title: Histone deacetylase inhibitors synergize p300 autoacetylation that regulates its transactivation activity and complex formation.
abstract: 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.
authors.affiliation: Cardeza Foundation for Hematologic Research, Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Stiehl
authors.affiliation: Cardeza Foundation for Hematologic Research, Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Fath
authors.affiliation: Cardeza Foundation for Hematologic Research, Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania.|Cellular Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Dongming
authors.initials: D
authors.lastname: Liang
authors.affiliation: Cardeza Foundation for Hematologic Research, Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania.|Cellular Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Yubao
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Cardeza Foundation for Hematologic Research, Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania.|Cellular Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Nianli
authors.initials: N
authors.lastname: Sang
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000595:Amino Acid Sequence; D020134:Catalytic Domain; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D006367:HeLa Cells; D051548:Histone Acetyltransferases / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008969:Molecular Sequence Data; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects*; D050880:p300-CBP Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
chemical_list: D018797:Cell Cycle Proteins; D051548:Histone Acetyltransferases; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C012589:trichostatin A