@article{1299948,

title = {Interaction with the DNA Repair Protein Thymine DNA Glycosylase Regulates Histone Acetylation by p300},

author = {Ryan A Henry and Pietro Mancuso and Yin-Ming Kuo and Rossella Tricarico and Marc Tini and Philip A Cole and Alfonso Bellacosa and Andrew J Andrews},

doi = {10.1021/acs.biochem.6b00841},

issn = {1520-4995},

year  = {2016},

date = {2016-12-01},

journal = {Biochemistry},

volume = {55},

number = {49},

pages = {6766-6775},

abstract = {How protein-protein interactions regulate and alter histone modifications is a major unanswered question in epigenetics. The histone acetyltransferase p300 binds thymine DNA glycosylase (TDG); utilizing mass spectrometry to measure site-specific changes in histone acetylation, we found that the absence of TDG in mouse embryonic fibroblasts leads to a reduction in the rate of histone acetylation. We demonstrate that TDG interacts with the CH3 domain of p300 to allosterically promote p300 activity to specific lysines on histone H3 (K18 and K23). However, when TDG concentrations approach those of histones, TDG acts as a competitive inhibitor of p300 histone acetylation. These results suggest a mechanism for how histone acetylation is fine-tuned via interaction with other proteins, while also highlighting a connection between regulators of two important biological processes: histone acetylation and DNA repair/demethylation.},

keywords = {Acetylation, Animals, Cell Line, Cells, Cultured, DNA Repair, E1A-Associated p300 Protein, Histones, Knockout, Mice, Thymine DNA Glycosylase},

pubstate = {published},

tppubtype = {article}

}

@article{1299963,

title = {Modulation of p300/CBP Acetylation of Nucleosomes by Bromodomain Ligand I-CBP112},

author = {B. E. Zucconi and B. Luef and W. Xu and R. A. Henry and I. M. Nodelman and G. D. Bowman and A. J Andrews and P. A. Cole},

doi = {10.1021/acs.biochem.6b00480},

issn = {1520-4995},

year  = {2016},

date = {2016-00-00},

journal = {Biochemistry},

volume = {55},

number = {27},

pages = {3727-34},

abstract = {The histone acetyltransferase (HAT) enzymes p300 and CBP are closely related paralogs that serve as transcriptional coactivators and have been found to be dysregulated in cancer and other diseases. p300/CBP is a multidomain protein and possesses a highly conserved bromodomain that has been shown to bind acetylated Lys residues in both proteins and various small molecules, including I-CBP112 and CBP30. Here we show that the ligand I-CBP112 can stimulate nucleosome acetylation up to 3-fold while CBP30 does not. Activation of p300/CBP by I-CBP112 is not observed with the isolated histone H3 substrate but requires a nucleosome substrate. I-CBP112 does not impact nucleosome acetylation by the isolated p300 HAT domain, and the effects of I-CBP112 on p300/CBP can be neutralized by CBP30, suggesting that I-CBP112 likely allosterically activates p300/CBP through bromodomain interactions. Using mass spectrometry and Western blots, we have found that I-CBP112 particularly stimulates acetylation of Lys18 of histone H3 (H3K18) in nucleosomes, an established in vivo site of p300/CBP. In addition, we show that I-CBP112 enhances H3K18 acetylation in acute leukemia and prostate cancer cells in a concentration range commensurate with its antiproliferative effects. Our findings extend the known pharmacology of bromodomain ligands in the regulation of p300/CBP and suggest a novel approach to modulating histone acetylation in cancer.},

keywords = {Acetylation, Bromine Compounds, Cell Proliferation, Crystallography, Cultured, E1A-Associated p300 Protein, Histones, Humans, Leukemia, Male, Models, Molecular, Mutagenesis, Nucleosomes, p300-CBP Transcription Factors, Prostatic Neoplasms, Protein Binding, Protein Conformation, Site-Directed, Tumor Cells, X-Ray},

pubstate = {published},

tppubtype = {article}

}

@article{1299979,

title = {Two histone/protein acetyltransferases, CBP and p300, are indispensable for Foxp3+ T-regulatory cell development and function},

author = {Yujie Liu and Liqing Wang and Rongxiang Han and Ulf H Beier and Tatiana Akimova and Tricia Bhatti and Haiyan Xiao and Philip A Cole and Paul K Brindle and Wayne W Hancock},

doi = {10.1128/MCB.00919-14},

issn = {1098-5549},

year  = {2014},

date = {2014-11-01},

journal = {Mol Cell Biol},

volume = {34},

number = {21},

pages = {3993-4007},

abstract = {T-regulatory (Treg) cells are important to immune homeostasis, and Treg cell deficiency or dysfunction leads to autoimmune disease. A histone/protein acetyltransferase (HAT), p300, was recently found to be important for Treg function and stability, but further insights into the mechanisms by which p300 or other HATs affect Treg biology are needed. Here we show that CBP, a p300 paralog, is also important in controlling Treg function and stability. Thus, while mice with Treg-specific deletion of CBP or p300 developed minimal autoimmune disease, the combined deletion of CBP and p300 led to fatal autoimmunity by 3 to 4 weeks of age. The effects of CBP and p300 deletion on Treg development are dose dependent and involve multiple mechanisms. CBP and p300 cooperate with several key Treg transcription factors that act on the Foxp3 promoter to promote Foxp3 production. CBP and p300 also act on the Foxp3 conserved noncoding sequence 2 (CNS2) region to maintain Treg stability in inflammatory environments by regulating pCREB function and GATA3 expression, respectively. Lastly, CBP and p300 regulate the epigenetic status and function of Foxp3. Our findings provide insights into how HATs orchestrate multiple aspects of Treg development and function and identify overlapping but also discrete activities for p300 and CBP in control of Treg cells.},

keywords = {Animals, Cell Survival, Colitis, CREB-Binding Protein, Cyclic AMP Response Element-Binding Protein, E1A-Associated p300 Protein, Epigenesis, Female, Forkhead Transcription Factors, GATA3 Transcription Factor, Genetic, Humans, Inbred C57BL, Male, Mice, Promoter Regions, Regulatory, Sequence Deletion, T-Lymphocytes},

pubstate = {published},

tppubtype = {article}

}

@article{1299941,

title = {Endotoxemia-mediated activation of acetyltransferase P300 impairs insulin signaling in obesity},

author = {Jia Cao and Jinghua Peng and Hongying An and Qiyi He and Tatiana Boronina and Shaodong Guo and Morris F White and Philip A Cole and Ling He},

doi = {10.1038/s41467-017-00163-w},

issn = {2041-1723},

journal = {Nat Commun},

volume = {8},

number = {1},

pages = {131},

abstract = {Diabetes and obesity are characterized by insulin resistance and chronic low-grade inflammation. An elevated plasma concentration of lipopolysaccharide (LPS) caused by increased intestinal permeability during diet-induced obesity promotes insulin resistance in mice. Here, we show that LPS induces endoplasmic reticulum (ER) stress and protein levels of P300, an acetyltransferase involved in glucose production. In high-fat diet fed and genetically obese ob/ob mice, P300 translocates from the nucleus into the cytoplasm of hepatocytes. We also demonstrate that LPS activates the transcription factor XBP1 via the ER stress sensor IRE1, resulting in the induction of P300 which, in turn, acetylates IRS1/2, inhibits its association with the insulin receptor, and disrupts insulin signaling. Pharmacological inhibition of P300 acetyltransferase activity by a specific inhibitor improves insulin sensitivity and decreases hyperglycemia in obese mice. We suggest that P300 acetyltransferase activity may be a promising therapeutic target for the treatment of obese patients.Elevated plasma LPS levels have been associated with insulin resistance. Here Cao et al. show that LPS induces ER stress and P300 activity via the XBP1/IRE1 pathway. P300 acetylates IRS1/2 and inhibits its binding with the insulin receptor. The consequent impairment of insulin signaling can be rescued by pharmacological inhibition of P300.},

keywords = {Animals, Cell Line, E1A-Associated p300 Protein, Endoplasmic Reticulum Stress, Endotoxemia, Gene Expression Profiling, Immunoblotting, Inbred C57BL, Insulin, Insulin Resistance, Lipopolysaccharides, Liver, Male, Membrane Proteins, Mice, Obese, Obesity, Protein-Serine-Threonine Kinases, Receptor, Signal Transduction, Tumor, X-Box Binding Protein 1},

pubstate = {published},

tppubtype = {article}

}

@article{1624368,

title = {Discovery of spirohydantoins as selective, orally bioavailable inhibitors of p300/CBP histone acetyltransferases},

author = {Zhiqin Ji and Richard F Clark and Vikram Bhat and T Matthew Hansen and Loren M Lasko and Kenneth D Bromberg and Vlasios Manaves and Mikkel Algire and Ruth Martin and Wei Qiu and Maricel Torrent and Clarissa G Jakob and Hong Liu and Philip A Cole and Ronen Marmorstein and Edward A Kesicki and Albert Lai and Michael R Michaelides},

doi = {10.1016/j.bmcl.2021.127854},

issn = {1464-3405},

journal = {Bioorg Med Chem Lett},

volume = {39},

pages = {127854},

abstract = {p300 and CREB-binding protein (CBP) are essential for a multitude of cellular processes. Dysregulation of p300/CBP histone acetyltransferase activity is linked to a broad spectrum of human diseases including cancers. A novel drug-like spirohydantoin (21) has been discovered as a selective orally bioavailable inhibitor of p300/CBP histone acetyltransferase. Lead compound 21 is more potent than the first-in-class lead A-485 in both enzymatic and cellular assays and lacks the off-target inhibition of dopamine and serotonin transporters, that was observed with A-485.},

keywords = {Administration, Biological Availability, CREB-Binding Protein, Dose-Response Relationship, Drug, Drug Discovery, E1A-Associated p300 Protein, Enzyme Inhibitors, Humans, Hydantoins, Molecular Structure, Oral, Spiro Compounds, Structure-Activity Relationship},

pubstate = {published},

tppubtype = {article}

}