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Molecular Pharmacology

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https://www.readbyqxmd.com/read/28087810/akt1-lkb1-and-yap1-revealed-as-myc-interactors-with-nanoluc-based-protein-fragment-complementation-assay
#1
Xiu-Lei Mo, Qi Qi, Andrei A Ivanov, Qiankun Niu, Yin Luo, Jonathan Havel, Russell Goetze, Sydney Bell, Carlos S Moreno, Lee A D Cooper, Margaret A Johns, Fadlo R Khuri, Yuhong Du, Haian Fu
The c-Myc (MYC) transcription factor is a major cancer driver and a well-validated therapeutic target. However, directly targeting MYC has been challenging. Thus, identifying proteins that interact with and regulate MYC may provide alternative strategies to inhibit its oncogenic activity. Here we report the development of a NanoLuc®-based protein-fragment complementation assay (NanoPCA) and mapping of the MYC protein interaction hub in live mammalian cells. The NanoPCA system was configured to enable detection of protein-protein interactions (PPI) at the endogenous level, as shown with PRAS40 dimerization, and detection of weak interactions, such as PINCH1-NCK2...
January 13, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28087809/trim13-potentiates-tlr2-mediated-nf-%C3%AE%C2%BAb-activation-via-k29-linked-polyubiquitination-of-traf6
#2
Bin Huang, Suk-Hwan Baek
Ubiquitination is a versatile post-translational modification involved in NF-κB activation of TLR signaling. Here, we demonstrated that Trim13, an E3 ubiquitin ligase, is up-regulated in macrophages upon stimulation with TLR2 ligand. Knock-down of Trim13 attenuated TLR2-mediated production of cytokines/chemokines and formation of foam cells, as well as activation of NF-κB. Trim13 interacts with TRAF6 and potentiates NF-κB activity via ubiquitination of TRAF6. Overexpression of inactive mutant (C10/13A) or RING deletion mutant of Trim13 did not potentiate ubiquitination of TRAF6 or activation of NF-κB...
January 13, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28087808/identification-of-a-novel-liver-x-receptor-agonist-that-regulates-the-expression-of-key-cholesterol-homeostasis-genes-with-distinct-pharmacological-characteristics
#3
Ni Li, Xiao Wang, Yanni Xu, Yuan Lin, Ningyu Zhu, Peng Liu, Duo Lu, Shuyi Si
Activation of Liver X receptor (LXR) is associated with cholesterol metabolism and anti-inflammatory processes, which makes beneficial to anti-atherosclerosis. Nevertheless, existing agonists which target LXR, for example TO901317, are related to unwanted side-effects. In the present study, using a screening method we identified IMB-808, which displayed potent dual LXRα/β agonistic activity. In vitro, IMB-808 effectively increased the expressing quantity of genes related to reverse cholesterol transport process as well as those associated with cholesterol metabolism pathway in multiple cell lines...
January 13, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28082305/modulation-of-chemokine-receptor-function-by-cholesterol-new-prospects-for-pharmacological-intervention
#4
Daniel F Legler, Christoph Matti, Julia M Laufer, Barbara D Jakobs, Vladimir Purvanov, Edith Uetz-von Allmen, Marcus Thelen
Chemokine receptors are seven transmembrane-domain receptors belonging to class A of G protein-coupled receptors (GPCRs). The receptors together with their chemokine ligands constitute the chemokine system, which is essential for directing cell migration and plays a crucial role in a variety of physiological and pathological processes. Given the importance of orchestrating cell migration, it is vital that chemokine receptor signaling is tightly regulated to ensure appropriate responses. Recent studies highlight a key role for cholesterol in modulating chemokine receptor activities...
January 12, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28082304/protein-kinase-c-activation-promotes-%C3%AE-1b-adrenoceptor-internalization-and-late-endosome-trafficking-through-rab9-interaction-role-in-heterologous-desensitization
#5
Marco A Alfonzo-Mendez, David A Hernandez-Espinosa, Gabriel Carmona-Rosas, M Teresa Romero-Avila, Guadalupe Reyes-Cruz, J Adolfo Garcia-Sainz
Upon agonist stimulation, α1B-adrenergic receptors (α1B-ARs) couple to Gq, calcium signaling and protein kinase C activation; subsequently, the receptors are phosphorylated, desensitized and internalized. Internalization seems to involve scaffolding proteins, such as α-arrestin and clathrin. However, the fine mechanisms that participate remain unsolved. The roles of protein kinase C and the small GTPase, Rab9, in α1B-AR vesicular traffic were investigated by studying α1B-adrenergic receptor-Rab protein interactions, using Forster resonance energy transfer (FRET), confocal microscopy, and intracellular calcium quantitation...
January 12, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28069778/differential-contribution-of-subunit-interfaces-to-%C3%AE-9%C3%AE-10-nicotinic-acetylcholine-receptor-function
#6
Juan C Boffi, Irina Marcovich, JasKiran K Gill-Thind, Jeremias Corradi, Toby Collins, Maria M Lipovsek, Marcelo Moglie, Paola V Plazas, Patricio O Craig, Neil S Millar, Cecilia Bouzat, Ana Belen Elgoyhen
Nicotinic acetylcholine receptors can be assembled from either homomeric or heteromeric pentameric subunit combinations. At the interface of the extracellular domains of adjacent subunits lies the acetylcholine binding site, composed of a principal component provided by one subunit and a complementary component of the adjacent subunit. Compared to neuronal nAChRs assembled from α and β subunits, the α9α10 receptor is an atypical member of the family. It is a heteromeric receptor composed only of α subunits...
January 9, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28062735/the-ability-of-btk-inhibitors-to-sequester-y551-and-prevent-phosphorylation-determines-potency-for-inhibition-of-fcr-but-not-b-cell-receptor-signaling
#7
Andrew T Bender, Anna Gardberg, Albertina Pereira, Theresa Johenson, Yin Wu, Roland Grenningloh, Jared Head, Federica Morandi, Philipp Haselmayer, Lesley Liu-Bujalski
Bruton's tyrosine kinase (Btk) is expressed in a variety of hematopoietic cells. Btk has been demonstrated to regulate signaling downstream of the B cell receptor (BCR), Fc receptors (FcR), and toll like receptors (TLRs). Btk has become an attractive drug target as Btk inhibition may provide significant efficacy by blocking multiple disease mechanisms simultaneously. Consequently, a large number of Btk inhibitors have been developed. The compounds have diverse binding modes and both reversible and irreversible inhibitors have been developed...
January 6, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28057800/olefin-isomers-of-a-triazole-bisphosphonate-synergistically-inhibit-geranylgeranyl-diphosphate-synthase
#8
Cheryl Allen, Sandhya Kortagere, Huaxiang Tong, Robert A Matthiesen, Joseph I Metzger, David F Wiemer, Sarah A Holstein
The isoprenoid donor for protein geranylgeranylation reactions, geranylgeranyl diphosphate (GGDP), is the product of the enzyme GGDP synthase (GGDPS) which condenses farnesyl diphosphate (FDP) and isopentenyl pyrophosphate. GGDPS inhibition is of interest from a therapeutic perspective for multiple myeloma as we have shown that targeting Rab GTPase geranylgeranylation impairs monoclonal protein trafficking, leading to endoplasmic reticulum stress and apoptosis. We have reported a series of triazole bisphosphonate GGDPS inhibitors of which the most potent was a 3:1 mixture of homogeranyl (HG) and homoneryl (HN) isomers...
January 5, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28049773/crosstalk-between-alternatively-spliced-ugt1a-isoforms-and-colon-cancer-cell-metabolism
#9
Yannick Audet-Delage, Michele Rouleau, Melanie Rouleau, Joannie Roberge, Stephanie Miard, Frederic Picard, Bernard Tetu, Chantal Guillemette
Alternative splicing at the human glucuronosyltransferase 1 gene locus (UGT1) produces alternate isoforms UGT1A_i2s that control glucuronidation activity through protein-protein interactions. Here, we hypothesized that UGT1A_i2s function into a complex protein network connecting other metabolic pathways with influence on cancer cell metabolism. This is based on a pathway enrichment analysis of proteomic data that identified several high-confidence candidate interaction proteins of UGT1A_i2 proteins in human tissues, namely the rate-limiting enzyme of glycolysis pyruvate kinase (PKM), which plays a critical role in cancer cell metabolism and tumor growth...
January 3, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28031332/regulator-of-g-protein-signaling-10-rgs10-expression-is-transcriptionally-silenced-in-activated-microglia-by-histone-deacetylase-activity
#10
Mohammed Alqinyah, Nagini Maganti, Mourad W Ali, Ruchi Yadav, Mei Gao, Han-Rong Weng, Susanna F Greer, Shelley B Hooks
RGS10 has emerged as a key regulator of pro-inflammatory cytokine production in microglia, functioning as an important neuroprotective factor. While RGS10 is normally expressed in microglia at high levels, expression is silenced in vitro following activation of TLR4 receptor. Given the ability of RGS10 to regulate inflammatory signaling, dynamic regulation of RGS10 levels in microglia may be an important mechanism to tune inflammatory responses. The goals of the current study were to confirm that RGS10 is suppressed in an in vivo inflammatory model of microglial activation and to determine the mechanism for activation-dependent silencing of Rgs10 expression in microglia...
December 28, 2016: Molecular Pharmacology
https://www.readbyqxmd.com/read/28007926/circadian-regulation-of-benzo-a-pyrene-metabolism-and-dna-adduct-formation-in-breast-cells-and-the-mouse-mammary-gland
#11
Emily E Schmitt, Rola Barhoumi, Richard P Metz, Weston W Porter
The circadian clock plays a role in many biological processes, yet very little is known about its role in metabolism of drugs and carcinogens. The purpose of this study was to define the impact of circadian rhythms on benzo-a-pyrene (BaP) metabolism in the mouse mammary gland and develop a circadian in vitro model for investigating changes in BaP metabolism resulting from cross-talk between the molecular clock and aryl hydrocarbon receptor. Female 129sv mice (12 weeks old) received a single gavage dose of 50 mg/kg BaP at either noon or midnight, and mammary tissues were isolated 4 or 24 hours later...
December 22, 2016: Molecular Pharmacology
https://www.readbyqxmd.com/read/28003426/pdk4-deficiency-results-in-expedited-cellular-proliferation-through-e2f1-mediated-increase-of-cyclins
#12
Jonathan P Choiniere, Jianguo Wu, Li Wang
Hepatocellular carcinoma (HCC) is a common form of cancer with prevalence worldwide. There are many factors that lead to the development and progression of HCC. The aim of this study was to identify potential new tumor suppressors and examine their function as cell cycle modulators and investigate their impact on the cyclin family of proteins and cyclin dependent kinases. In this study the pyruvate dehydrogenase kinase 4 (PDK4) gene was shown to have potential tumor suppressor characteristics. PDK4 expression was significantly downregulated in human HCC...
December 21, 2016: Molecular Pharmacology
https://www.readbyqxmd.com/read/27974484/buprenorphine-norbuprenorphine-r-methadone-and-s-methadone-upregulate-bcrp-abcg2-expression-by-activating-aryl-hydrocarbon-receptor-in-human-placental-trophoblasts
#13
Naveen K Neradugomma, Michael Z Liao, Qingcheng Mao
Opioid dependence during pregnancy is a rising concern. Maintaining addicted pregnant women on long-acting opioid receptor agonist is the most common strategy to manage pregnancy drug abuse. Methadone (MET) and Buprenorphine (BUP) are widely prescribed for opiate-maintenance therapy. Norbuprenorphine (NBUP) is the primary active metabolite of BUP. These medications can cross the placenta to the fetus, leading to postpartum neonatal abstinence syndrome. Despite their use during pregnancy, little is known about the cellular changes brought about by these drugs in the placenta...
December 14, 2016: Molecular Pharmacology
https://www.readbyqxmd.com/read/27965304/targeted-degradation-of-proteins-localized-in-subcellular-compartments-by-hybrid-small-molecules
#14
Keiichiro Okuhira, Takuji Shoda, Risa Omura, Nobumichi Ohoka, Takayuki Hattori, Norihito Shibata, Yosuke Demizu, Ryo Sugihara, Asato Ichino, Haruka Kawahara, Yukihiro Itoh, Minoru Ishikawa, Yuichi Hashimoto, Masaaki Kurihara, Susumu Itoh, Hiroyuki Saito, Mikihiko Naito
Development of novel small molecules that selectively degrade pathogenic proteins would provide an important advance in targeted therapy. Recently, we have devised a series of hybrid small molecules named SNIPER (Specific and Non-genetic IAP-dependent Protein ERaser) that induces the degradation of target proteins via the ubiquitin-proteasome system. To understand the localization of proteins that can be targeted by this protein knockdown technology, we examined whether SNIPERs are able to induce degradation of CRABP-II proteins localized in subcellular compartments of cells...
December 13, 2016: Molecular Pharmacology
https://www.readbyqxmd.com/read/27932556/orally-administered-berberine-modulates-hepatic-lipid-metabolism-by-altering-microbial-bile-acid-metabolism-and-the-intestinal-fxr-signaling-pathway
#15
Runbin Sun, Na Yang, Bo Kong, Bei Cao, Dong Feng, Xiaoyi Yu, Chun Ge, Jingqiu Huang, Jianliang Shen, Pei Wang, Siqi Feng, Fei Fei, Jiahua Guo, Jun He, Nan Aa, Qiang Chen, Yang Pan, Justin D Schumacher, Chung S Yang, Grace L Guo, Jiye Aa, Guangji Wang
Previous studies suggest that the lipid-lowering effect of BBR involves actions on the LDL receptor and the AMPK signaling pathways. However, the implication of these mechanisms is unclear because of the low bioavailability of BBR. Because the main action site of BBR is the gut and intestinal FXR plays a pivotal role in the regulation of lipid metabolism, we hypothesized that the effects of BBR on intestinal FXR signaling pathway might account for its pharmacological effectiveness. Using wild type (WT) and intestine-specific FXR knockout (FXRint-/-) mice, we found that BBR prevented the development of high-fat-diet induced obesity and ameliorated triglyceride accumulation in livers of WT, but not FXRint-/- mice...
December 8, 2016: Molecular Pharmacology
https://www.readbyqxmd.com/read/27903755/homobivalent-conjugation-increases-the-allosteric-effect-of-9-aminoacridine-at-the-%C3%AE-1-adrenergic-receptors
#16
Adrian P Campbell, Laurence P G Wakelin, William A Denny, Angela M Finch
The α1-adrenergic receptors are targets for a number of cardiovascular and central nervous system conditions, but the current drugs for these receptors lack specificity to be of optimal clinical value. Allosteric modulators offer an alternative mechanism of action to traditional α1-adrenergic ligands, yet there is little information describing this drug class at the α1-adrenergic receptors. We have identified a series of 9-aminoacridine compounds that demonstrate allosteric modulation of the α1A- and α1B-adrenergic receptors...
February 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/27895163/g-protein-coupled-receptor-kinase-2-grk2-as-a-potential-modulator-of-the-hallmarks-of-cancer
#17
Laura Nogues, Clara Reglero, Veronica Rivas, Maria Neves, Petronila Penela, Federico Mayor
Malignant features such as sustained proliferation, refractoriness to growth suppressors, resistance to cell death or aberrant motility and metastasis can be triggered by a variety of mutations and signaling adaptations. Signaling nodes can act as cancer-associated factors by cooperating with oncogene-governed pathways or participating in compensatory transduction networks to strengthen tumor properties. G-protein-coupled receptor kinase 2 (GRK2) is arising as one of such nodes. Via its complex network of connections with other cellular proteins, GRK2 contributes to the modulation of basic cellular functions such as cell proliferation, survival or motility, and is involved in metabolic homeostasis, inflammation or angiogenic processes...
November 28, 2016: Molecular Pharmacology
https://www.readbyqxmd.com/read/27895162/cannabinoid-receptor-interacting-protein-crip-1a-competition-with-%C3%AE-arrestin-for-cb1-receptor-binding-sites
#18
Lawrence C Blume, Theresa Patten, Khalil Eldeeb, Sandra Leone-Kabler, Alexander A Ilyasov, Bradley M Keegan, Jeremy E O'Neal, Caroline E Bass, Roy R Hantgan, W Todd Lowther, Dana E Selley, Allyn C Howlett
Cannabinoid Receptor Interacting Protein1a (CRIP1a) is a CB1 receptor (CB1R) distal C-terminus-associated protein that alters CB1R interactions with G-proteins (Blume et al.,2015; Smith et al.,2015). We tested the hypothesis that CRIP1a is capable of also altering CB1R interactions with β-arrestin proteins that interact with the CB1R at the C-terminal. Co-immunoprecipitation studies indicated that CB1R associates in complexes with either CRIP1a or β-arrestin, but CRIP1a and β-arrestin fail to co-immunoprecipitate with each other...
November 28, 2016: Molecular Pharmacology
https://www.readbyqxmd.com/read/27895161/the-e-loop-of-the-transmitter-binding-site-is-a-key-determinant-of-the-modulatory-effects-of-physostigmine-on-neuronal-nicotinic-%C3%AE-4%C3%AE-2-receptors
#19
Xiaochun Jin, Megan M McCollum, Allison L Germann, Gustav Akk, Joseph H Steinbach
Physostigmine is a well-known inhibitor of acetylcholinesterase, which can also activate, potentiate and inhibit acetylcholine receptors, including neuronal nicotinic receptors comprising α4 and β2 subunits. We have found that the two stoichiometric forms of this receptor differ in the effects of physostigmine. The form containing 3 copies of α4 and 2 of β2 was potentiated at low concentrations of ACh and physostigmine, while the form containing 2 copies of α4 and 3 of β2 was inhibited. Chimeric constructs of subunits indicated that the presence of inhibition or potentiation depended on the source of the extracellular ligand-binding domain of the subunit...
November 28, 2016: Molecular Pharmacology
https://www.readbyqxmd.com/read/27879341/dynamin-functions-and-ligands-classical-mechanisms-behind
#20
Mahaveer Singh, Hemant R Jadhav, Tanya Bhatt
Dynamin is a GTPase that plays a vital role in clathrin-dependent endocytosis and other vesicular trafficking processes by acting as a pair of molecular scissors for newly formed vesicles originating from the plasma membrane. Dynamins and related proteins are important components for the cleavage of clathrin-coated vesicles, phagosomes, and mitochondria. These proteins help in organelle division, viral resistance, and mitochondrial fusion/fission. Dysfunction and mutations in dynamin have been implicated in the pathophysiology of various disorders, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Charcot-Marie-Tooth disease, heart failure, schizophrenia, epilepsy, cancer, dominant optic atrophy, osteoporosis, and Down's syndrome...
February 2017: Molecular Pharmacology
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