regulation of their HAT activity. Here, we 
show that six lysine-rich regions in several highly conserved functional domains 
of p300 are targeted by p300HAT for acetylation in cell-free systems. We show 
that p300 is susceptible to acetylation in cultured tumor cells and that its 
acetylation status is affected by histone deacetylase inhibitor trichostatin A. 
We further show that either treatment with deacetylase inhibitors or 
coexpression of Gal4-p300HAT, which alone has no transactivation activity, 
stimulates the activity of the COOH-terminal TAD of p300 (p300C-TAD). We have 
defined the minimal p300C-TAD and show that it is sufficient to respond to 
deacetylase inhibitors and is a substrate for p300HAT. Finally, we show that 
acetylated p300 possesses enhanced ability to interact with p53. Taken together, 
our data suggest that acetylation regulates p300C-TAD and that acetylation of 
p300/CBP may contribute to the dynamic regulation of their complex formation 
with various interacting partners.