@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{1299964,

title = {Correction to Protein Lysine Acetylation by p300/CBP},

author = {Beverley M Dancy and Philip A Cole},

doi = {10.1021/acs.chemrev.6b00351},

issn = {1520-6890},

journal = {Chem Rev},

volume = {116},

number = {14},

pages = {8314},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{1299965,

title = {Enzymatic Analysis of PTEN Ubiquitylation by WWP2 and NEDD4-1 E3 Ligases},

author = {Zan Chen and Stefani N Thomas and David M Bolduc and Xuejun Jiang and Xiangbin Zhang and Cynthia Wolberger and Philip A Cole},

doi = {10.1021/acs.biochem.6b00448},

issn = {1520-4995},

journal = {Biochemistry},

volume = {55},

number = {26},

pages = {3658-66},

abstract = {PTEN is a lipid phosphatase that converts phosphatidylinositol 3,4,5-phosphate (PIP3) to phosphatidylinositol 4,5-phosphate (PIP2) and plays a critical role in the regulation of tumor growth. PTEN is subject to regulation by a variety of post-translational modifications, including phosphorylation on a C-terminal cluster of four Ser/Thr residues (380, 382, 383, and 385) and ubiquitylation by various E3 ligases, including NEDD4-1 and WWP2. It has previously been shown that C-terminal phosphorylation of PTEN can increase its cellular half-life. Using in vitro ubiquitin transfer assays, we show that WWP2 is more active than NEDD4-1 in ubiquitylating unphosphorylated PTEN. The mapping of ubiquitylation sites in PTEN by mass spectrometry showed that both NEDD4-1 and WWP2 can target a broad range of Lys residues in PTEN, although NEDD4-1 versus WWP2 showed a stronger preference for ubiquitylating PTEN’s C2 domain. Whereas tetraphosphorylation of PTEN did not significantly affect its ubiquitylation by NEDD4-1, it inhibited PTEN ubiquitylation by WWP2. Single-turnover and pull-down experiments suggested that tetraphosphorylation of PTEN appears to weaken its interaction with WWP2. These studies reveal how the PTEN E3 ligases WWP2 and NEDD4-1 exhibit distinctive properties in Lys selectivity and sensitivity to PTEN phosphorylation. Our findings also provide a molecular mechanism for the connection between PTEN Ser/Thr phosphorylation and PTEN’s cellular stability.},

keywords = {Chromatography, Endosomal Sorting Complexes Required for Transport, Humans, Immunoprecipitation, Liquid, Nedd4 Ubiquitin Protein Ligases, Phosphorylation, Post-Translational, Protein Processing, PTEN Phosphohydrolase, Tandem Mass Spectrometry, Ubiquitin, Ubiquitin-Protein Ligases, Ubiquitination, X-Linked Inhibitor of Apoptosis Protein},

pubstate = {published},

tppubtype = {article}

}

@article{1299962,

title = {Erratum to: CBP binding outside of promoters and enhancers in Drosophila melanogaster},

author = {Philge Philip and Ann Boija and Roshan Vaid and Allison M Churcher and David J Meyers and Philip A Cole and Mattias Mannervik and Per Stenberg},

doi = {10.1186/s13072-016-0088-y},

issn = {1756-8935},

journal = {Epigenetics Chromatin},

volume = {9},

number = {1},

pages = {38},

abstract = {[This corrects the article DOI: 10.1186/s13072-015-0042-4.].},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{1299961,

title = {An Fc-Small Molecule Conjugate for Targeted Inhibition of the Adenosine 2A Receptor},

author = {Po-Yuan Hsiao and Jay H Kalin and Im-Hong Sun and Mohammed N Amin and Ying-Chun Lo and Meng-Jung Chiang and John Giddens and Polina Sysa-Shah and Kathleen Gabrielson and Lai-Xi Wang and Jonathan D Powell and Philip A Cole},

doi = {10.1002/cbic.201600337},

issn = {1439-7633},

journal = {Chembiochem},

volume = {17},

number = {20},

pages = {1951-1960},

abstract = {The adenosine A2A receptor (A2A R) is expressed in immune cells, as well as brain and heart tissue, and has been intensively studied as a therapeutic target for multiple disease indications. Inhibitors of the A2A R have the potential for stimulating immune response, which could be valuable for cancer immune surveillance and mounting a response against pathogens. One well-established potent and selective small molecule A2A R antagonist, ZM-241385 (ZM), has a short pharmacokinetic half-life and the potential for systemic toxicity due to A2A R effects in the brain and the heart. In this study, we designed an analogue of ZM and tethered it to the Fc domain of the immunoglobulin IgG3 by using expressed protein ligation. The resulting protein-small molecule conjugate, Fc-ZM, retained high affinity for two Fc receptors: FcγRI and the neonatal Fc receptor, FcRn. In addition, Fc-ZM was a potent A2A R antagonist, as measured by a cell-based cAMP assay. Cell-based assays also revealed that Fc-ZM could stimulate interferon γ production in splenocytes in a fashion that was dependent on the presence of A2A R. We found that Fc-ZM, compared with the small molecule ZM, was a superior A2A R antagonist in mice, consistent with the possibility that Fc attachment can improve pharmacokinetic and/or pharmacodynamic properties of the small molecule.},

keywords = {Adenosine A2 Receptor Antagonists, Adenosine A2A, Animals, Female, Humans, Immunoglobulin Fab Fragments, Inbred C57BL, Knockout, Male, Mice, Models, Molecular, Molecular Structure, Receptor, Respiratory Tract Infections, Triazines, Triazoles, Vaccinia virus},

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}

}

@article{1624367,

title = {HDAC2 targeting stabilizes the CoREST complex in renal tubular cells and protects against renal ischemia/reperfusion injury},

author = {David D Aufhauser and Paul Hernandez and Seth J Concors and Ciaran O’Brien and Zhonglin Wang and Douglas R Murken and Arabinda Samanta and Ulf H Beier and Lauren Krumeich and Tricia R Bhatti and Yanfeng Wang and Guanghui Ge and Liqing Wang and Shayan Cheraghlou and Florence F Wagner and Edward B Holson and Jay H Kalin and Philip A Cole and Wayne W Hancock and Matthew H Levine},

doi = {10.1038/s41598-021-88242-3},

issn = {2045-2322},

journal = {Sci Rep},

volume = {11},

number = {1},

pages = {9018},

abstract = {Histone/protein deacetylases (HDAC) 1 and 2 are typically viewed as structurally and functionally similar enzymes present within various co-regulatory complexes. We tested differential effects of these isoforms in renal ischemia reperfusion injury (IRI) using inducible knockout mice and found no significant change in ischemic tolerance with HDAC1 deletion, but mitigation of ischemic injury with HDAC2 deletion. Restriction of HDAC2 deletion to the kidney via transplantation or PAX8-controlled proximal renal tubule-specific Cre resulted in renal IRI protection. Pharmacologic inhibition of HDAC2 increased histone acetylation in the kidney but did not extend renal protection. Protein analysis demonstrated increased HDAC1-associated CoREST protein in HDAC2-/- versus WT cells, suggesting that in the absence of HDAC2, increased CoREST complex occupancy of HDAC1 can stabilize this complex. In vivo administration of a CoREST inhibitor exacerbated renal injury in WT mice and eliminated the benefit of HDAC2 deletion. Gene expression analysis of endothelin showed decreased endothelin levels in HDAC2 deletion. These data demonstrate that contrasting effects of HDAC1 and 2 on CoREST complex stability within renal tubules can affect outcomes of renal IRI and implicate endothelin as a potential downstream mediator.},

keywords = {Animals, Co-Repressor Proteins, Endothelins, Enzyme Inhibitors, Female, Gene Deletion, Histone Deacetylase 1, Histone Deacetylase 2, Isoenzymes, Kidney Tubules, Knockout, Male, Mice, Proximal, Reperfusion Injury},

pubstate = {published},

tppubtype = {article}

}