Person: Shair, Matthew
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Shair
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Matthew
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Shair, Matthew
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Publication Mediator Kinase Phosphorylation of STAT1 S727 Promotes Growth of Neoplasms With JAK-STAT Activation(Elsevier, 2017) Nitulescu, Ioana I.; Meyer, Sara C.; Wen, Qiang Jeremy; Crispino, John D.; Lemieux, Madeleine E.; Levine, Ross L.; Pelish, Henry E.; Shair, MatthewConstitutive JAK-STAT signaling drives the proliferation of most myeloproliferative neoplasms (MPN) and a subset of acute myeloid leukemia (AML), but persistence emerges with chronic exposure to JAK inhibitors. MPN and post-MPN AML are dependent on tyrosine phosphorylation of STATs, but the role of serine STAT1 phosphorylation remains unclear. We previously demonstrated that Mediator kinase inhibitor cortistatin A (CA) reduced proliferation of JAK2-mutant AML in vitro and in vivo and also suppressed CDK8-dependent phosphorylation of STAT1 at serine 727. Here we report that phosphorylation of STAT1 S727 promotes the proliferation of AML cells with JAK-STAT pathway activation. Inhibition of serine phosphorylation by CA promotes growth arrest and differentiation, inhibits colony formation in MPN patient samples and reduces allele burden in MPN mouse models. These results reveal that STAT1 pS727 regulates growth and differentiation in JAK-STAT activated neoplasms and suggest that Mediator kinase inhibition represents a therapeutic strategy to regulate JAK-STAT signaling.Publication Enantioselective Total Synthesis of Hyperforin(American Chemical Society, 2013) Sparling, Brian Andrew; Moebius, David C.; Shair, MatthewA modular, 18-step total synthesis of hyperforin is described. The natural product was quickly accessed using latent symmetry elements, whereby a group-selective, Lewis acid-catalyzed epoxide-opening cascade cyclization was used to furnish the bicyclo[3.3.1]nonane core and set two key quaternary stereocenters.Publication Synthesis of the C4-Epi-Lomaiviticin B Core Reveals Subtle Stereoelectronic Effects(American Chemical Society (ACS), 2013) Lee, Amy S; Shair, MatthewAn efficient synthesis of the C4-epi-lomaiviticin B core is reported. The synthesis features a diastereoselective anionic formal furan Diels-Alder reaction and a stereoselective oxidative enolate dimerization. During the investigation, subtle yet critical stereoelectronic effects imparted by the C4-stereocenter were observed.Publication The Small Molecule Dispergo Tubulates the Endoplasmic Reticulum and Inhibits Export(American Society for Cell Biology, 2013) Lu, Lei; Hannoush, Rami N.; Goess, Brian C.; Varadarajan, Shankar; Shair, Matthew; Kirchhausen, TomasThe mammalian endoplasmic reticulum (ER) is an organelle that maintains a complex, compartmentalized organization of interconnected cisternae and tubules while supporting a continuous flow of newly synthesized proteins and lipids to the Golgi apparatus. Using a phenotypic screen, we identify a small molecule, dispergo, that induces reversible loss of the ER cisternae and extensive ER tubulation, including formation of ER patches comprising densely packed tubules. Dispergo also prevents export from the ER to the Golgi apparatus, and this traffic block results in breakdown of the Golgi apparatus, primarily due to maintenance of the constitutive retrograde transport of its components to the ER. The effects of dispergo are reversible, since its removal allows recovery of the ER cisternae at the expense of the densely packed tubular ER patches. This recovery occurs together with reactivation of ER-to-Golgi traffic and regeneration of a functional Golgi with correct morphology. Because dispergo is the first small molecule that reversibly tubulates the ER and inhibits its export function, it will be useful in studying these complex processes.Publication ITRACONAZOLE INHIBITS ENTEROVIRUS REPLICATION BY TARGETING THE OXYSTEROL-BINDING PROTEIN(2014) Strating, Jeroen R.P.M.; van der Linden, Lonneke; Albulescu, Lucian; Bigay, Joëlle; Arita, Minetaro; Delang, Leen; Leyssen, Pieter; van der Schaar, Hilde M.; Lanke, Kjerstin H.W.; Thibaut, Hendrik Jan; Ulferts, Rachel; Drin, Guillaume; Schlinck, Nina; Wubbolts, Richard W.; Sever, Navdar; Head, Sarah A.; Liu, Jun O.; Beachy, Philip A.; De Matteis, Maria A.; Shair, Matthew; Olkkonen, Vesa M.; Neyts, Johan; van Kuppeveld, Frank J.M.SUMMARY Itraconazole (ITZ) is a well-known antifungal agent that also has anti-cancer activity. In this study, we identified ITZ as a broad-spectrum inhibitor of enteroviruses (e.g. poliovirus, coxsackievirus, enterovirus-71, rhinovirus). We demonstrate that ITZ inhibits viral RNA replication by targeting oxysterol-binding protein (OSBP) and OSBP-related protein 4 (ORP4). Consistently, OSW-1, a specific OSBP/ORP4 antagonist, also inhibits enterovirus replication. Knockdown of OSBP inhibits virus replication whereas overexpression of OSBP or ORP4 counteracts the antiviral effects of ITZ and OSW-1. ITZ binds OSBP and inhibits its function, i.e. shuttling of cholesterol and phosphatidylinositol-4-phosphate between membranes, thereby likely perturbing the virus-induced membrane alterations essential for viral replication organelle formation. ITZ also inhibits hepatitis C virus replication, which also relies on OSBP. Together, these data implicate OSBP/ORP4 as novel molecular targets of ITZ and point to an essential role of OSBP/ORP4-mediated lipid exchange in virus replication that can be targeted by antiviral drugs.Publication Mediator Kinase Inhibition Further Activates Super-Enhancer Associated Genes in AML(2015) Pelish, Henry E.; Liau, Brian; Nitulescu, Ioana I.; Tangpeerachaikul, Anupong; Poss, Zachary C.; Da Silva, Diogo; Caruso, Brittany T.; Arefolov, Alexander; Fadeyi, Olugbeminiyi; Christie, Amanda L.; Du, Karrie; Banka, Deepti; Schneider, Elisabeth V.; Jestel, Anja; Zou, Ge; Si, Chong; Ebmeier, Christopher C.; Bronson, Roderick T.; Krivtsov, Andrei V.; Myers, Andrew; Kohl, Nancy E.; Kung, Andrew L.; Armstrong, Scott A.; Lemieux, Madeleine E.; Taatjes, Dylan J.; Shair, MatthewSuper-enhancers (SEs), which are composed of large clusters of enhancers densely loaded with the Mediator complex, transcription factors (TFs), and chromatin regulators, drive high expression of genes implicated in cell identity and disease, such as lineage-controlling TFs and oncogenes 1, 2. BRD4 and CDK7 are positive regulators of SE-mediated transcription3,4,5. In contrast, negative regulators of SE-associated genes have not been well described. Here we report that Mediator-associated kinases cyclin-dependent kinase 8 (CDK8) and CDK19 restrain increased activation of key SE-associated genes in acute myeloid leukaemia (AML) cells. We determined that the natural product cortistatin A (CA) selectively inhibited Mediator kinases, had antileukaemic activity in vitro and in vivo, and disproportionately induced upregulation of SE-associated genes in CA-sensitive AML cell lines but not in CA-insensitive cell lines. In AML cells, CA upregulated SE-associated genes with tumour suppressor and lineage-controlling functions, including the TFs CEBPA, IRF8, IRF1 and ETV6 6, 7, 8. The BRD4 inhibitor I-BET151 downregulated these SE-associated genes, yet also has antileukaemic activity. Individually increasing or decreasing expression of these TFs suppressed AML cell growth, providing evidence that leukaemia cells are sensitive to dosage of SE-associated genes. Our results demonstrate that Mediator kinases can negatively regulate SE-associated gene expression in specific cell types and can be pharmacologically targeted as a therapeutic approach to AML.Publication Identification of Mediator Kinase Substrates in Human Cells using Cortistatin A and Quantitative Phosphoproteomics(Elsevier BV, 2016) Poss, Zachary C.; Ebmeier, Christopher C.; Odell, Aaron T.; Tangpeerachaikul, Anupong; Lee, Thomas; Pelish, Henry E.; Shair, Matthew; Dowell, Robin D.; Old, William M.; Taatjes, Dylan J.Cortistatin A (CA) is a highly selective inhibitor of the Mediator kinases CDK8 and CDK19. Using CA, we now report a large-scale identification of Mediator kinase substrates in human cells (HCT116). We identified over 16,000 quantified phosphosites including 78 high-confidence Mediator kinase targets within 64 proteins, including DNA-binding transcription factors and proteins associated with chromatin, DNA repair, and RNA polymerase II. Although RNA-Seq data correlated with Mediator kinase targets, the effects of CA on gene expression were limited and distinct from CDK8 or CDK19 knockdown. Quantitative proteome analyses, tracking around 7,000 proteins across six time points (0 – 24h), revealed that CA selectively affected pathways implicated in inflammation, growth, and metabolic regulation. Contrary to expectations, increased turnover of Mediator kinase targets was not generally observed. Collectively, these data support Mediator kinases as regulators of chromatin and RNA polymerase II activity and suggest their roles extend beyond transcription to metabolism and DNA repair.Publication Gram-Scale Synthesis of the A′B′-Subunit of Angelmicin B(American Chemical Society (ACS), 2011) Milgram, Benjamin Charles; Liau, Brian; Shair, MatthewA gram-scale enantiospecific synthesis of the A’B’-subunit of angelmicin B is reported. The synthesis involves a Lewis acid-catalyzed contrasteric Diels–Alder reaction and a tandem silyl zincate 1,6-addition/enolate oxidation sequence.Publication Natural products reveal cancer cell dependence on oxysterol-binding proteins(Springer Nature, 2011) Burgett, Anthony W G; Poulsen, Thomas B; Wangkanont, Kittikhun; Anderson, D Ryan; Kikuchi, Chikako; Shimada, Kousei; Okubo, Shuichi; Fortner, Kevin C; Mimaki, Yoshihiro; Kuroda, Minpei; Murphy, Jason P; Schwalb, David J; Petrella, Eugene C; Cornella-Taracido, Ivan; Schirle, Markus; Tallarico, John A; Shair, MatthewCephalostatin 1, OSW-1, ritterazine B and schweinfurthin A are natural products that potently, and in some cases selectively, inhibit the growth of cultured human cancer cell lines. The cellular targets of these small molecules have yet to be identified. We have discovered that these molecules target oxysterol binding protein (OSBP) and its closest paralog, OSBP-related protein 4L (ORP4L)—proteins not known to be involved in cancer cell survival. OSBP and the ORPs constitute an evolutionarily conserved protein superfamily, members of which have been implicated in signal transduction, lipid transport and lipid metabolism. The functions of OSBP and the ORPs, however, remain largely enigmatic. Based on our findings, we have named the aforementioned natural products ORPphilins. Here we used ORPphilins to reveal new cellular activities of OSBP. The ORPphilins are powerful probes of OSBP and ORP4L that will be useful in uncovering their cellular functions and their roles in human diseases.Publication Synthesis of the N-(tert-butyloxycarbonyl)-O-triisopropylsilyl-d-pyrrolosamine glycal of lomaiviticins A and B via epimerization of l-Threonine(Elsevier BV, 2010) Morris, William J.; Shair, MatthewAn efficient synthesis of the N-(tert-butyloxycarbonyl)-O-triisopropylsilyl-D-pyrrolosamine glycal of lomaiviticin A (1) and lomaiviticin B (2) is described. The synthesis is highlighted by the epimerization of the L-threonine-derived oxazolidine 10 to oxazolidine 11. This key epimerization reaction, which serves to establish the correct relative configuration of the carbohydrate unit, was made possible only after conformational analysis indicated that substituted oxazolidines may adopt conformations that preclude enolization.