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Academic literature on the topic 'Ras protein inhibitors'

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Published: 9 March 2023
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Journal articles on the topic "Ras protein inhibitors"

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Rowinsky, Eric K., Jolene J. Windle, and Daniel D. Von Hoff. "Ras Protein Farnesyltransferase: A Strategic Target for Anticancer Therapeutic Development." Journal of Clinical Oncology 17, no. 11 (November 1999): 3631–52. http://dx.doi.org/10.1200/jco.1999.17.11.3631.

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ABSTRACT: Ras proteins are guanine nucleotide–binding proteins that play pivotal roles in the control of normal and transformed cell growth and are among the most intensively studied proteins of the past decade. After stimulation by various growth factors and cytokines, Ras activates several downstream effectors, including the Raf-1/mitogen-activated protein kinase pathway and the Rac/Rho pathway. In approximately 30% of human cancers, including a substantial proportion of pancreatic and colon adenocarcinomas, mutated ras genes produce mutated proteins that remain locked in an active state, thereby relaying uncontrolled proliferative signals. Ras undergoes several posttranslational modifications that facilitate its attachment to the inner surface of the plasma membrane. The first—and most critical—modification is the addition of a farnesyl isoprenoid moiety in a reaction catalyzed by the enzyme protein farnesyltransferase (FTase). It follows that inhibiting FTase would prevent Ras from maturing into its biologically active form, and FTase is of considerable interest as a potential therapeutic target. Different classes of FTase inhibitors have been identified that block farnesylation of Ras, reverse Ras-mediated cell transformation in human cell lines, and inhibit the growth of human tumor cells in nude mice. In transgenic mice with established tumors, FTase inhibitors cause regression in some tumors, which appears to be mediated through both apoptosis and cell cycle regulation. FTase inhibitors have been well tolerated in animal studies and do not produce the generalized cytotoxic effects in normal tissues that are a major limitation of most conventional anticancer agents. There are ongoing clinical evaluations of FTase inhibitors to determine the feasibility of administering them on dose schedules like those that portend optimal therapeutic indices in preclinical studies. Because of the unique biologic aspects of FTase, designing disease-directed phase II and III evaluations of their effectiveness presents formidable challenges.
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Graham, Timothy E., Janet R. Pfeiffer, Rebecca J. Lee, Donna F. Kusewitt, A. Marina Martinez, Terry Foutz, Bridget S. Wilson, and Janet M. Oliver. "MEK and ERK Activation in Ras-Disabled RBL-2H3 Mast Cells and Novel Roles for Geranylgeranylated and Farnesylated Proteins in FcεRI-Mediated Signaling." Journal of Immunology 161, no. 12 (December 15, 1998): 6733–44. http://dx.doi.org/10.4049/jimmunol.161.12.6733.

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Abstract Cross-linking the high affinity IgE receptor FcεRI of basophils and mast cells activates receptor-associated protein-tyrosine kinases and stimulates a signaling cascade leading to secretion, ruffling, spreading, and cytokine production. Previous evidence that the pan-prenylation inhibitor lovastatin blocks Ag-stimulated Ca2+ influx, secretion, and membrane/cytoskeletal responses implicated isoprenylated proteins in the FcεRI-coupled signaling cascade but could not distinguish between contributions of C15 (farnesylated) and C20 (geranylgeranylated) species. Here we establish concentrations of lovastatin and the farnesyl-specific inhibitor BZA-5B that inhibit the farnesylation and Ag-induced activation of Ras species in RBL-2H3 cells (H-Ras, K-RasA, and K-RasB). These inhibitors have little effect on tyrosine kinase activation, which initiates FcεRI signaling. Although Ras is disabled, only lovastatin substantially blocks Raf-1 activation, and neither inhibitor affects mitogen-activated protein kinase kinase/extracellular signal regulated kinase kinase (MEK) or ERK1/ERK2 activation. Thus, the pathway to FcεRI-mediated MEK/ERK and ERK activation can apparently bypass Ras and Raf-1. Predictably, only lovastatin inhibits Ag-induced ruffling, spreading, and secretion, previously linked to geranylgeranylated Rho and Rab family members. Additionally, only lovastatin inhibits phospholipase Cγ-mediated inositol (1,4,5) trisphosphate production, sustained Ca2+ influx, and Ca2+-dependent IL-4 production, suggesting novel roles for geranylgeranylated (lovastatin-sensitive, BZA-5B-insensitive) proteins in FcεRI signal propagation. Remarkably, BZA-5B concentrations too low to inactivate Ras reduce the lag time to Ag-induced Ca2+ stores release and enhance secretion. These results link a non-Ras farnesylated protein(s) to the negative regulation of Ca2+ release from intracellular stores and secretion. We identified no clear role for Ras in FcεRI-coupled signaling but suggest its involvement in mast cell growth regulation based on the inhibition of cell proliferation by both BZA-5B and lovastatin.
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Sugita, Kenji, and Mitsuaki Ohtani. "Inhibitors of Ras-Transformation." Current Pharmaceutical Design 3, no. 3 (June 1997): 323–34. http://dx.doi.org/10.2174/138161280303221007125314.

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Abstract: Ras-oncogene is now thought to be one of the most important oncogenes which is evidenced in the correlation with human cancers. Point mutation in ras-gene correlates with transformation caused by ras and is found in human cancers with high frequency, such as 90% in pancreatic cancer, 50% in colon cancer and 30% in lung cancer. Ras (product of ms-oncogene) has GTPase activity and loses its activity with point mutation, leading to transformation. Active GTP-binding form of Ras is a key molecule of signal transduction in cell growth, differentiation and transformation. Inhibitors of ms-transformation will be good candidates of anti-cancer agents. Although many inhibitors of ras­ transformation have been reported up to now including macromolecules (genes, nucleotides, antibodies), we summarize the small-molecule compounds, which inhibit ms-transformation in direct or indirect manner in this review. Direct inhibitors of ras include inhibitors of farnesylation of Ras. Farnesyltransferase inhibitors (L- 744,832, etc) include peptidomimetics with the rational drug design for C-terminus of Ras and natural products. Inhibitors of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase (Lovastatin, etc) which block cholesterol metabolism, inhibit farnesylation of Ras by decreasing the amount of the substrate of farnesyltransferase (Frase). Indirect inhibitors of ras with known mechanisms include the inhibitor of inositol monophosphate (IMP) dehydrogenase (oxanosine), the inhibitor of mitogen-activated protein kinase kinase (MAPK kinase)(PD98059), the inhibitor of MAPK (apigenin), the inhibitors of protein kinase C (PKC) (UCN- 01, etc), the inhibitors of phosphatidylinositol 3-kinase (Pl3K) (Wortmannin and L-294002), the inducer of the transcription factor JunD (oxamflatin) and the inhibitors of histone deacetylase [trichostatin A (TSA) and trapoxins]. Almost all compounds are now under development, and will be evaluated in clinical studies as anticancer agents.
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Mattox, Tyler E., Xi Chen, Yulia Y. Maxuitenko, Adam B. Keeton, and Gary A. Piazza. "Exploiting RAS Nucleotide Cycling as a Strategy for Drugging RAS-Driven Cancers." International Journal of Molecular Sciences 21, no. 1 (December 24, 2019): 141. http://dx.doi.org/10.3390/ijms21010141.

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Oncogenic mutations in RAS genes result in the elevation of cellular active RAS protein levels and increased signal propagation through downstream pathways that drive tumor cell proliferation and survival. These gain-of-function mutations drive over 30% of all human cancers, presenting promising therapeutic potential for RAS inhibitors. However, many have deemed RAS “undruggable” after nearly 40 years of failed drug discovery campaigns aimed at identifying a RAS inhibitor with clinical activity. Here we review RAS nucleotide cycling and the opportunities that RAS biochemistry presents for developing novel RAS inhibitory compounds. Additionally, compounds that have been identified to inhibit RAS by exploiting various aspects of RAS biology and biochemistry will be covered. Our current understanding of the biochemical properties of RAS, along with reports of direct-binding inhibitors, both provide insight on viable strategies for the discovery of novel clinical candidates with RAS inhibitory activity.
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Zeng, Jun, Thao Nheu, Anna Zorzet, Bruno Catimel, Ed Nice, Hiroshi Maruta, Antony W.Burgess, and Herbert R.Treutlein. "Design of inhibitors of Ras–Raf interaction using a computational combinatorial algorithm." Protein Engineering, Design and Selection 14, no. 1 (January 2001): 39–45. http://dx.doi.org/10.1093/protein/14.1.39.

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Cruz-Migoni, Abimael, Peter Canning, Camilo E. Quevedo, Carole J. R. Bataille, Nicolas Bery, Ami Miller, Angela J. Russell, Simon E. V. Phillips, Stephen B. Carr, and Terence H. Rabbitts. "Structure-based development of new RAS-effector inhibitors from a combination of active and inactive RAS-binding compounds." Proceedings of the National Academy of Sciences 116, no. 7 (January 25, 2019): 2545–50. http://dx.doi.org/10.1073/pnas.1811360116.

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The RAS gene family is frequently mutated in human cancers, and the quest for compounds that bind to mutant RAS remains a major goal, as it also does for inhibitors of protein–protein interactions. We have refined crystallization conditions for KRAS169Q61H-yielding crystals suitable for soaking with compounds and exploited this to assess new RAS-binding compounds selected by screening a protein–protein interaction-focused compound library using surface plasmon resonance. Two compounds, referred to as PPIN-1 and PPIN-2, with related structures from 30 initial RAS binders showed binding to a pocket where compounds had been previously developed, including RAS effector protein–protein interaction inhibitors selected using an intracellular antibody fragment (called Abd compounds). Unlike the Abd series of RAS binders, PPIN-1 and PPIN-2 compounds were not competed by the inhibitory anti-RAS intracellular antibody fragment and did not show any RAS-effector inhibition properties. By fusing the common, anchoring part from the two new compounds with the inhibitory substituents of the Abd series, we have created a set of compounds that inhibit RAS-effector interactions with increased potency. These fused compounds add to the growing catalog of RAS protein–protein inhibitors and show that building a chemical series by crossing over two chemical series is a strategy to create RAS-binding small molecules.
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ZHAN, JIN-HUI, XI ZHAO, XU-RI HUANG, and CHIA-CHUNG SUN. "MOLECULAR DYNAMICS AND FREE ENERGY ANALYSES OF ERK2–PYRAZOLYLPYRROLE INHIBITORS INTERACTIONS: INSIGHT INTO STRUCTURE-BASED LIGAND DESIGN." Journal of Theoretical and Computational Chemistry 08, no. 05 (October 2009): 887–908. http://dx.doi.org/10.1142/s0219633609005131.

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The extracellular signal-regulated protein kinase 2 (ERK2) is a pivotal member involving in Ras/Raf/MEK/ERK signal transduction pathway, acting as a central point where multiple signaling pathways coalesce to drive transcription. The pyrazolylpyrrole compounds as ATP competitive inhibitors of ERK2 can bind target with a special binding mode and have higher inhibitory potency than other ERK2-inhibitors. We investigated the interaction mode of ERK2-inhibitor using molecular dynamics simulation. The molecular mechanics Poisson–Boltzmann surface area approach is used to calculate the binding free energy of ERK2 with pyrazolylpyrrole inhibitors to analyze the factors of improving the affinity. The results indicated that the electrostatic interactions play the most important role in keeping the stabilization of ERK2-inhibitor. The structural analyses showed that the protein motions can be controlled by changing the structures of inhibitors; furthermore, the full use of available space in the binding site by improving the flexibilities of inhibitors and introducing hydrophobic groups can increase the inhibitory effect.
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Überall, Florian, Karina Hellbert, Sonja Kampfer, Karl Maly, Andreas Villunger, Martin Spitaler, James Mwanjewe, Gabriele Baier-Bitterlich, Gottfried Baier, and Hans H. Grunicke. "Evidence That Atypical Protein Kinase C-λ and Atypical Protein Kinase C-ζ Participate in Ras-mediated Reorganization of the F-actin Cytoskeleton." Journal of Cell Biology 144, no. 3 (February 8, 1999): 413–25. http://dx.doi.org/10.1083/jcb.144.3.413.

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Expression of transforming Ha-Ras L61 in NIH3T3 cells causes profound morphological alterations which include a disassembly of actin stress fibers. The Ras-induced dissolution of actin stress fibers is blocked by the specific PKC inhibitor GF109203X at concentrations which inhibit the activity of the atypical aPKC isotypes λ and ζ, whereas lower concentrations of the inhibitor which block conventional and novel PKC isotypes are ineffective. Coexpression of transforming Ha-Ras L61 with kinase-defective, dominant-negative (DN) mutants of aPKC-λ and aPKC-ζ, as well as antisense constructs encoding RNA-directed against isotype-specific 5′ sequences of the corresponding mRNA, abrogates the Ha-Ras–induced reorganization of the actin cytoskeleton. Expression of a kinase-defective, DN mutant of cPKC-α was unable to counteract Ras with regard to the dissolution of actin stress fibers. Transfection of cells with constructs encoding constitutively active (CA) mutants of atypical aPKC-λ and aPKC-ζ lead to a disassembly of stress fibers independent of oncogenic Ha-Ras. Coexpression of (DN) Rac-1 N17 and addition of the phosphatidylinositol 3′-kinase (PI3K) inhibitors wortmannin and LY294002 are in agreement with a tentative model suggesting that, in the signaling pathway from Ha-Ras to the cytoskeleton aPKC-λ acts upstream of PI3K and Rac-1, whereas aPKC-ζ functions downstream of PI3K and Rac-1. This model is supported by studies demonstrating that cotransfection with plasmids encoding L61Ras and either aPKC-λ or aPKC-ζ results in a stimulation of the kinase activity of both enzymes. Furthermore, the Ras-mediated activation of PKC-ζ was abrogated by coexpression of DN Rac-1 N17.
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Tisdale, E. J., J. R. Bourne, R. Khosravi-Far, C. J. Der, and W. E. Balch. "GTP-binding mutants of rab1 and rab2 are potent inhibitors of vesicular transport from the endoplasmic reticulum to the Golgi complex." Journal of Cell Biology 119, no. 4 (November 15, 1992): 749–61. http://dx.doi.org/10.1083/jcb.119.4.749.

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We have examined the role of ras-related rab proteins in transport from the ER to the Golgi complex in vivo using a vaccinia recombinant T7 RNA polymerase virus to express site-directed rab mutants. These mutations are within highly conserved domains involved in guanine nucleotide binding and hydrolysis found in ras and all members of the ras superfamily. Substitutions in the GTP-binding domains of rab1a and rab1b (equivalent to the ras 17N and 116I mutants) resulted in proteins which were potent trans dominant inhibitors of vesicular stomatitis virus glycoprotein (VSV-G protein) transport between the ER and cis Golgi complex. Immunofluorescence analysis indicated that expression of rab1b121I prevented delivery of VSV-G protein to the Golgi stack, which resulted in VSV-G protein accumulation in pre-Golgi punctate structures. Mutants in guanine nucleotide exchange or hydrolysis of the rab2 protein were also strong trans dominant transport inhibitors. Analogous mutations in rab3a, rab5, rab6, and H-ras did not inhibit processing of VSV-G to the complex, sialic acid containing form diagnostic of transport to the trans Golgi compartment. We suggest that at least three members of the rab family (rab1a, rab1b, and rab2) use GTP hydrolysis to regulate components of the transport machinery involved in vesicle traffic between early compartments of the secretory pathway.
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Cooley, Rachel, Neesha Kara, Ning Sze Hui, Jonathan Tart, Chloë Roustan, Roger George, David C. Hancock, et al. "Development of a cell-free split-luciferase biochemical assay as a tool for screening for inhibitors of challenging protein-protein interaction targets." Wellcome Open Research 5 (February 6, 2020): 20. http://dx.doi.org/10.12688/wellcomeopenres.15675.1.

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Targeting the interaction of proteins with weak binding affinities or low solubility represents a particular challenge for drug screening. The NanoLucâ ® Binary Technology (NanoBiTâ ®) was originally developed to detect protein-protein interactions in live mammalian cells. Here we report the successful translation of the NanoBit cellular assay into a biochemical, cell-free format using mammalian cell lysates. We show that the assay is suitable for the detection of both strong and weak protein interactions such as those involving the binding of RAS oncoproteins to either RAF or phosphoinositide 3-kinase (PI3K) effectors respectively, and that it is also effective for the study of poorly soluble protein domains such as the RAS binding domain of PI3K. Furthermore, the RAS interaction assay is sensitive and responds to both strong and weak RAS inhibitors. Our data show that the assay is robust, reproducible, cost-effective, and can be adapted for small and large-scale screening approaches. The NanoBit Biochemical Assay offers an attractive tool for drug screening against challenging protein-protein interaction targets, including the interaction of RAS with PI3K.
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Dissertations / Theses on the topic "Ras protein inhibitors"

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AIROLDI, CRISTINA. "Development of new potential antitumor drugs based on Ras protein inhibition." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2007. http://hdl.handle.net/10281/116562.

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Because of their role in oncogenesis, inhibition of Ras proteins, particularly of their tumorigenic variants, represents today one of the principal strategies finalized to the obtainment of new antitumoral therapies. Among the different possible approaches, one of the most innovative and less explored is represented by the inhibition of this protein activation, key event for the explication of their biological activity, but also for the Ras-induced tumoral cell transformation. Objective of this thesis has been the development of new small molecules able to inhibit, at least partially (total inhibition in fact would result lethal for cell), Ras protein activation, in particular the GEFs-promoted GDP/GTP nucleotide exchange. Inhibitors able of inactivating Ras have been previously described by Schering-Plough. All these molecules contain a phenylhydroxylamino group that binds Ras in a region close to the nucleotide binding site and one aromatic group. Nevertheless, they present some negative characteristics that prevent their employment as potential drugs: (1) they are chemically unstable and (2) they are insoluble in water and in the most commonly used organic solvents. In order to obtain new more efficient inhibitors, we adopted the rational drug design strategy. Firstly, we studied the structure-activity relationship (SAR) of Schering-Plough compounds and of new molecules containing variants of their functional groups that we designed and synthesized. The data collected demonstrated that the phenylhydroxylamino group is an essential pharmacophore, while other positions are not so critical for the biological activity.Keeping in mind this, we prepared new compounds in which the phenylhydroxylamino moiety is supported on glycidic templates, in an attempt to try to take advantage of carbohydrate capability of orienting substituents in space, in this case in a suitable manner for the interaction with Ras proteins. In addition, the sugar portion can improve compound pharmacokinetic properties and decrease their toxicity. In this way, a new class of Ras inhibitors was obtained, their biological activity and the nature of their interaction with the molecular target were characterized.
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Volk, Catherine B. "Role of inhibition of protein prenylation in the cholesterol-dependent and cholesterol-independent effects of simvastatin." Virtual Press, 2006. http://liblink.bsu.edu/uhtbin/catkey/1339597.

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Statins are widely used to treat hypercholesterolemia. Statins inhibit cholesterol biosynthesis, thereby activating genes involved in cholesterol homeostasis, which are under the control of the Sterol Regulatory Element (SRE). Statins also have cholesterol-independent beneficial cardiovascular effects mediated through the phosphoinositide 3-kinase (PI3-K) / Akt signaling pathway and by inhibition of protein prenylation. Because statins inhibit the synthesis of isoprenoids, they can act by inhibiting the small signaling GTPases Ras and Rho, which require post-translational prenylation to become membrane-anchored and functional. We showed that simvastatin-mediated inhibition of protein prenylation does not appear to play a role in activation of SRE transcriptional activity in HepG2 cells. We also found that when isoprenoids were replenished, basal phospho-Akt decreased, suggesting that inhibition of prenylation by simvastatin mediates Akt phosphorylation. Future studies will be needed to investigate the role that inhibition of protein prenylation plays in the activation of the PI3-K/Akt pathway by simvastatin.
Department of Biology
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Ganesan, Ramya. "IDENTIFICATION OF THE SITES OF ACTION OF INHIBITORS OF MAMMALIAN PHOSPHOLIPASE D2 (PLD2) AND THE ROLE OF INTERACTING PROTEIN PARTNERS." Wright State University / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=wright1421201049.

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Adhikari, Anirban. "Regulation of guanine nucelotide exchange in inhibitory G protein alpha subunit by activator of G protein signaling 3 and novel regulatory peptides." Embargoed access until after 12/19/2006, 2005. http://www4.utsouthwestern.edu/library/ETD/etdDetails.cfm?etdID=114.

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Bolick, Sophia C. E. "Regulation of transcription and analysis of drug targets in lymphoma and myeloma cells." [Tampa, Fla] : University of South Florida, 2006. http://purl.fcla.edu/usf/dc/et/SFE0001750.

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Falsetti, Samuel C. "The Role of RalA and RalB in Cancer." [Tampa, Fla] : University of South Florida, 2008. http://purl.fcla.edu/usf/dc/et/SFE0002307.

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Cooper, Jahan. "Optimizing the Potency of a Bicyclic Peptide Inhibitor of the Ras-Raf Protein-Protein Interaction via Combinatorial Screening." The Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu152570020664904.

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Bessa, Tiphany Coralie de. "Mecanismo associados à perda da regulação da nox1 NADPH oxidase pela dissulfeto isomerase proteica em células com ativação sustentada da via ras." Universidade de São Paulo, 2018. http://www.teses.usp.br/teses/disponiveis/5/5131/tde-03072018-090616/.

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Dissulfeto isomerase proteica como a PDIA1 tem sido implicada na progressão do câncer, porém os mecanismos envolvidos ainda não foram claramente identificados. Previamente, nós demonstramos um importante efeito da PDIA1 induzindo a superexpressão da Nox1 NADPH oxidase, associada à geração de espécie reativas de oxigênio (ROS). Uma vez que a perda na regulação de ROS envolve o crescimento tumoral, nós propusemos que a PDIA1 atua como um mecanismo regulador proximal na produção de ROS em tumores. No presente estudo, nós focamos no câncer colorretal (CRC) com distintos efeitos na ativação de KRas. Resultados provenientes de bancos de dados de RNAsec e validação direta, indicam um significante aumento na expressão de PDIA1 em CRC com alta ativação constitutiva da Kras (HCT116) vs. ativação intermediária (HKE3) ou basal (Caco2). A PDIA1 sustenta a produção de superóxido dependente da Nox1 em CRC; entretanto, observamos pela primeira vez uma ação dupla da PDIA1 correlacionada ao nível de ativação da Ras: em células Caco2 e HKE3, experimentos de perda de função indicam que o PDIA1 sustenta a produção de superóxido dependente de Nox1; no entanto, em células HCT116, PDIA1 limita a produção de superóxido pela Nox1. Este comportamento da PDIA1 é associado ao aumento da expressão / atividade da Rac1. A transfecção do mutante constitutivamente ativo Rac1G12V em células HKE3 faz com que a PDIA1 se torne restritiva a produção de superóxido dependente de Nox1, paralelamente, em células HCT116 tratadas com inibidor da Rac1, PDIA1 se torna favorável à produção de superóxido. Um screening em importantes vias de sinalização celular em HKE3 mostrou que a perda de função da PDIA1 promove inativação da GSK3? em paralelo à diminuicão da ativacção de Stat3; em HCT116 em estado basal, GSK3beta é inativada enquanto Stat3 está ativa, já o silenciamento da PDIA1 não resulta em nenhum efeito adicional. As implicações funcionais do silenciamento da PDIA1 incluíram uma diminuição da proliferação e migração celular em HKE3, não detectável em HCT116. Além disso, a PDIA1 parece sustentar a transição epitélio-mesenquimal (EMT), uma vez que após o silenciamento da PDIA1, observamos um aumento da expressão da E-caderina em HKE3 e uma diminuição em HCT116. Assim, a superativação da Ras se associa a uma alteração no padrão de regulação da Nox1 pela PDIA1. A supressão do efeito regulador da PDIA1 pela Kras é provavelmente devido a uma ativação sustentada da Rac1. Portanto, PDIA1 pode exercer um papel redox-dependente adaptativo crucial relacionado à progressão tumoral
Protein disulfide isomerases such as PDIA1 have been implicated in cancer progression, but the underlying mechanisms are unclear. We showed previously important PDIA1 effects enabling vascular Nox1 NADPH oxidase expression and associated generation of reactive oxygen species (ROS). Since deregulated ROS production underlies tumor growth, we proposed that PDIA1 acts as an upstream regulatory mechanism of tumor-associated ROS production. We focused on colorectal cancer (CRC) with distinct levels of KRas activation. Our results from RNAseq databanks and direct validation indicate significant increase in PDIA1 expression in CRC with constitutive high (HCT116) vs. moderate (HKE3) or basal (e.g. Caco2) Ras activity. PDIA1 supported Nox1-dependent superoxide production in CRC; however, we observed for the first time a dual effect correlated with Ras level activity: in Caco2 and HKE3 cells, loss-of-function experiments indicate that PDIA1 sustains Nox1-dependent superoxide production; however, in HCT116 cells, PDIA1 restricted Nox1-dependent superoxide production. This PDIA1 behavior in HCT116 is associated with increased Rac1 expression/activity. Transfection of Rac1G12V active mutant into HKE3 cells induced PDIA1 to become restrictive of Nox1-dependent superoxide; accordingly, in HCT116 cells treated with Rac1 inhibitor, PDIA1 became supportive of superoxide production. Screening of cell signaling routes affected by PDIA1 silencing showed induced GSK3beta inactivation and parallel decrease of active Stat3 in HKE3 cells; in baseline HCT116 cells, GSK3beta was inactivated and Stat3 active, whereas PDIA1 silencing had no further effect. Functional implications of PDIA1 silencing included a decrease of cell proliferation and migration in HKE3, not detectable in HCT116 cells. Also, PDIA1 may support epithelial-mesenchymal transition (EMT), since after PDIA1 silencing, E-cadherin expression increased in HKE3 and decreased in HCT116. Thus, Ras overaction associates with a switched in PDIA1 pattern regulation of Nox1. Ras-induced PDIA1 bypass may involve direct Rac1 activation. Therefore, PDIA1 may be a crucial regulator of redox-dependent adaptive processes related to cancer progression
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McGee, John Hanney. "Evolving a Direct Inhibitor of the Ras Proteins." Thesis, Harvard University, 2013. http://dissertations.umi.com/gsas.harvard:10915.

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In recent years, great advances have been made in understanding the molecular causes of human disease, but our ability to exploit these discoveries for therapeutic benefit is frequently limited by the inability to make drugs that target the processes responsible. Many diseases can be linked to the aberrant activity of proteins, and while the development of inhibitors for enzymes and extracellular targets is often feasible, these proteins account for only a small fraction of all the proteins in cells. The remaining proteins are, in most cases, considered therapeutically intractable and are sometimes referred to as "undruggable." Many proteins, particularly in higher organisms, carry out their activity in part through interactions with other proteins and biomolecules. The ability to specifically disrupt these interactions could have great therapeutic benefit, as it may provide a means of targeting otherwise intractable processes. The focus of this dissertation is on the development and characterization of molecules that inhibit the interactions of an “undruggable” protein target, Ras, which is linked to both the initiation and progression of a wide array of human cancers. Our approach has been to use high-throughput screening, coupled with directed evolution, to identify and improve small proteins (peptides) that bind Ras and block its ability to engage the effector proteins necessary for its oncogenic activity. We report these efforts, along with a series of biochemical experiments aimed at characterizing the properties and binding mechanism of the peptides discovered in the screen. These peptides bind the three human Ras proteins with mid-to-low nanomolar affinity, and with high specificity for Ras proteins over their close family members. The peptides directly engage the Ras effector domain, and can block Ras from binding a canonical effector protein in the context of cancer cell lysates. Based on a series of observations, we hypothesize that the peptides bind Ras as head-to-tail homodimers, and report preliminary attempts to exploit this observation and identify peptides with improved affinity to Ras. Finally, we discuss the preliminary results from a conceptually related effort to identify peptide inhibitors of the Myc transcription factor, which is another protein heavily implicated in human cancer.
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Reid, Anne Marie. "Raf-1 kinase inhibitor protein modulation of the cellular response to chemotherapeutic drugs and PDE5 inhibitors." Thesis, University of Glasgow, 2011. http://theses.gla.ac.uk/2497/.

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RKIP was initially discovered as an endogenous inhibitor of the ERK and NF-κB pathways,and was also shown to prolong the activation of GPCRs via inhibition of the GRK2 protein. Now increasing evidence has linked RKIP to a metastases suppressing and chemo-sensitising role in cancer cells.The chemo-sensitising effect of RKIP was investigated in a colon carcinoma cell line using a variety of chemotherapeutic agents from conventional agents to newer targeted therapies. Initial results suggested that role of RKIP in the modulation of chemotherapeutic drug response was at the level of apoptosis; there did not appear to be great observable effects in the cell proliferative response and the cell cycle distribution of the colon carcinoma cells after treatment with selected agents. Apoptosis modulation by RKIP occurred after treatment with doxorubicin, FasL, paclitaxel and TRAIL. TRAIL-treated colon carcinoma cells displayed increased cell death as the levels of RKIP within the cell were increased. In contrast, doxorubicin, FasL and paclitaxel-treated cells displayed a scaffold-like response as the levels of RKIP were increased in the cell; with WT RKIP-expressing cells being more sensitive to doxorubicin, FasL and paclitaxel-induced apoptosis than low or high RKIP-expressing colon carcinoma cells. There was no modulation of 5-FU, cisplatin and etoposide-induced apoptosis by RKIP. Indeed, these three agents did not appear to induce cell death in this colon carcinoma cell line. RKIP modulation of chemo-sensitivity has never been shown before in a colon carcinoma cell line and this is the first time that doxorubicin and FasL-induced apoptosis has been shown to be modulated by RKIP. Further, it is shown here, for the first time, that the modulation of chemotherapy-induced apoptosis by RKIP can change depending upon the cytotoxic drug employed as treatment. TRAIL and FasL, both members of the TNF super-family, were selected for further analysis due to the distinctive cell death responses observed as a consequence of the levels of RKIP within the cell. WT RKIP cells were sensitive to FasL treatment, and high RKIP cells were most sensitive to TRAIL administration. Increased sensitivity of high RKIP-expressing colon cells to TRAIL treatment appeared to involve up-regulation of the DR5 receptor; down-regulation of the anti-apoptotic molecule Bcl-xl; pIKK which activates the NF-κB pathway; and TRAF2 which has been shown to activate the NF-κB pathway. Whether RKIP directly interacts with these molecules is unknown however RKIP has been shown to bind upstream activators of the NF-κB pathway and another TRAF subtype TRAF6. YY1 expression was evident in the TRAIL-treated cells but the expression was unchanged as the levels of RKIP within the cell were altered. The FasL-treated cells also displayed decreased pIKK levels as the levels of RKIP were increased; it is possible that NF-κB was behaving as both pro- and anti-apoptotic within this cell line. Thus RKIP inhibition of the NF-κB pathway may have prevented FasL-induced apoptosis in the high RKIP-expressing colon carcinoma cells. The expression of TRAF6, which has been shown to bind RKIP, displayed a scaffold-like response with WT RKIP-expressing cells having the highest TRAF6 expression. This was also the case for the transcriptional regulator YY1, thus it is possible that both YY1 and TRAF6 were behaving in a pro-apoptotic-like manner in the WT RKIP-expressing cells. TRAF2 was also evident in the FasL-administered cells but the expression did not change regardless of the levels of RKIP within the cell. Overall, it appears that differential expression of TRAF adaptor proteins is responsible for the contrasting responses of TRAIL and FasL-treated cells with low, WT and high RKIP expression. Utilisation of particular TRAF adaptors or TRAF combinations by the TRAIL and Fas receptors may also account for the pro- and anti-apoptotic roles of the NF-κB pathway, and the recruitment or down-regulation of other proteins dependent upon the cell stimulus. How RKIP affects these proteins requires further investigation, however these results are exciting and novel, and strengthen evidence surrounding the role of RKIP in chemosensitivity. On another note, RKIP has been shown to bind the PDE5 inhibitor PF-3717842, therefore investigation of the effects of the PDE5 inhibitors sildenafil citrate and vardenafil citrate on RKIP inhibition of the ERK pathway in a colon carcinoma cell line were examined. The effects of the PDE5 inhibitors were compared to the cell migration inhibitor locostatin that has been shown to bind and inhibit RKIP, and prevent the RKIP-Raf-1 interaction. With TPA and EGF stimulation, locostatin appeared to act in a manner consistent with its known function as an RKIP inhibitor. The PDE5 inhibitors sildenafil citrate and vardenafil citrate displayed a similar trend to that of locostatin, although their effects on the ERK pathway were not as potent. It is possible that after EGF stimulation, the strong activation of B-Raf was over-shadowing the subtle effects of the drug treatments. Under growth conditions, the RKIP inhibitor locostatin did not appear to behave as an inhibitor of RKIP nor did the PDE5 inhibitors sildenafil citrate and vardenafil citrate. It is possible that the strong activation of various growth and proliferative cascades was impinging upon the ERK pathway, were overshadowing the drug effects, or resulting in off-target (RKIP-unrelated) effects of the drugs. In summary, the role of RKIP within the cell is becoming an increasingly exciting avenue of research and is consistently yielding new and interesting roles and interactions within the cell. Understanding and elucidating the roles of this intriguing protein within the cell will not only strengthen our knowledge of signal transduction regulation and modulation, but may also provide a new source of targeted therapy and means of manipulation in the treatment of cancer and chemotherapeutic drug resistance.
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Books on the topic "Ras protein inhibitors"

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Tamanoi, Fuyuhiko. Inhibitors of the Ras Superfamily G-Proteins, Part A. Elsevier Science & Technology Books, 2013.

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Tamanoi, Fuyuhiko. Inhibitors of the Ras Superfamily G-Proteins, Part A. Elsevier Science & Technology Books, 2013.

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Inhibitors of the Ras Superfamily G-Proteins, Part B. Elsevier Science & Technology, 2013.

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Tamanoi, Fuyuhiko, and Channing J. Der. Inhibitors of the Ras Superfamily G-Proteins, Part B. Elsevier Science & Technology Books, 2013.

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Inhibitors of the Ras Superfamily G-proteins, Part A. Elsevier, 2013. http://dx.doi.org/10.1016/c2012-0-03660-5.

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Inhibitors of the Ras superfamily G-proteins, Part B. Elsevier, 2013. http://dx.doi.org/10.1016/c2012-0-03661-7.

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Sullivan, Ryan J. BRAF Targets in Melanoma: Biological Mechanisms, Resistance, and Drug Discovery. Humana, 2016.

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Sullivan, Ryan J. BRAF Targets in Melanoma: Biological Mechanisms, Resistance, and Drug Discovery. Humana, 2014.

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Sullivan, Ryan J. BRAF Targets in Melanoma: Biological Mechanisms, Resistance, and Drug Discovery. Springer, 2014.

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Shepherd, Angela J., and Juliet M. Mckee. Osteoporosis. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780190466268.003.0015.

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Osteoporotic fractures are major causes of suffering and death. Dual-energy x-ray absorptiometry (DEXA) is the standard of care for diagnosis (T-score ≤ –2.5) of osteoporosis. Prevention of fractures requires addressing bone and muscle strength and balance. Physical exercise, good nutrition (fruits, vegetables, adequate calcium), adequate vitamin intake (C, D, and K), tobacco cessation, and no more than moderate alcohol intake enhance bone health and decrease fracture risk. Long-term treatment with glucocorticoids, certain drugs used in breast or prostate cancer treatment, and proton pump inhibitors used for gastroesophageal reflux disease may increase the risk for osteoporosis. Pharmacologically, bisphosphonates are the mainstay of osteoporosis treatment.
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Book chapters on the topic "Ras protein inhibitors"

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Leftheris, K., T. Kline, W. Lau, L. Mueller, V. S. Goodfellow, M. K. DeVirgilio, Y. H. Cho, et al. "Tetrapeptide based inhibitors of p21 ras protein farnesyl transferase." In Peptides, 622–24. Dordrecht: Springer Netherlands, 1994. http://dx.doi.org/10.1007/978-94-011-0683-2_205.

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Khazak, Vladimir, Erica A. Golemis, and Lutz Weber. "Development of a Yeast Two-Hybrid Screen for Selection of Human Ras-Raf Protein Interaction Inhibitors." In Methods in Molecular Biology™, 253–71. Totowa, NJ: Humana Press, 2005. http://dx.doi.org/10.1007/978-1-59259-948-6_18.

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Dekker, Frank J., Nachiket Vartak, and Christian Hedberg. "Development of Acyl Protein Thioesterase 1 (APT1) Inhibitor Palmostatin B That Revert Unregulated H/N-Ras Signaling." In Concepts and Case Studies in Chemical Biology, 123–40. Weinheim, Germany: Wiley-VCH Verlag GmbH & Co. KGaA, 2014. http://dx.doi.org/10.1002/9783527687503.ch8.

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Weitzdoerfer, R., D. Stolzlechner, M. Dierssen, J. Ferreres, M. Fountoulakis, and G. Lubec. "Reduction of nucleoside diphosphate kinase B, Rab GDP- dissociation inhibitor beta and histidine triad nucleotide-binding protein in fetal Down Syndrome brain." In Protein Expression in Down Syndrome Brain, 347–59. Vienna: Springer Vienna, 2001. http://dx.doi.org/10.1007/978-3-7091-6262-0_29.

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Kursunluoglu, Gizem, Duygu Erdogan, Elcin Cagatay, Esra Bulut Atalay, Seminay Guler, Yonca Gungor, and Hulya Ayar Kayali. "The Role of Kinase Inhibitors in Cancer Therapies." In Protein Kinases - Promising Targets for Anticancer Drug Research. IntechOpen, 2021. http://dx.doi.org/10.5772/intechopen.99070.

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Protein kinases are enzymes that transfer a phosphate group to the threonine, serine, or tyrosine residues of the target protein, regulating its activity. The activity of these enzymes are very important and strictly regulated in the cell as they promote cell proliferation, survival, and migration. In the case of any dysregulation of these enzymes, they can be associated with cancer initiation and progression. Small-molecule kinase inhibitors approved by the FDA for their improved clinical benefits are currently used in targeted therapy for the treatment of various cancers. So far, there are 62 FDA-approved therapeutic agents targeting different protein kinases, eight of which were approved in 2020. Today, kinase inhibitors are used as FDA approved cancer agents and newly developed ones are evaluated in clinical trials. Those protein kinase inhibitors can be grouped as growth factor receptor inhibitors, Ras/Raf/Mek inhibitors, phosphoinositide 3-kinase (PI3K) and cyclin dependent kinase inhibitors, other targets, and agents such as protein kinase c and 3 phosphoinositide-dependent kinase 1. In this chapter, these kinases, their pathways, and their inhibitors will be discussed in detail.
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Gentry, Leanna, Ahmed A. Samatar, and Channing J. Der. "Inhibitors of the ERK Mitogen-Activated Protein Kinase Cascade for Targeting RAS Mutant Cancers." In Inhibitors of the Ras superfamily G-proteins, Part B, 67–106. Elsevier, 2013. http://dx.doi.org/10.1016/b978-0-12-420146-0.00004-4.

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Kohl, Nancy E., Francine R. Wilson, Tracy J. Thomas, Rhonda L. Bock, Scott D. Mosser, Allen Oliff, and Jackson B. Gibbs. "[38] Inhibition of Ras function in Vitro and in Vivo using inhibitors of farnesyl-protein transferase." In Methods in Enzymology, 378–86. Elsevier, 1995. http://dx.doi.org/10.1016/s0076-6879(95)55040-2.

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Kloog, Yoel, Galit Elad-Sfadia, Roni Haklai, and Adam Mor. "Ras Chaperones." In Inhibitors of the Ras Superfamily G-proteins, Part A, 267–89. Elsevier, 2013. http://dx.doi.org/10.1016/b978-0-12-416749-0.00012-9.

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Khazak, Vladimir, Susanne Eyrisch, Juran Kato, Fuyuhiko Tamanoi, and Erica A. Golemis. "A Two-Hybrid Approach to Identify Inhibitors of the RAS–RAF Interaction." In Inhibitors of the Ras Superfamily G-proteins, Part A, 213–48. Elsevier, 2013. http://dx.doi.org/10.1016/b978-0-12-416749-0.00010-5.

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Tetlow, Ashley L., and Fuyuhiko Tamanoi. "The Ras Superfamily G-Proteins." In Inhibitors of the Ras Superfamily G-proteins, Part A, 1–14. Elsevier, 2013. http://dx.doi.org/10.1016/b978-0-12-416749-0.00001-4.

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Conference papers on the topic "Ras protein inhibitors"

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Ismail, Mohamed S., and Julian Downward. "Abstract LB-A17: Identification and Characterization of Cyclic Peptide Inhibitors for Ras/PI3K and Ras/Raf Protein Complexes." In Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; October 26-30, 2017; Philadelphia, PA. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1535-7163.targ-17-lb-a17.

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Merkel, A., S. Hetjens, P. Weidner, T. Gaiser, S. Belle, Ebert MP, E. Burgermeister, and T. Gutting. "Der Verlust des RAS - Inhibitors Docking Protein 1 (DOK1) ist ein häufiges Ereignis in serratierten kolorektalen Läsionen." In DGVS Digital: BEST OF DGVS. © Georg Thieme Verlag KG, 2020. http://dx.doi.org/10.1055/s-0040-1716138.

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Hamilton, Mark, Alexandra K. Bernardino, Yan Liu, Kathleen Provoncha, Dorothy Paul, Yakov Rotshteyn, Amy Han, and Dapeng Qian. "Abstract 4491: Novel multiplex PI3-kinase inhibitors potently inhibit Ras-mutated tumors via suppression of eIF-4E-mediated protein translation." In Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC. American Association for Cancer Research, 2010. http://dx.doi.org/10.1158/1538-7445.am10-4491.

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Baker, J. B., M. P. McGrogan, C. Simonsen, R. L. Gronke, and B. W. Festoff. "STRUCTURE AND PROPERTIES OF PROTEASE NEXIN I." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644765.

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Human foreskin fibroblasts secrete several different serine protease inhibitors which differ in size and protease specificities. These proteins, called protease nexins (PNs) all form SDS-resistant complexes with their protease targets. Fibroblast surface receptors recognize the protease-PN complexes and mediate their delivery to lysosomes. PNI is a 45 kilodalton glycoprotein that rapidly inhibits several arg or lys-specific proteases including trypsin, thrombin, and urokinase (k assoc.∼ 4×l06,∼ 6×105 and ∼ 2×105, m−1s−1 respectively). Like antithrombin III, PNI binds heparin and inhibits thrombin at a vastly accelerated rate in the presence of this glycoaminoglycan. Immunofluorescence studies show that in addition to secreting PNI foreskin fibroblasts carry this inhibitor on their surfaces. PNI cDNA has been cloned and sequenced. A mixed oligonucleotide probe derived from PNI N-terminal sequence was used to probe a foreskin fibroblast cDNA library constructed with λGT10. Identification of PNI cDNAs has been verified by sequencing and by expressing active PNI protein in mammalian cells. The full amino acid sequence of PNI, deduced from cDNA sequencing, is 392 residues long and has 30% homology to antithrombin III. An arg-ser pair 32 residues from the C-terminus of the inhibitor is proposed as the reactive center P1-P1 residues. In the hinge region a lys residue is present in a position occupied by a ginor glu residue in other serpins. PNI mRNA exists in 2 slightly different forms:One (αPNI) yields a thr-arg-ser sequence wherethe other βPNI) yields a thr-thr-gly-ser sequence. The presence of the appropriate splice acceptor sites in the genome indicates that these forms are generated from a single gene by alternative splicing. Expressed aPNI and 0PNI proteins both bind thrombin and urokinase. In foreskin fibroblaststhe α form of PNI mRNA predominates over the β form by about 2:1. In foreskin fibroblast cultures secreted PNI inhibits the mitogenic response to thrombin and regulate secreted urokinase. Purified PNI added to human fibrosarcoma (HT1080) cells inhibitsthe tumor cell-mediated destruction of extracellular matrix and transiently, but dramatically, inhibits tumor cell growth. PNI or PNI-like inhibitors may function at multiple physiological sites. The β form of PNI is virtually identical to a glia-derived neurite promoting factor, the cDNA for which has been recently cloned and sequenced by Gloor et al (1). The neurite outgrowth activity of PNI may result from inhibition of a thrombin-like protease that is associated with neurons, since a number of thrombin inhibitors stimulate neurite extension. Recent immunofluoresence experiments, carried out with D. Hantai (Inserm; Paris) demonstrate that anti-PNI antibody intensely stains neuromuscular synapses. In addition, a PNI-like inhibitor is associated with platelets. At low (0.5 nM <) 125I-thrombin concentrations formation of 125I-thrombin-platelet PNI complexes accounts for most of the specific binding of 125I-thrombin to platelets (2). Although the platelet-associated form of PNI is electrophoretically and immunologically indistinguishable from fibroblast PNI, it does not bind urokinase, suggesting that it may be distinct.(1) Gloor, S., K. Odink, J. Guenther, H. Nick, and D. Monard. (1986) Cell 47:687-693.(2) Gronke, R.S., B.L. Bergman, and J.B. Baker. (1987) J. Biol. Chem. (in press)
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Johannessen, Liv, Jarrett R. Remsberg, Alla Ivanova, Vadim Gaponenko, Lyuba Khavrutskii, Sergey G. Tarasov, Michael Dean, Joseph Kates, and Nadya I. Tarasova. "Abstract LB-426: Potent inhibitors of RAS pathways that bind directly to Ras proteins." In Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL. American Association for Cancer Research, 2012. http://dx.doi.org/10.1158/1538-7445.am2012-lb-426.

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Weidner, P., M. Söhn, T. Gutting, T. Gaiser, P. Kienle, J. Magdeburg, C. Röcken, et al. "Myotubularin Related Protein 7 – ein dualer Ras- und mTORC-Inhibitor im kolorektalen Karzinom." In Viszeralmedizin 2017. Georg Thieme Verlag KG, 2017. http://dx.doi.org/10.1055/s-0037-1604734.

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Divakar, SaiKrishna, Rodrigo Vasqez-Del Caprio, Stacey J. Baker, M. V. Ramana Reddy, Daniel A. Ritt, Deborah K. Morrison, and E. Premkumar Reddy. "Abstract LB-108: Targeting the Ras-Binding domain of RAS effector proteins by a small molecule inhibitor, Rigosertib." In Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA. American Association for Cancer Research, 2014. http://dx.doi.org/10.1158/1538-7445.am2014-lb-108.

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Poll, C. T., P. A. Kyrle, and J. Westwick. "ACTIVATION OF PROTEIN KINASE C INHIBITS THROMBIN AND FLUORIDE STIMULATED EICOSANOID PRODUCTION IN HUMAN PLATELETS." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644633.

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Touqui et al (1986) have suggested that phosphorylation by protein kinase C of a 1ipomodulin-1 ike polypeptide extracted from platelets renders it inactive as an inhibitor of phospholipase A2. We have examined this suggestion by measuring thromboxane (Tx) B2 generation and cytosolic free calcium concentration ([Ca++]i) in stimulated, washed human platelets loaded with or without quin-2. Addition of thrombin (0.077, 0.23, 0.77, 2.3 and 7.7 nM) to control platelets produces a dose-related elevation of [Ca++]i (10±5, 50±7, 260±30, 550±25 and 1500±100 nM respectively) and generation of TxB2 (0, 9±4, 45±6, 194±10 and 375±30 pmoles/108 platelets respectively). Preincubation of platelets for 1 min with 1-oleoyl-2-acetyl-rac-glycerol (OAG, 22-198 μM), phorbol myristate acetate (PMA, 1.616 nM) or EGTA (2 mM) produces a marked inhibition of high and low dose thrombin (7.7 nM and 0.77 nM) or NaF (18 mM) induced elevation of [Ca++]i and TxB2 generation. Pretreatment of platelets with the protein kinase C inhibitor, H-7 (60 uM), prevented the inhibition of TxB2 formation induced by PMA (4.816 nM) or OAG (66-198 μM) in either thrombin (0.77 nM) or NaF (18 mM) stimulated platelets. When arachidonic acid (AA, 10 μM) is used as the stimulus, the Δ[Ca++]i is 190±15 nM and TxB2 generation is 35.9±2 pmoles/108 platelets. While pretreatment with 4.8 nM PMA obliterates the AA-induced Δ[Ca++]i and partially reduces (p< 0.05) the TxB2 generation to 27.8+3 pmoles/108 platelets. PMA and OAG pretreatment also inhibits TxB2 generation in thrombin-stimulated, non-quin-2-1oaded platelets. Thus, at least with intact, agonist- and NaF-stimulated platelets, activation of protein kinase C inhibits eicosanoid production.We thank the British Heart Foundation and Ciba-Geigy USA for financial support.
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Cheon, Y. H., Y. S. Suh, S. M. Yi, M. Kim, S. I. Lee, and H. S. Noh. "AB0140 The role of raf kinase inhibitory protein in rheumatoid arthritis." In Annual European Congress of Rheumatology, EULAR 2018, Amsterdam, 13–16 June 2018. BMJ Publishing Group Ltd and European League Against Rheumatism, 2018. http://dx.doi.org/10.1136/annrheumdis-2018-eular.5076.

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Aihara, M., S. Morimoto, Y. Sawada, A. Kimura, Y. Chiba, and Y. Yoshida. "A ROLE OF PLATELET MEMBRANE COMPONENTS IN THE INTERACTION OF PLATELET-COLLAGEN-VON WILLEBRAND FACTOR." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644480.

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To determine a role of platelet membrane components on the interaction of platelet-collagen-von Willebrand factor(vWF), several experimental approaches were used. The adhesion of human fixed washed platelets(FWP) to collagen was decreased after the treatment with Serratia marcescens protease(100 ug/ml), but the collagen cofactor activity(COo) of vWF that enhances the adhesion of FWP to collagen was still present after the digestion. Although the platelet adhesion in the absence of normal plasma was not changed by the addition of monoclonal antibody(M-ab) against platelet membrane glycoprotein(GP) IIb/lIIa(1 0E5, BS Coller), the adhesion was decreased by 30-50% after the treatment of the platelets with 10-100 ug/ml anti-GPIb(6D1, BS Coller). The adhesion of FWP to collagen was inhibited by lectins;the adhesion was 58-75% in the presence of 100-400 ug/ml L. culinaris lectin or weat germ agglutinin and the adhesion was nil in the presence of 100 ug/ml Ricinus communis agglutinin I or 200 ug/ml concanavalin A. By the crossed aff ino-immunoelectrophoresis, the binding of GP Ilb/lIIa in Triton-solubilized platelet supernatant to the collagen spacer gel was observed. When CHAPSO solubilized platelet was applied to the collagen column and the fractions containing adhesion inhibitor were eluated by 0.3M NaCl, Mr of 240K, 220K, 21 OK, 116K, 61K, 54K, 50K and 45K proteins were identified besides the proteins which correspond to thrombospondin, GPIb, GP lib or Ilia by SDS-PAGE(7.5% gel, silver stain). GOo in normal plasma was not changed by anti-GPIIb/lIIa but was decreased to 32-38%by anti-GPIb. M-ab against vWF, CLB-RAg 35(van Mourik), that inhibits the binding of vWF to platelet by ristocetin decreased COo in normal plasma by 70% and CLB-RAg 201 (van Mourik) that inhibits the binding of vWF to collagen did completely inhibit the COo in normal plasma. In conclusion, our data suggest that (1) GPIb is partly involved in the platelet adhesion to collagen; (2) the binding of vWF to collagen is required for the expression of CCo; (3) CCo of vWF is partly mediated though GPIb; and (4) several platelet membrane protein(s) besides GPIb or GPIIb/lIIa may be also involved in both the adhesion of platelets to collagen and CCo of vWF.
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Reports on the topic "Ras protein inhibitors"

1

Dickman, Martin B., and Oded Yarden. Regulation of Early Events in Hyphal Elongation, Branching and Differentiation of Filamentous Fungi. United States Department of Agriculture, 2000. http://dx.doi.org/10.32747/2000.7580674.bard.

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In filamentous fungi, hyphal elongation, branching and morphogenesis are in many cases the key to successful saprophytic and pathogenic fungal proliferation. The understanding of the fungal morphogenetic response to environmental cues is in its infancy. Studies concerning the regulation of fungal growth and development (some of which have been obtained by the participating collaborators in this project) point to the fact that ser/thr protein kinases and phosphatases are (i) involved in the regulation of such processes and (ii) share common structural and functional features between saprophytes and pathogens. It is our objective to combine a pharmaceutical and a genetic approach in order to identify, characterize and functionally dissect some of the regulatory factors involved in hyphal growth, branching and differentiation. Using an immunohistochemical approach, a ser/thr protein kinase involved in hyphal elongation in both Neurospora crassa and Colletotrichum trifolii has been localized in order to identify the physical arena of regulation of hyphal elongation. The analysis of additional kinases and phosphatases (e.g. Protein kinase C, cAMP-dependent kinase, lipid-activated protein kinase, components of the type 2A protein phosphatase) as well as a RAS-related gene (an additional key participant in signal transduction) has been performed. In order to succeed in advancing the goals of this project, we have taken advantage of available elongation/branching mutants in N. crassa and continuously combined the accumulated information obtained while studying the two systems in order to dissect the elements involved in these processes. The various inhibitors/effectors analyzed can serve as a basis for modification to be used as anti-fungal compounds. Understanding the regulation of hyphal proliferation is a key requirement for identifying novel target points for either curbing fungal growth (as in the case of pathogenesis) or affecting growth patterns in various biotechnological processes. The major objective of our joint project was to advance our understanding of regulation of hyphal growth, especially during early events of fungal germination. Towards achieving this goal, we have coupled the analysis of a genetically tractable organism (N. crassa) with a plant pathogen o economic importance (C. trifolii). As the project progressed we believe that the results obtained have provided a reinforcement to our basic approach which called for combining the two fungal systems for a joint research project. On the one hand, we feel that much of the advance made was possible due to the amenability of N. crassa to genetic manipulations. The relevance of some of the initial findings obtained in Neurospora have been proven to be relevant to the plant pathogen while unique features of the pathogen have been identified in Colletotrichum. Most of the results obtained from this research project have been published. Thus, the main volume of this report is comprised of the relevant publications describing the research and results obtained.
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Elroy-Stein, Orna, and Dmitry Belostotsky. Mechanism of Internal Initiation of Translation in Plants. United States Department of Agriculture, December 2010. http://dx.doi.org/10.32747/2010.7696518.bard.

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Original objectives Elucidation of PABP's role in crTMV148 IRES function in-vitro using wheat germ extract and krebs-2 cells extract. Fully achieved. Elucidation of PABP's role in crTMV148 IRES function in-vivo in Arabidopsis. Characterization of the physical interactions of PABP and other potential ITAFs with crTMV148 IRES. Partly achieved. To conduct search for additional ITAFs using different approaches and evaluate the candidates. Partly achieved. Background of the topic The power of internal translation via the activity of internal ribosomal entry site (IRES) elements allow coordinated synthesis of multiple gene products from a single transcription unit, and thereby enables to bypass the need for sequential transformation with multiple independent transgenes. The key goal of this project was to identify and analyze the IRES-trans-acting factors (ITAFs) that mediate the activity of a crucifer-infecting tobamovirus (crTMV148) IRES. The remarkable conservation of the IRES activity across the phylogenetic spectrum (yeast, plants and animals) strongly suggests that key ITAFs that mediate its activity are themselves highly conserved. Thus, crTMV148 IRES offers opportunity for elucidation of the fundamental mechanisms underlying internal translation in higher plants in order to enable its rational manipulation for the purpose of agricultural biotechnology. Major conclusions and achievements. - CrTMV IRES requires PABP for maximal activity. This conclusion was achieved by PABP depletion and reconstitution of wheat germ- and Krebs2-derived in-vitro translation assays using Arabidopsis-derived PABP2, 3, 5, 8 and yeast Pab1p. - Mutations in the internal polypurine tract of the IRES decrease the high-affinity binding of all phylogenetically divergent PABPs derived from Arabidopsis and yeast in electro mobility gel shift assays. - Mutations in the internal polypurine tract decrease IRES activity in-vivo. - The 3'-poly(A) tail enhances crTMV148 IRES activity more efficiently in the absence of 5'-methylated cap. - In-vivo assembled RNPs containing proteins specifically associated with the IRES were purified from HEK293 cells using the RNA Affinity in Tandem (RAT) approach followed by their identification by mass spectroscopy. - This study yielded a list of potential protein candidates that may serve as ITAFs of crTMV148 IRES activity, among them are a/b tubulin, a/g actin, GAPDH, enolase 1, ribonuclease/angiogenin inhibitor 1, 26S proteasome subunit p45, rpSA, eEF1Bδ, and proteasome b5 subunit. Implications, both scientific and agriculture. The fact that the 3'-poly(A) tail enhances crTMV148 IRES activity more efficiently in the absence of 5'-methylated cap suggests a potential joint interaction between PABP, the IRES sequence and the 3'-poly(A). This has an important scientific implication related to IRES function in general.
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Shomer, Ilan, Ruth E. Stark, Victor Gaba, and James D. Batteas. Understanding the hardening syndrome of potato (Solanum tuberosum L.) tuber tissue to eliminate textural defects in fresh and fresh-peeled/cut products. United States Department of Agriculture, November 2002. http://dx.doi.org/10.32747/2002.7587238.bard.

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The project sought to understand factors and mechanisms involved in the hardening of potato tubers. This syndrome inhibits heat softening due to intercellular adhesion (ICA) strengthening, compromising the marketing of industrially processed potatoes, particularly fresh peeled-cut or frozen tubers. However, ICA strengthening occurs under conditions which are inconsistent with the current ideas that relate it to Ca-pectate following pectin methyl esterase (PME) activity or to formation of rhamnogalacturonan (RG)-II-borate. First, it was necessary to induce strengthening of the middle lamellar complex (MLX) and the ICA as a stress response in some plant parenchyma. As normally this syndrome does not occur uniformly enough to study it, we devised an efficient model in which ICA-strengthening is induced consistently under simulated stress by short-chain, linear, mono-carboxylic acid molecules (OAM), at 65 oC [appendix 1 (Shomer&Kaaber, 2006)]. This rapid strengthening was insufficient for allowing the involved agents assembly to be identifiable; but it enabled us to develop an efficient in vitro system on potato tuber parenchyma slices at 25 ºC for 7 days, whereas unified stress was reliably simulated by OAMs in all the tissue cells. Such consistent ICA-strengthening in vitro was found to be induced according to the unique physicochemical features of each OAM as related to its lipophilicity (Ko/w), pKa, protonated proportion, and carbon chain length by the following parameters: OAM dissociation constant (Kdiss), adsorption affinity constant (KA), number of adsorbed OAMs required for ICA response (cooperativity factor) and the water-induced ICA (ICAwater). Notably, ICA-strengthening is accompanied by cell sap leakage, reflecting cell membrane rupture. In vitro, stress simulation by OAMs at pH<pKa facilitated the consistent assembly of ICAstrengthening agents, which we were able to characterize for the first time at the molecular level within purified insoluble cell wall of ICA-strengthened tissue. (a) With solid-state NMR, we established the chemical structure and covalent binding to cell walls of suberin-like agents associated exclusively with ICA strengthening [appendix 3 (Yu et al., 2006)]; (b) Using proteomics, 8 isoforms of cell wall-bound patatin (a soluble vacuolar 42-kDa protein) were identified exclusively in ICA-strengthened tissue; (c) With light/electron microscopy, ultrastructural characterization, histochemistry and immunolabeling, we co-localized patatin and pectin in the primary cell wall and prominently in the MLX; (d) determination of cell wall composition (pectin, neutral sugars, Ca-pectate) yielded similar results in both controls and ICA-strengthened tissue, implicating factors other than PME activity, Ca2+ or borate ions; (e) X-ray powder diffraction experiments revealed that the cellulose crystallinity in the cell wall is masked by pectin and neutral sugars (mainly galactan), whereas heat or enzymatic pectin degradation exposed the crystalline cellulose structure. Thus, we found that exclusively in ICA-strengthened tissue, heat-resistant pectin is evident in the presence of patatin and suberinlike agents, where the cellulose crystallinity was more hidden than in fresh control tissue. Conclusions: Stress response ICA-strengthening is simulated consistently by OAMs at pH< pKa, although PME and formation of Ca-pectate and RG-II-borate are inhibited. By contrast, at pH>pKa and particularly at pH 7, ICA-strengthening is mostly inhibited, although PME activity and formation of Ca-pectate or RG-II-borate are known to be facilitated. We found that upon stress, vacuolar patatin is released with cell sap leakage, allowing the patatin to associate with the pectin in both the primary cell wall and the MLX. The stress response also includes formation of covalently bound suberin-like polyesters within the insoluble cell wall. The experiments validated the hypotheses, thus led to a novel picture of the structural and molecular alterations responsible for the textural behavior of potato tuber. These findings represent a breakthrough towards understanding of the hardening syndrome, laying the groundwork for potato-handling strategies that assure textural quality of industrially processed particularly in fresh peeled cut tubers, ready-to-prepare and frozen preserved products.
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