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Maryam Ataeian, Justus Tegha-Dunghu, Donna G Curtis, Ellen M E Sykes, Ashkan Nozohourmehrabad, Megha Bajaj, Karen Cheung, Martin Srayko
In most animals, female meiosis completes only after fertilization. Sperm entry has been implicated in providing a signal for the initiation of the final meiotic processes, however, a maternal component required for this process has not been previously identified. We report the characterization of a novel family of three highly similar paralogs (memi-1, memi-2, memi-3) that encode oocyte-specific proteins. A hypermorphic mutation memi-1(sb41) results in failure to exit female meiosis II properly, however, loss of all three paralogs results in a "skipped meiosis II" phenotype...
October 11, 2016: Genetics
Miriam Fontanillo, Ivan Zemskov, Maximilian Häfner, Ulrike Uhrig, Francesca Salvi, Bernd Simon, Valentin Wittmann, Maja Köhn
Research and therapeutic targeting of the phosphoserine/threonine phosphatases PP1 and PP2A is hindered by the lack of selective inhibitors. The microcystin (MC) natural toxins target both phosphatases with equal potency, and their complex synthesis has complicated structure-activity relationship studies in the past. We report herein the synthesis and biochemical evaluation of 11 MC analogues, which was accomplished through an efficient strategy combining solid- and solution-phase approaches. Our approach led to the first MC analogue with submicromolar inhibitory potency that is strongly selective for PP2A over PP1 and does not require the complex lipophilic Adda group...
October 10, 2016: Angewandte Chemie
Gopal Iyer, James Price, Shay Bourgeois, Eric Armstrong, Shyhmin Huang, Paul M Harari
BACKGROUND: The epidermal growth factor receptor (EGFR) is frequently overexpressed in head and neck squamous cell carcinoma (HNSCC) and several other human cancers. Monoclonal antibodies, such as cetuximab that block EGFR signaling, have emerged as valuable molecular targeting agents in clinical cancer therapy. Prolonged exposure to cetuximab can result in cells acquiring resistance by a process that remains incompletely understood. METHODS: In this study, we analyzed the immediate early molecular response of cetuximab on physical interactions between EGFR and Insulin growth factor 1 like receptor (IGF-1R) in head and neck cancer cells that are resistant to cetuximab...
October 6, 2016: BMC Cancer
Jihoon Shin, Hong-Duk Youn
In embryonic stem cells (ESCs), cell cycle regulation is deeply connected to pluripotency. Especially, core transcription factors (CTFs) which are essential to maintain the pluripotency transcription programs should be reset during M/G1 transition. However, it remains unknown about how CTFs are governed during cell cycle progression. Here, we describe that the regulation of Oct4 by Aurora kinase b (Aurkb)/protein phosphatase 1 (PP1) axis during the cell cycle is important for resetting Oct4 to pluripotency and cell cycle related target genes in determining the identity of ESCs...
September 29, 2016: BMB Reports
Lijiang Ma, Yavuz Bayram, Heather M McLaughlin, Megan T Cho, Alyson Krokosky, Clesson E Turner, Kristin Lindstrom, Caleb P Bupp, Katey Mayberry, Weiyi Mu, Joann Bodurtha, Veronique Weinstein, Neda Zadeh, Wendy Alcaraz, Zöe Powis, Yunru Shao, Daryl A Scott, Andrea M Lewis, Janson J White, Shalani N Jhangiani, Elif Yilmaz Gulec, Seema R Lalani, James R Lupski, Kyle Retterer, Rhonda E Schnur, Ingrid M Wentzensen, Sherri Bale, Wendy K Chung
Intellectual disabilities are genetically heterogeneous and can be associated with congenital anomalies. Using whole-exome sequencing (WES), we identified five different de novo missense variants in the protein phosphatase-1 catalytic subunit beta (PPP1CB) gene in eight unrelated individuals who share an overlapping phenotype of dysmorphic features, macrocephaly, developmental delay or intellectual disability (ID), congenital heart disease, short stature, and skeletal and connective tissue abnormalities. Protein phosphatase-1 (PP1) is a serine/threonine-specific protein phosphatase involved in the dephosphorylation of a variety of proteins...
December 2016: Human Genetics
Tobias Bartscht, Benjamin Rosien, Dirk Rades, Roland Kaufmann, Harald Biersack, Hendrik Lehnert, Hendrik Ungefroren
BACKGROUND: Earlier results from our group have shown that in pancreatic ductal adenocarcinoma (PDAC)-derived cells transforming growth factor (TGF)-β1-dependent epithelial-mesenchymal transition (EMT) and cell motility was inhibited by the Src inhibitors PP2 and PP1 both of which targeted the TGF-β receptors for inhibition. OBJECTIVE: In this study we evaluated the impact of another Src inhibitor, AZM475271, on various TGF-β responses in PDAC cells. METHOD: The effect of AZM475271 on TGF-β1-induced random cell migration (chemokinesis), the expression of EMT and migration/invasion-associated genes, TGF-β-induced luciferase activity, and C-terminal phosphorylation of Smad2 and Smad3 was measured in the PDAC-derived Panc-1 and Colo357 cell lines using real-time cell migration assays, quantitative real-time PCR, luciferase reporter gene assays and phosphoimmunoblotting, respectively...
September 26, 2016: Anti-cancer Agents in Medicinal Chemistry
Zhuxia Zhang, Jie Yang, Xiaolei Liu, Xiaoe Jia, Shengdi Xu, Kerui Gong, Shaochun Yan, Chunyang Zhang, Guo Shao
BACKGROUND: Learning and memory is a complex process. Some reports have shown that protein kinases (PKs) and phosphatases (PPs) are important mediators in this process. And it is also well known that protein serine/threonine phosphatase 1 (PP1) and DNA methylation are critically involved in learning and memory. METHODS: In the current study, the mice and cultured cells (NG108-15) were treated with vehicle or 5-Aza-2'-deoxycytidine (5-aza-cdR), a DNA methyltransferase (DNMT) inhibitor...
September 22, 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Jason E McDermott, Hugh D Mitchell, Lisa E Gralinski, Amie J Eisfeld, Laurence Josset, Armand Bankhead, Gabriele Neumann, Susan C Tilton, Alexandra Schäfer, Chengjun Li, Shufang Fan, Shannon McWeeney, Ralph S Baric, Michael G Katze, Katrina M Waters
BACKGROUND: The complex interplay between viral replication and host immune response during infection remains poorly understood. While many viruses are known to employ anti-immune strategies to facilitate their replication, highly pathogenic virus infections can also cause an excessive immune response that exacerbates, rather than reduces pathogenicity. To investigate this dichotomy in severe acute respiratory syndrome coronavirus (SARS-CoV), we developed a transcriptional network model of SARS-CoV infection in mice and used the model to prioritize candidate regulatory targets for further investigation...
2016: BMC Systems Biology
David Y Chiang, Albert J R Heck, Dobromir Dobrev, Xander H T Wehrens
Reversible phosphorylation of proteins is a delicate yet dynamic balancing act between kinases and phosphatases, the disturbance of which underlies numerous disease processes. While our understanding of protein kinases has grown tremendously over the past decades, relatively little is known regarding protein phosphatases. This may be because protein kinases are great in number and relatively specific in function, and thereby amenable to be studied in isolation, whereas protein phosphatases are much less abundant and more unspecific in their function...
September 20, 2016: Journal of Molecular and Cellular Cardiology
Jacklynn V Egger, Maria V Lane, Lisa A Antonucci, Brixhilda Dedi, Nancy A Krucher
The tumor suppressor Retinoblastoma (Rb) protein is highly phosphorylated in cancer cells largely due to the overexpression of cyclins or the loss of expression of cyclin dependent kinase inhibitors (cdki). Hyperphosphorylation of Rb promotes proliferation, and plays a role in the regulation of apoptosis. Recently, inhibition of cyclin dependent activity toward Rb has been identified as a strategy that has shown clinical efficacy. We utilized a method to induce phosphatase activity toward Rb in cells by shRNA silencing of PNUTS (Phosphatase Nuclear Targeting Subunit) that regulates PP1-mediated dephosphorylation of Rb...
September 19, 2016: Cancer Biology & Therapy
Shunyu Gao, Jiannan Zhang, Chen He, Fengyan Meng, Guixian Bu, Guoqiang Zhu, Juan Li, Yajun Wang
Neuropeptide Y (NPY) receptors and its ligands, NPY, peptide YY (PYY) and pancreatic polypeptide (PP), are suggested to regulate many physiological processes including food intake in birds. However, our knowledge regarding this avian NPY system remains rather limited. Here, we examined the tissue expression of NPY, PYY and PP and the gene structure, expression and signaling of three NPY receptors (cY1, cY4 and cY6) in chickens. The results showed that 1) NPY is widely expressed in chicken tissues with abundance noted in the hypothalamus via quantitative real-time PCR, whereas PYY is highly expressed in the pancreas, gastrointestinal tract and various brain regions, and PP is expressed almost exclusively in the pancreas; 2) cY1, cY4 and cY6 contain novel non-coding exon(s) at their 5'-UTR; 3) The wide tissue distribution of cY1 and cY4 and cY6 were detected in chickens by quantitative real-time PCR and their expression is controlled by the promoter near exon 1, which displays strong promoter activity in DF-1 cells as demonstrated by Dual-luciferase reporter assay; 4) Monitored by luciferase reporter assays, activation of cY1 and cY4 expressed in HEK293 cells by chicken NPY1-36, PYY1-37, and PP1-36 treatment inhibits cAMP/PKA and activates MAPK/ERK signaling pathways, while cY6-expressing cells show little response to peptide treatment, indicating that cY1 and cY4, and not cY6, can transmit signals in vitro...
September 15, 2016: General and Comparative Endocrinology
Fangzhen Jiang, Kai Jin, Shenyu Huang, Qi Bao, Zheren Shao, Xueqing Hu, Juan Ye
Melanoma is one common skin cancer. In the present study, the potential anti-melanoma activity by a liposomal C6 ceramide was tested in vitro. We showed that the liposomal C6 (ceramide) was cytotoxic and anti-proliferative against a panel of human melanoma cell lines (SK-Mel2, WM-266.4 and A-375 and WM-115). In addition, liposomal C6 induced caspase-dependent apoptotic death in the melanoma cells. Reversely, its cytotoxicity was attenuated by several caspase inhibitors. Intriguingly, liposomal C6 was non-cytotoxic to B10BR mouse melanocytes and primary human melanocytes...
2016: PloS One
Mark Swingle, Claude-Henry Volmar, S Adrian Saldanha, Peter Chase, Christina Eberhart, Edward A Salter, Brandon D'Arcy, Chad E Schroeder, Jennifer E Golden, Andrzej Wierzbicki, Peter Hodder, Richard E Honkanen
Although there has been substantial success in the development of specific inhibitors for protein kinases, little progress has been made in the identification of specific inhibitors for their protein phosphatase counterparts. Inhibitors of PP1 and PP5 are desired as probes for research and to test their potential for drug development. We developed and miniaturized (1536-well plate format) nearly identical homogeneous, fluorescence intensity (FLINT) enzymatic assays to detect inhibitors of PP1 or PP5. The assays were used in an ultra-high-throughput screening (uHTS) campaign, testing >315,000 small-molecule compounds...
September 14, 2016: Journal of Biomolecular Screening
Amanda M Bonner, R Scott Hawley
In this issue of Developmental Cell, Hattersley et al. (2016) use the unique biology of meiosis I, in which the cell can exit the division without reforming the nuclear envelope, to uncover an intriguing role of the nucleoporin MEL-28 in mediating chromosome segregation via its interaction with PP1 at the kinetochore.
September 12, 2016: Developmental Cell
F Cao, M Liu, Q-Z Zhang, R Hao
OBJECTIVE: Phosphatase and actin regulator 4 (PHACTR4) is one member of the largely uncharacterized PHACTR family of protein phosphatase 1 (PP1)-and actin-binding proteins. PHACTR4 is significantly deleted or mutant in many tumor subtypes, such as breast, colorectal, lung, neural, ovarian, and renal cancers. However, the role of PHACTR4 in human hepatocellular carcinoma (HCC) is completely unknown. MATERIALS AND METHODS: Ten paired HCC tissues and adjacent non-cancerous tissues were used to detect the expression PHACTR4...
August 2016: European Review for Medical and Pharmacological Sciences
Dmitry Terentyev, Shanna Hamilton
The amount and timing of Ca(2+) release from the sarcoplasmic reticulum (SR) during cardiac cycle are the main determinants of cardiac contractility. Reversible phosphorylation of the SR Ca(2+) release channel, ryanodine receptor type 2 (RyR2) is the central mechanism of regulation of Ca(2+) release in cardiomyocytes. Three major serine-threonine phosphatases including PP1, PP2A and PP2B (calcineurin) have been implicated in modulation of RyR2 function. Changes in expression levels of these phosphatases, their activity and targeting to the RyR2 macromolecular complex were demonstrated in many animal models of cardiac disease and humans and are implicated in cardiac arrhythmia and heart failure...
August 29, 2016: Journal of Molecular and Cellular Cardiology
Anu G Nair, Upinder S Bhalla, Jeanette Hellgren Kotaleski
In reward learning, the integration of NMDA-dependent calcium and dopamine by striatal projection neurons leads to potentiation of corticostriatal synapses through CaMKII/PP1 signaling. In order to elicit the CaMKII/PP1-dependent response, the calcium and dopamine inputs should arrive in temporal proximity and must follow a specific (dopamine after calcium) order. However, little is known about the cellular mechanism which enforces these temporal constraints on the signal integration. In this computational study, we propose that these temporal requirements emerge as a result of the coordinated signaling via two striatal phosphoproteins, DARPP-32 and ARPP-21...
September 2016: PLoS Computational Biology
Emily Chen, Meng S Choy, Katalin Petrényi, Zoltán Kónya, Ferenc Erdődi, Viktor Dombrádi, Wolfgang Peti, Rebecca Page
UNLABELLED: The opportunistic pathogen Candida is one of the most common causes of nosocomial bloodstream infections. Because candidemia is associated with high mortality rates and because the incidences of multidrug-resistant Candida are increasing, efforts to identify novel targets for the development of potent antifungals are warranted. Here, we describe the structure and function of the first member of a family of protein phosphatases that is specific to fungi, protein phosphatase Z1 (PPZ1) from Candida albicans We show that PPZ1 not only is active but also is as susceptible to inhibition by the cyclic peptide inhibitor microcystin-LR as its most similar human homolog, protein phosphatase 1α (PP1α [GLC7 in the yeast Saccharomyces cerevisiae])...
2016: MBio
Ganesan Senthil Kumar, Ezgi Gokhan, Sofie De Munter, Mathieu Bollen, Paola Vagnarelli, Wolfgang Peti, Rebecca Page
Ki-67 and RepoMan have key roles during mitotic exit. Previously, we showed that Ki-67 organizes the mitotic chromosome periphery and recruits protein phosphatase 1 (PP1) to chromatin at anaphase onset, in a similar manner as RepoMan (Booth et al., 2014). Here we show how Ki-67 and RepoMan form mitotic exit phosphatases by recruiting PP1, how they distinguish between distinct PP1 isoforms and how the assembly of these two holoenzymes are dynamically regulated by Aurora B kinase during mitosis. Unexpectedly, our data also reveal that Ki-67 and RepoMan bind PP1 using an identical, yet novel mechanism, interacting with a PP1 pocket that is engaged only by these two PP1 regulators...
2016: ELife
Bisrat T Woldemichael, Ali Jawaid, Eloïse A Kremer, Niharika Gaur, Jacek Krol, Antonin Marchais, Isabelle M Mansuy
Memory formation is a complex cognitive function regulated by coordinated synaptic and nuclear processes in neurons. In mammals, it is controlled by multiple molecular activators and suppressors, including the key signalling regulator, protein phosphatase 1 (PP1). Here, we show that memory control by PP1 involves the miR-183/96/182 cluster and its selective regulation during memory formation. Inhibiting nuclear PP1 in the mouse brain, or training on an object recognition task similarly increases miR-183/96/182 expression in the hippocampus...
2016: Nature Communications
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