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https://www.readbyqxmd.com/read/28893318/icg-001-suppresses-growth-of-gastric-cancer-cells-and-reduces-chemoresistance-of-cancer-stem-cell-like-population
#1
Yi Liu, Hui Chen, Peiming Zheng, Yingxia Zheng, Qin Luo, Guohua Xie, Yanhui Ma, Lisong Shen
BACKGROUND: ICG-001, a small molecule, binds CREB-binding protein (CBP) to disrupt its interaction with β-catenin and inhibits CBP function as a co-activator of Wnt/β-catenin-mediated transcription. Given its ability to inhibit Wnt/β-catenin signaling pathway, ICG-001 has been used in some tumor types to exert its anticarcinogenic effect. Here, we examined ICG-001 and its potential role as a therapeutic in gastric cancer (GC). METHODS: The gastric cancer cell lines SGC-7901, MGC-803, BGC-823 and MKN-45 were used in vitro and in vivo...
September 11, 2017: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/28892380/gne-781-a-highly-advanced-potent-and-selective-bromodomain-inhibitor-of-cyclic-adenosine-monophosphate-response-element-binding-protein-binding-protein-cbp
#2
F Anthony Romero, Jeremy M Murray, Kwong Wah Lai, Vickie Tsui, Brian K Albrecht, Le An, Maureen H Beresini, Gladys de Leon Boenig, Sarah M Bronner, Emily W Chan, Kevin X Chen, Zhongguo Chen, Edna F Choo, Kyle Clagg, Kevin Clark, Terry D Crawford, Patrick Cyr, Denise De Almeida Nagata, Karen E Gascoigne, Jane L Grogan, Georgia Hatzivassiliou, Wei Huang, Thomas L Hunsaker, Susan Kaufman, Stefan G Koenig, Ruina Li, Yingjie Li, Xiaorong Liang, Jiangpeng Liao, Wenfeng Liu, Justin Q Ly, Jonathan Maher, Colin Masui, Mark Merchant, Yingqing Ran, Alexander M Taylor, John S Wai, Fei Wang, Xiaocang Wei, Dong Yu, Bing-Yan Zhu, Xiaoyu Zhu, Steven R Magnuson
Inhibition of the bromodomain of the transcriptional regulator CBP/P300 is an especially interesting new therapeutic approach in oncology. We recently disclosed in vivo chemical tool 1 (GNE-272) for the bromodomain of CBP that was moderately potent and selective over BRD4(1). In pursuit of a more potent and selective CBP inhibitor we used structure-based design. Constraining the aniline of 1 into a tetrahydroquinoline motif maintained potency and increased selectivity 2-fold. Structure-activity relationship studies coupled with further structure-based design targeting the LPF shelf, BC loop and KAc regions allowed us to significantly increase potency and selectivity, resulting in the identification of non-CNS penetrant 19 (GNE-781; TR-FRET IC50 = 0...
September 11, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28891741/erna-binding-produces-tailored-cbp-activity-profiles-to-regulate-gene-expression
#3
Daniel A Bose, Shelley L Berger
Enhancers are cis- regulatory genetic elements crucial for controlling temporal and cell-type specific patterns of gene expression. Active enhancers generate bi-directional non-coding RNA transcripts called enhancer RNAs (eRNAs). eRNAs are important for stimulating gene expression, but precise mechanisms for this ability remain unclear. Here we highlight recent findings that demonstrate a direct interaction between RNAs and the transcriptional co-activator Creb-binding protein (CBP). Notably, RNA binding could stimulate the core histone acetyltransferase activity of the enzyme, observable in cells as a link between eRNA production, CBP-dependent histone acetylation and expression of genes regulated by specific enhancers...
September 11, 2017: RNA Biology
https://www.readbyqxmd.com/read/28846111/acetylation-is-essential-for-nuclear-heme-oxygenase-1-enhanced-tumor-growth-and-invasiveness
#4
F-F Hsu, M-T Chiang, F-A Li, C-T Yeh, W-H Lee, L-Y Chau
Overexpression of heme oxygenase-1 (HO-1), an endoplasmic reticulum-anchored enzyme, is observed in many cancers. HO-1 nuclear translocation has been shown to correlate with progression of several cancers. We recently reported that HO-1 is susceptible to intramembrane proteolysis and translocates to the nucleus to promote cancer growth and invasiveness without depending on its enzymatic activity. In the present study, we show that the HO-1 lacking C-terminal transmembrane segment (t-HO-1) was susceptible to acetylation by p300 and CREB-binding protein (CBP) histone acetyltransferase in the nucleus...
August 28, 2017: Oncogene
https://www.readbyqxmd.com/read/28844863/structural-and-functional-impacts-of-er-coactivator-sequential-recruitment
#5
Ping Yi, Zhao Wang, Qin Feng, Chao-Kai Chou, Grigore D Pintilie, Hong Shen, Charles E Foulds, Guizhen Fan, Irina Serysheva, Steven J Ludtke, Michael F Schmid, Mien-Chie Hung, Wah Chiu, Bert W O'Malley
Nuclear receptors recruit multiple coactivators sequentially to activate transcription. This "ordered" recruitment allows different coactivator activities to engage the nuclear receptor complex at different steps of transcription. Estrogen receptor (ER) recruits steroid receptor coactivator-3 (SRC-3) primary coactivator and secondary coactivators, p300/CBP and CARM1. CARM1 recruitment lags behind the binding of SRC-3 and p300 to ER. Combining cryo-electron microscopy (cryo-EM) structure analysis and biochemical approaches, we demonstrate that there is a close crosstalk between early- and late-recruited coactivators...
September 7, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28819026/therapeutic-targeting-of-the-cbp-p300-bromodomain-blocks%C3%A2-the-growth-of-castration-resistant-prostate-cancer
#6
Lingyan Jin, Jesse Garcia, Emily Chan, Cecile de la Cruz, Ehud Segal, Mark Merchant, Samir Kharbanda, Ryan Raisner, Peter M Haverty, Zora Modrusan, Justin Ly, Edna Choo, Susan Kaufman, Maureen H Beresini, F Anthony Romero, Steven Magnuson, Karen E Gascoigne
Resistance invariably develops to anti-androgen therapies used to treat newly diagnosed prostate cancers, but effective treatments for castration-resistant disease remain elusive. Here we report that the transcriptional co-activator CBP/p300 is required to maintain the growth of castration-resistant prostate cancer. To exploit this vulnerability, we developed a novel small-molecule inhibitor of the CBP/p300 bromodomain that blocks prostate cancer growth in vitro and in vivo. Molecular dissection of the consequences of drug treatment revealed a critical role for CBP/p300 in histone acetylation required for the transcriptional activity of the androgen receptor and its target gene expression...
August 17, 2017: Cancer Research
https://www.readbyqxmd.com/read/28790157/sirt7-and-the-dead-box-helicase-ddx21-cooperate-to-resolve-genomic-r-loops-and-safeguard-genome-stability
#7
Chenlin Song, Agnes Hotz-Wagenblatt, Renate Voit, Ingrid Grummt
R loops are three-stranded nucleic acid structures consisting of an RNA:DNA heteroduplex and a "looped-out" nontemplate strand. As aberrant formation and persistence of R loops block transcription elongation and cause DNA damage, mechanisms that resolve R loops are essential for genome stability. Here we show that the DEAD (Asp-Glu-Ala-Asp)-box RNA helicase DDX21 efficiently unwinds R loops and that depletion of DDX21 leads to accumulation of cellular R loops and DNA damage. Significantly, the activity of DDX21 is regulated by acetylation...
August 8, 2017: Genes & Development
https://www.readbyqxmd.com/read/28782640/effect-of-melatonin-on-neuronal-differentiation-requires-cbp-p300-mediated-acetylation-of-histone-h3-lysine-14
#8
Xian Li, Xueran Chen, Wenjuan Zhou, Shufang Ji, Xinyue Li, Guanchong Li, Guowei Liu, Fuwu Wang, Aijun Hao
The transition from multipotent neural stem cells (NSCs) to terminally differentiated neurons is a multistep process, and the transition is finely regulated by transcription factors with basic helix-loop-helix (bHLH) motifs. Melatonin is an endogenous neurohormone with profound neurotrophic and neuroprotective effects both during the embryonic developmental stage and adulthood. The effects of melatonin on the differentiation of NSCs have been reported, and these effects may be responsible for its neuroprotective properties...
August 3, 2017: Neuroscience
https://www.readbyqxmd.com/read/28768874/pgc1%C3%AE-transcriptional-adaptor-function-governs-hepatitis-b-virus-replication-by-controlling-hbcag-p21-protein-mediated-capsid-formation
#9
Rasha E Shalaby, Saira Iram, Bülent Çakal, Claudia E Oropeza, Alan McLachlan
In the human hepatoma cell line, Huh7, co-expression of the coactivators, peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α), cAMP responsive element binding protein binding protein (CBP), steroid receptor coactivator 1 (SRC1) and protein arginine methyltransferase 1 (PRMT1) only modestly increase HBV biosynthesis. However, utilizing the human embryonic kidney cell line, HEK293T, it was possible to demonstrate that PGC1α alone can support viral biosynthesis independently of additional coactivator or transcription factor expression...
August 2, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28752224/early-preclinical-changes-in-hippocampal-creb-binding-protein-expression-in-a-mouse-model-of-familial-alzheimer-s-disease
#10
Miren Ettcheto, Sonia Abad, Dmitry Petrov, Ignacio Pedrós, Oriol Busquets, Elena Sánchez-López, Gemma Casadesús, Carlos Beas-Zarate, Eva Carro, Carme Auladell, Jordi Olloquequi, Merce Pallàs, Jaume Folch, Antoni Camins
The molecular basis of memory loss in Alzheimer's disease (AD), the main cause of senile dementia, is under investigation. In the present study, we have focused on the early hippocampal memory-related changes in APPswe/PS1dE9 (APP/PS1) mice, a well-established mouse model of familial AD. It is well known that molecules like cAMP response element binding (CREB) and binding protein (CBP) play a crucial role in memory consolidation. We analyzed CBP on its transcriptional activity and protein levels, finding a significant downregulation of both of them at 3-month-old mice...
July 27, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28751935/chk1-promotes-dna-damage-response-bypass-following-oxidative-stress-in-a-model-of-hydrogen-peroxide-associated-ulcerative-colitis-through-jnk-inactivation-and-chromatin-binding
#11
Kathrin Reissig, Andrew Silver, Roland Hartig, Antje Schinlauer, Diana Walluscheck, Thomas Guenther, Sandra Siedentopf, Jochen Ross, Diep-Khanh Vo, Albert Roessner, Angela Poehlmann-Nitsche
Dysregulation of c-Jun N-terminal kinase (JNK) activation promoted DNA damage response bypass and tumorigenesis in our model of hydrogen peroxide-associated ulcerative colitis (UC) and in patients with quiescent UC (QUC), UC-related dysplasia, and UC-related carcinoma (UC-CRC), thereby adapting to oxidative stress. In the UC model, we have observed features of oncogenic transformation: increased proliferation, undetected DNA damage, and apoptosis resistance. Here, we show that Chk1 was downregulated but activated in the acute and quiescent chronic phases...
2017: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/28740501/hac1-and-haf1-histone-acetyltransferases-have-different-roles-in-uv-b-responses-in-arabidopsis
#12
Julieta P Fina, Fiorella Masotti, Sebastián P Rius, Franco Crevacuore, Paula Casati
Arabidopsis has 12 histone acetyltransferases grouped in four families: the GNAT/HAG, the MYST/HAM, the p300/CBP/HAC and the TAFII250/HAF families. We previously showed that ham1 and ham2 mutants accumulated higher damaged DNA after UV-B exposure than WT plants. In contrast, hag3 RNA interference transgenic plants showed less DNA damage and lower inhibition of plant growth by UV-B, and increased levels of UV-B-absorbing compounds. These results demonstrated that HAM1, HAM2, and HAG3 participate in UV-B-induced DNA damage repair and signaling...
2017: Frontiers in Plant Science
https://www.readbyqxmd.com/read/28713342/nf-%C3%AE%C2%BAbp50-and-hdac1-interaction-is-implicated-in-the-host-tolerance-to-infection-mediated-by-the-bacterial-quorum-sensing-signal-2-aminoacetophenone
#13
Arunava Bandyopadhaya, Amy Tsurumi, Laurence G Rahme
Some bacterial quorum sensing (QS) small molecules are important mediators of inter-kingdom signaling and impact host immunity. The QS regulated small volatile molecule 2-aminoacetophenone (2-AA), which has been proposed as a biomarker of Pseudomonas aeruginosa colonization in chronically infected human tissues, is critically involved in "host tolerance training" that involves a distinct molecular mechanism of host chromatin regulation through histone deacetylase (HDAC)1. 2-AA's epigenetic reprogramming action enables host tolerance to high bacterial burden and permits long-term presence of P...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28700938/golgi-outpost-synthesis-impaired-by-toxic-polyglutamine-proteins-contributes-to-dendritic-pathology-in-neurons
#14
Chang Geon Chung, Min Jee Kwon, Keun Hye Jeon, Do Young Hyeon, Myeong Hoon Han, Jeong Hyang Park, In Jun Cha, Jae Ho Cho, Kunhyung Kim, Sangchul Rho, Gyu Ree Kim, Hyobin Jeong, Jae Won Lee, TaeSoo Kim, Keetae Kim, Kwang Pyo Kim, Michael D Ehlers, Daehee Hwang, Sung Bae Lee
Dendrite aberration is a common feature of neurodegenerative diseases caused by protein toxicity, but the underlying mechanisms remain largely elusive. Here, we show that nuclear polyglutamine (polyQ) toxicity resulted in defective terminal dendrite elongation accompanied by a loss of Golgi outposts (GOPs) and a decreased supply of plasma membrane (PM) in Drosophila class IV dendritic arborization (da) (C4 da) neurons. mRNA sequencing revealed that genes downregulated by polyQ proteins included many secretory pathway-related genes, including COPII genes regulating GOP synthesis...
July 11, 2017: Cell Reports
https://www.readbyqxmd.com/read/28680062/linking-functions-an-additional-role-for-an-intrinsically-disordered-linker-domain-in-the-transcriptional-coactivator-cbp
#15
Sara Contreras-Martos, Alessandro Piai, Simone Kosol, Mihaly Varadi, Angela Bekesi, Pierre Lebrun, Alexander N Volkov, Kris Gevaert, Roberta Pierattelli, Isabella C Felli, Peter Tompa
The multi-domain transcriptional coactivators CBP/p300 integrate a multitude of signaling inputs, interacting with more than 400 proteins via one or more of their globular domains. While CBP/p300 function is typically considered in terms of these structured domains, about half of the protein consists of intrinsically disordered regions (IDRs) of varying length. However, these IDRs have only been thought of as linkers that allow flexible spatial arrangement of the structured domains, but recent studies have shown that similar IDRs mediate specific and critical interactions in other proteins...
July 5, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28669924/histone-h3-lysine-4-methyltransferase-kmt2d
#16
REVIEW
Eugene Froimchuk, Younghoon Jang, Kai Ge
Histone-lysine N-methyltransferase 2D (KMT2D), also known as MLL4 and MLL2 in humans and Mll4 in mice, belongs to a family of mammalian histone H3 lysine 4 (H3K4) methyltransferases. It is a large protein over 5500 amino acids in size and is partially functionally redundant with KMT2C. KMT2D is widely expressed in adult tissues and is essential for early embryonic development. The C-terminal SET domain is responsible for its H3K4 methyltransferase activity and is necessary for maintaining KMT2D protein stability in cells...
September 5, 2017: Gene
https://www.readbyqxmd.com/read/28638460/zeb1-mediates-drug-resistance-and-emt-in-p300-deficient-crc
#17
Darina Lazarova, Michael Bordonaro
We discuss the hypothesis that ZEB1-Wnt-p300 signaling integrates epithelial to mesenchymal transition (EMT) and resistance to histone deacetylase inhibitors (HDACis) in colorectal cancer (CRC) cells. The HDACi butyrate, derived from dietary fiber, has been linked to CRC prevention, and other HDACis have been proposed as therapeutic agents against CRC. We have previously discussed that resistance to butyrate likely contributes to colonic carcinogenesis, and we have demonstrated that butyrate resistance leads to cross-resistance to cancer therapeutic HDACis...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/28627884/hydrogen-deuterium-exchange-mass-spectrometry-reveals-calcium-binding-properties-and-allosteric-regulation-of-downstream-regulatory-element-antagonist-modulator-dream
#18
Jun Zhang, Jing Li, Theodore A Craig, Rajiv Kumar, Michael L Gross
Downstream regulatory element antagonist modulator (DREAM) is an EF-hand Ca(2+)-binding protein that also binds to a specific DNA sequence, downstream regulatory elements (DRE), and thereby regulates transcription in a calcium-dependent fashion. DREAM binds to DRE in the absence of Ca(2+) but detaches from DRE under Ca(2+) stimulation, allowing gene expression. The Ca(2+) binding properties of DREAM and the consequences of the binding on protein structure are key to understanding the function of DREAM. Here we describe the application of hydrogen-deuterium exchange mass spectrometry (HDX-MS) and site-directed mutagenesis to investigate the Ca(2+) binding properties and the subsequent conformational changes of full-length DREAM...
July 18, 2017: Biochemistry
https://www.readbyqxmd.com/read/28625977/acetylation-of-mastermind-like-1-by-p300-drives-the-recruitment-of-nack-to-initiate-notch-dependent-transcription
#19
Ke Jin, Wen Zhou, Xiaoqing Han, Zhiqiang Wang, Bin Li, Shawn Jeffries, Wensi Tao, David J Robbins, Anthony J Capobianco
Although it has long been appreciated that p300 acts as a critical Notch coactivator, the mechanistic details of p300 in Notch-mediated transcription remain unclear. We previously demonstrated that PEAK1-related kinase activating pseudokinase 1 (NACK), also known as SGK223, is a critical coactivator of Notch signaling and binds to the Notch1 ternary complex. Herein we report that p300 and CBP acetylate Mastermind-like 1 (Maml1) on amino acid residues K188 and K189 to recruit NACK to the Notch1 ternary complex, which results in the recruitment of RNA polymerase II to initiate transcription...
August 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28616572/reversible-lysine-acetylation-regulates-nuclear-translocation-of-tyrrs-to-counteract-genotoxic-oxidative-stress
#20
Chaoqun Li, Wei Yu
Aminoacyl-tRNA synthetases, catalyzing the first step of protein synthesis, have been shown to involve with multiple additional physiologic responses. Here, we summarize our findings that p300/CBP-Associated Factor and Sirtuin 1 play the reversible acetylation role in regulating the nuclear translocation of Tyrosyl-tRNA synthetase and activating transcription factor E2F1, thus facilitating the repair of damaged DNA.
2017: Molecular & Cellular Oncology
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