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https://www.readbyqxmd.com/read/29149589/bond-with-me-if-you-can-natural-product-covalent-ligand-and-reactivity-based-probe-compete-for-cysteine-in-pp2a-complex
#1
Douglas S Johnson, Jaimeen D Majmudar
In this issue of Cell Chemical Biology, Grossman et al. (2017) disclose a chemoproteomics-enabled strategy to identify the cysteine-reactive target(s) of the anti-cancer natural product withaferin A and then screen a cysteine-reactive fragment library to discover a covalent ligand for the same target.
November 16, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/29142109/the-ndc80-complex-targets-bod1-to-human-mitotic-kinetochores
#2
Katharina Schleicher, Michael Porter, Sara Ten Have, Ramasubramanian Sundaramoorthy, Iain M Porter, Jason R Swedlow
Regulation of protein phosphatase activity by endogenous protein inhibitors is an important mechanism to control protein phosphorylation in cells. We recently identified Biorientation defective 1 (Bod1) as a small protein inhibitor of protein phosphatase 2A containing the B56 regulatory subunit (PP2A-B56). This phosphatase controls the amount of phosphorylation of several kinetochore proteins and thus the establishment of load-bearing chromosome-spindle attachments in time for accurate separation of sister chromatids in mitosis...
November 2017: Open Biology
https://www.readbyqxmd.com/read/29139553/distinct-b-subunits-of-pp2a-regulate-the-nf-%C3%AE%C2%BAb-signaling-pathway-through-dephosphorylation-of-ikk%C3%AE-i%C3%AE%C2%BAb%C3%AE-and-rela
#3
Yoshihiro Tsuchiya, Keiko Osaki, Mayu Kanamoto, Yuki Nakao, Ena Takahashi, Toru Higuchi, Hideaki Kamata
PP2A is composed of a scaffolding subunit (A), a catalytic subunit (C), and a regulatory subunit (B) that is classified into four families including B, B', B'', and B'''/striatin. Here, we found that a distinct PP2A complex regulates NF-κB signaling by dephosphorylation of IKKβ, IκBα, and RelA/p65. The PP2A core enzyme AC dimer and the holoenzyme AB'''C trimer dephosphorylate IKKβ, IκBα, and RelA, whereas the ABC trimer dephosphorylates IκBα but not IKKβ and RelA in cells. In contrast, AB'C and AB''C trimers have little effect on dephosphorylation of these signaling proteins...
November 15, 2017: FEBS Letters
https://www.readbyqxmd.com/read/29136249/natural-polyphenol-chlorogenic-acid-protects-against-acetaminophen-induced-hepatotoxicity-by-activating-erk-nrf2-antioxidative-pathway
#4
Mengjuan Wei, Zhiyong Zheng, Liang Shi, Yao Jin, Lili Ji
Hepatotoxicity due to acetaminophen (APAP) overdose is a leading cause of drug-induced acute liver failure in clinic. Chlorogenic acid (CGA), a dietary polyphenol, was reported to prevent APAP-induced liver injury in our previous studies. This study aims to investigate the protection provided by CGA against APAP-induced hepatotoxicity via focusing on nuclear factor erythroid 2-related factor 2 (Nrf2) and extracellular regulated protein kinases (ERK)1/2. CGA prevented APAP-induced oxidative liver injury and enhanced Nrf2 activation in mice and in hepatocytes in vitro...
November 10, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/29128580/reduction-of-protein-phosphatase-2a-c%C3%AE-promotes-in-vivo-bone-formation-and-adipocyte-differentiation
#5
Kaya Yoshida, Jumpei Teramachi, Kenta Uchibe, Mika Ikegame, Lihong Qiu, Di Yang, Hirohiko Okamura
Serine/threonine protein phosphatase 2A (PP2A) regulates diverse physiological processes such as cell cycle, growth, apoptosis, and signal transduction. Previously, we demonstrated that silencing of the α-isoform of PP2A catalytic subunit (PP2A Cα) in osteoblasts accelerated osteoblast differentiation, whereas its overexpression suppressed differentiation. In this study, we examined the role of PP2A Cα in in vivo bone formation by generating transgenic mice (PP2A-Tg), in which the dominant negative form of PP2A Cα was specifically expressed in osteoblasts...
November 8, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/29121398/protein-phosphatase-2a-and-tau-an-orchestrated-pas-de-deux
#6
REVIEW
Goce Taleski, Estelle Sontag
The neuronal microtubule-associated protein tau serves a critical role in regulating axonal microtubule dynamics to support neuronal and synaptic functions. Furthermore, it contributes to glutamatergic regulation and synaptic plasticity. Emerging evidence also suggests that tau serves as a signaling scaffold. Tau function and subcellular localisation are tightly regulated, in part, by the orchestrated interplay between phosphorylation and dephosphorylation events. Significantly, protein phosphatase type 2A (PP2A), encompassing the regulatory PPP2R2A (or Bα) subunit, is a major brain heterotrimeric enzyme and the primary tau Ser/Thr phosphatase in vivo...
November 9, 2017: FEBS Letters
https://www.readbyqxmd.com/read/29116159/the-effects-of-transcription-directions-of-transgenes-and-the-gypsy-insulators-on-the-transcript-levels-of-transgenes-in-transgenic-arabidopsis
#7
Weijia Jiang, Li Sun, Xiaojie Yang, Maohua Wang, Nardana Esmaeili, Necla Pehlivan, Rongli Zhao, Hong Zhang, Yun Zhao
Manipulation of a single abiotic stress-related gene could improve plant performance under abiotic stress conditions. To simultaneously increase plant tolerance to multiple stresses, it is usually required to overexpress two (or more) genes in transgenic plants. The common strategy is to assemble two or more expression cassettes, where each gene has its own promoter and terminator, within the same T-DNA. Does the arrangement of the two expression cassettes affect expression of the two transgenes? Can we use the Drosophila gypsy insulator sequence to increase the expression of the two transgenes? Answers to these questions would contribute to design better transformation vectors to maximize the effects of multi-gene transformation...
November 7, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29116110/publisher-correction-pp2a-inhibition-from-lb100-therapy-enhances-daunorubicin-cytotoxicity-in-secondary-acute-myeloid-leukemia-via-mir-181b-1-upregulation
#8
Chao Hu, Mengxia Yu, Yanling Ren, Kongfei Li, Dominic M Maggio, Chen Mei, Li Ye, Juying Wei, Jie Jin, Zhengping Zhuang, Hongyan Tong
A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper.
November 7, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29113343/pp2a-mediates-apoptosis-or-autophagic-cell-death-in-multiple-myeloma-cell-lines
#9
Hang Zhou, Wei Luo, Chao Zeng, Yu Zhang, Liyang Wang, Wenxiu Yao, Chunlai Nie
The crosstalk between apoptosis and autophagy contributes to tumorigenesis and cancer therapy. The process by which BetA (betulinic acid), a naturally occurring triterpenoid, regulates apoptosis and autophagy as a cancer therapy is unclear. In this study, we show for the first time that protein phosphatase 2A (PP2A) acts as a switch to regulate apoptosis and autophagic cell death mediated by BetA. Under normal conditions, caspase-3 is activated by the mitochondrial pathway upon BetA treatment. Activated caspase-3 cleaves the A subunit of PP2A (PP2A/A), resulting in the association of PP2A and Akt...
October 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/29107183/therapeutic-targeting-of-pp2a
#10
REVIEW
Caitlin M O'Connor, Abbey Perl, Daniel Leonard, Jaya Sangodkar, Goutham Narla
Protein phosphatase 2A (PP2A) is a major serine/threonine phosphatase that regulates many cellular processes. Given the central role of PP2A in regulating diverse biological functions and its dysregulation in many diseases, including cancer, PP2A directed therapeutics have become of great interest. The main approaches leveraged thus far can be categorized as follows: 1) inhibiting endogenous inhibitors of PP2A, 2) targeted disruption of post translational modifications on PP2A subunits, or 3) direct targeting of PP2A...
October 26, 2017: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/29101268/disturbed-spermatogenic-signaling-in-pacap-deficient-mice
#11
Dora Reglodi, Sandor Cseh, Bence Somoskoi, Balazs Fulop, Eszter Szentleleky, Vince Szegeczki, Anna Kovacs, Andrea Varga, Peter Kiss, Hitoshi Hashimoto, Andrea Tamas, Attila Bardosi, Sridharan Manavalan, Eva Bako, Roza Zakany, Tamas Juhasz
PACAP is a neuropeptide with diverse functions in various organs, including reproductive system. It is present in the testis in high concentrations, and in addition to the stage-specific expression within the seminiferous tubules, PACAP affects spermatogenesis and the functions of Leydig and Sertoli cells. Mice lacking endogenous PACAP show reduced fertility, but the possibility of abnormalities in spermatogenic signaling has not yet been investigated. Therefore, we performed a detailed morphological analysis of spermatozoa, sperm motility, and investigated signaling pathways that play a role during spermatogenesis in knockout mice...
November 3, 2017: Reproduction: the Official Journal of the Society for the Study of Fertility
https://www.readbyqxmd.com/read/29091948/selection-and-validation-of-appropriate-reference-genes-for-quantitative-real-time-pcr-analysis-in-salvia-hispanica
#12
Rahul Gopalam, Sunny D Rupwate, Ajay W Tumaney
Quantitative real-time polymerase chain reaction (qRT-PCR) has become the most popular choice for gene expression studies. For accurate expression analysis, it is pertinent to select a stable reference gene to normalize the data. It is now known that the expression of internal reference genes varies considerably during developmental stages and under different experimental conditions. For Salvia hispanica, an economically important oilseed crop, there are no reports of stable reference genes till date. In this study, we chose 13 candidate reference genes viz...
2017: PloS One
https://www.readbyqxmd.com/read/29089450/mark3-mediated-phosphorylation-of-arhgef2-couples-microtubules-to-the-actin-cytoskeleton-to-establish-cell-polarity
#13
María-José Sandí, Christopher B Marshall, Marc Balan, Étienne Coyaud, Ming Zhou, Daniel M Monson, Noboru Ishiyama, Arun A Chandrakumar, José La Rose, Amber L Couzens, Anne-Claude Gingras, Brian Raught, Wei Xu, Mitsuhiko Ikura, Deborah K Morrison, Robert Rottapel
The PAR-1-MARK pathway controls cell polarity through the phosphorylation of microtubule-associated proteins. Rho-Rac guanine nucleotide exchange factor 2 (ARHGEF2), which activates Ras homolog family member A (RHOA), is anchored to the microtubule network and sequestered in an inhibited state through binding to dynein light chain Tctex-1 type 1 (DYNLT1). We showed in mammalian cells that liver kinase B1 (LKB1) activated the microtubule affinity-regulating kinase 3 (MARK3), which in turn phosphorylated ARHGEF2 at Ser(151) This modification disrupted the interaction between ARHGEF2 and DYNLT1 by generating a 14-3-3 binding site in ARHGEF2, thus causing ARHGEF2 to dissociate from microtubules...
October 31, 2017: Science Signaling
https://www.readbyqxmd.com/read/29084198/distinct-kinetics-of-serine-and-threonine-dephosphorylation-are-essential-for-mitosis
#14
Jamin B Hein, Emil P T Hertz, Dimitriya H Garvanska, Thomas Kruse, Jakob Nilsson
Protein phosphatase 2A (PP2A) in complex with B55 regulatory subunits reverses cyclin-dependent kinase 1 (Cdk1) phosphorylations at mitotic exit. Interestingly, threonine and serine residues phosphorylated by Cdk1 display distinct phosphorylation dynamics, but the biological significance remains unexplored. Here we demonstrate that the phosphothreonine preference of PP2A-B55 provides an essential regulatory element of mitotic exit. To allow rapid activation of the anaphase-promoting complex/cyclosome (APC/C) co-activator Cdc20, inhibitory phosphorylation sites are conserved as threonines while serine substitutions delay dephosphorylation and Cdc20 activation...
October 30, 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/29079657/torc1-and-torc2-converge-to-regulate-the-saga-co-activator-in-response-to-nutrient-availability
#15
Thomas Laboucarié, Dylane Detilleux, Ricard A Rodriguez-Mias, Céline Faux, Yves Romeo, Mirita Franz-Wachtel, Karsten Krug, Boris Maček, Judit Villén, Janni Petersen, Dominique Helmlinger
Gene expression regulation is essential for cells to adapt to changes in their environment. Co-activator complexes have well-established roles in transcriptional regulation, but less is known about how they sense and respond to signaling cues. We have previously shown that, in fission yeast, one such co-activator, the SAGA complex, controls gene expression and the switch from proliferation to differentiation in response to nutrient availability. Here, using a combination of genetic, biochemical, and proteomic approaches, we show that SAGA responds to nutrients through the differential phosphorylation of its Taf12 component, downstream of both the TORC1 and TORC2 pathways...
October 27, 2017: EMBO Reports
https://www.readbyqxmd.com/read/29078372/dephosphorylation-by-protein-phosphatase-2a-regulates-visual-pigment-regeneration-and-the-dark-adaptation-of-mammalian-photoreceptors
#16
Alexander V Kolesnikov, Tivadar Orban, Hui Jin, Celine Brooks, Lukas Hofmann, Zhiqian Dong, Maxim Sokolov, Krzysztof Palczewski, Vladimir J Kefalov
Resetting of G-protein-coupled receptors (GPCRs) from their active state back to their biologically inert ground state is an integral part of GPCR signaling. This "on-off" GPCR cycle is regulated by reversible phosphorylation. Retinal rod and cone photoreceptors arguably represent the best-understood example of such GPCR signaling. Their visual pigments (opsins) are activated by light, transduce the signal, and are then inactivated by a GPCR kinase and arrestin. Although pigment inactivation by phosphorylation is well understood, the enzyme(s) responsible for pigment dephosphorylation and the functional significance of this reaction remain unknown...
October 23, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29078276/targeting-autophagy-inhibits-melanoma-growth-by-enhancing-nk-cells-infiltration-in-a-ccl5-dependent-manner
#17
Takouhie Mgrditchian, Tsolere Arakelian, Jérôme Paggetti, Muhammad Zaeem Noman, Elodie Viry, Etienne Moussay, Kris Van Moer, Stephanie Kreis, Coralie Guerin, Stephanie Buart, Caroline Robert, Christophe Borg, Philippe Vielh, Salem Chouaib, Guy Berchem, Bassam Janji
While blocking tumor growth by targeting autophagy is well established, its role on the infiltration of natural killer (NK) cells into tumors remains unknown. Here, we investigate the impact of targeting autophagy gene Beclin1 (BECN1) on the infiltration of NK cells into melanomas. We show that, in addition to inhibiting tumor growth, targeting BECN1 increased the infiltration of functional NK cells into melanoma tumors. We provide evidence that driving NK cells to the tumor bed relied on the ability of autophagy-defective tumors to transcriptionally overexpress the chemokine gene CCL5 Such infiltration and tumor regression were abrogated by silencing CCL5 in BECN1-defective tumors...
October 31, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29070518/digoxin-enhances-radiation-response-in-radioresistant-a549-cells-by-reducing-protein-phosphatase-2a-pp2a
#18
Ji Young Lee, Mi-Sook Kim, Mi So Lee, Jae Eun Ju, Namhyun Chung, Youn Kyoung Jeong
Protein phosphatase 2A (PP2A) is a ubiquitous multifunctional enzyme usually known as a tumor suppressor. Recent studies have reported that although inhibition of PP2A leads to acceleration of cell growth, it also induces damaged cells to pass through the cell cycle and renders them sensitive to radiotherapy. Here, we investigated the radiosensitizing effects of digoxin as a PP2A inhibitor in two non-small cell lung cancer cell types (H460 and A549) with differential sensitivity to radiation. Digoxin inhibited the proliferation of H460 and A549 cells in a dose-dependent fashion and was especially effective on radioresistant A549 cells...
October 25, 2017: Bioscience Reports
https://www.readbyqxmd.com/read/29068100/upregulated-osterix-expression-elicited-by-runx2-and-dlx5-is-required-for-the-accelerated-osteoblast-differentiation-in-pp2a-c%C3%AE-knockdown-cells
#19
Di Yang, Hirohiko Okamura, Lihong Qiu
Serine/threonine protein phosphatase 2A (PP2A) is involved in regulating various physiological processes including cell cycle, growth, apoptosis, and signal transduction. Osteoblast differentiation is controlled by main bone specific transcription factors including Osterix, distal-less homeobox 5 (Dlx5), and Runt-related transcription factor 2 (Runx2). We previously reported that knockdown of PP2A Cα increases the expression of Osterix, leading to the accelerated osteoblast differentiation through the upregulation of bone-related genes...
October 25, 2017: Cell Biology International
https://www.readbyqxmd.com/read/29066346/characterization-of-overexpression-of-the-alternatively-spliced-isoform-of-the-protein-phosphatase-2a-catalytic-subunit-in-cells
#20
Shen Tang, Yuyang Liu, Xinhang Wang, Ziwei Liang, Haiqing Cai, Laiming Mo, Deqiang Xiao, Songchao Guo, Yiqiang Ouyang, Bin Sun, Cailing Lu, Xiyi Li
PP2Acα2 is a recently discovered PP2Acα alternative splicing isoform that can be induced following serum withdrawal. It shows enhanced binding to immunoglobulin binding protein 1 and is overexpressed in chronic lymphocytic leukemia patients. Current knowledge concerning PP2Acα2 is limited. In this study, we induced and cloned PP2Acα2 from HL-60 cells and human lymphocytes, transfected them into human embryonic kidney 293 cells and constructed a stable overexpression cell line. We found that PP2Acα2 mRNA inhibits expression of its longer isoform PP2Acα mRNA but had no effect on the final protein expression and modification of this longer isoform...
October 21, 2017: Biochemical and Biophysical Research Communications
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