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Academic literature on the topic 'Ras proteins'

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Published: 4 June 2021
Last updated: 29 July 2024

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Journal articles on the topic "Ras proteins"

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Takács, Tamás, Gyöngyi Kudlik, Anita Kurilla, Bálint Szeder, László Buday, and Virag Vas. "The effects of mutant Ras proteins on the cell signalome." Cancer and Metastasis Reviews 39, no. 4 (July 9, 2020): 1051–65. http://dx.doi.org/10.1007/s10555-020-09912-8.

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AbstractThe genetic alterations in cancer cells are tightly linked to signaling pathway dysregulation. Ras is a key molecule that controls several tumorigenesis-related processes, and mutations in RAS genes often lead to unbiased intensification of signaling networks that fuel cancer progression. In this article, we review recent studies that describe mutant Ras-regulated signaling routes and their cross-talk. In addition to the two main Ras-driven signaling pathways, i.e., the RAF/MEK/ERK and PI3K/AKT/mTOR pathways, we have also collected emerging data showing the importance of Ras in other signaling pathways, including the RAC/PAK, RalGDS/Ral, and PKC/PLC signaling pathways. Moreover, microRNA-regulated Ras-associated signaling pathways are also discussed to highlight the importance of Ras regulation in cancer. Finally, emerging data show that the signal alterations in specific cell types, such as cancer stem cells, could promote cancer development. Therefore, we also cover the up-to-date findings related to Ras-regulated signal transduction in cancer stem cells.
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Jelinek, T., P. Dent, T. W. Sturgill, and M. J. Weber. "Ras-induced activation of Raf-1 is dependent on tyrosine phosphorylation." Molecular and Cellular Biology 16, no. 3 (March 1996): 1027–34. http://dx.doi.org/10.1128/mcb.16.3.1027.

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Although Rafs play a central role in signal transduction, the mechanism(s) by which they become activated is poorly understood. Raf-1 activation is dependent on the protein's ability to bind Ras, but Ras binding is insufficient to activate Raf-1 tyrosine phosphorylation to this Ras-induced activation, in the absence of an over-expressed tyrosine kinase. We demonstrate that Raf-1 purified form Sf9 cells coinfected with baculovirus Ras but not Src could be inactivated by protein tyrosine phosphatase PTP-1B. 14-3-3 and Hsp90 proteins blocked both the tyrosine dephosphorylation and inactivation of Raf-1, suggesting that Raf-1 activity is phosphotyrosine dependent. In Ras-transformed NIH 3T3 cells, a minority of Raf-1 protein was membrane associated, but essentially all Raf-1 activity and Raf-1 phosphotyrosine fractionated with plasma membranes. Thus, the tyrosine-phosphorylated and active pool of Raf-1 constitute a membrane-localized subfraction which could also be inactivated with PTP-1B. By contrast, B-Raf has aspartic acid residues at positions homologous to those of the phosphorylated tyrosines (at 340 and 341) of Raf-1 and displays a high basal level of activity. B-Raf was not detectably tyrosine phosphorylated, membrane localized, or further activated upon Ras transformation, even though B-Raf has been shown to bind to Ras in vitro. We conclude that tyrosine phosphorylation is an essential component of the mechanism by which Ras activates Raf-1 kinase activity and that steady-state activated Ras is insufficient to activate B-Raf in vivo.
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Bhattacharya, M., A. V. Babwah, and S. S. G. Ferguson. "Small GTP-binding protein-coupled receptors." Biochemical Society Transactions 32, no. 6 (October 26, 2004): 1040–44. http://dx.doi.org/10.1042/bst0321040.

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Heterotrimeric GPCRs (G-protein-coupled receptors) form the largest group of integral membrane receptor proteins and mediate diverse physiological processes. In addition to signalling via heterotrimeric G-proteins, GPCRs can also signal by interacting with various small G-proteins to regulate downstream effector pathways. The small G-protein superfamily is structurally classified into at least five families: the Ras, Rho/Rac/cdc42, Rab, Sar1/Arf and Ran families. They are monomeric G-proteins with molecular masses over the range 20–30 kDa, which function as molecular switches to control many eukaryotic cell functions. Several studies have provided evidence of crosstalk between GPCRs and small G-proteins. It is well documented that GPCR signalling through heterotrimeric G-proteins can lead to the activation of Ras and Rho GTPases. In addition, RhoA, Rabs, ARFs and ARF GEFs (guanine nucleotide-exchange factors) can associate directly with GPCRs, and GPCRs may also function as GEFs for small GTPases. In this review, we summarize the recent progress made in understanding the interaction between GPCRs and small GTPases, focusing on understanding how the association of small G-proteins with GPCRs and GPCR-regulatory proteins may influence GPCR signalling and intracellular trafficking.
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Tang, Yi, Jong Yu, and Jeffrey Field. "Signals from the Ras, Rac, and Rho GTPases Converge on the Pak Protein Kinase in Rat-1 Fibroblasts." Molecular and Cellular Biology 19, no. 3 (March 1, 1999): 1881–91. http://dx.doi.org/10.1128/mcb.19.3.1881.

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ABSTRACT Ras plays a key role in regulating cellular proliferation, differentiation, and transformation. Raf is the major effector of Ras in the Ras > Raf > Mek > extracellular signal-activated kinase (ERK) cascade. A second effector is phosphoinositide 3-OH kinase (PI 3-kinase), which, in turn, activates the small G protein Rac. Rac also has multiple effectors, one of which is the serine threonine kinase Pak (p65Pak). Here we show that Ras, but not Raf, activates Pak1 in cotransfection assays of Rat-1 cells but not NIH 3T3 cells. We tested agents that activate or block specific components downstream of Ras and demonstrate a Ras > PI 3-kinase > Rac/Cdc42 > Pak signal. Although these studies suggest that the signal from Ras through PI 3-kinase is sufficient to activate Pak, additional studies suggested that other effectors contribute to Pak activation. RasV12S35 and RasV12G37, two effector mutant proteins which fail to activate PI 3-kinase, did not activate Pak when tested alone but activated Pak when they were cotransfected. Similarly, RacV12H40, an effector mutant that does not bind Pak, and Rho both cooperated with Raf to activate Pak. A dominant negative Rho mutant also inhibited Ras activation of Pak. All combinations of Rac/Raf and Ras/Raf and Rho/Raf effector mutants that transform cells cooperatively stimulated ERK. Cooperation was Pak dependent, since all combinations were inhibited by kinase-deficient Pak mutants in both transformation assays and ERK activation assays. These data suggest that other Ras effectors can collaborate with PI 3-kinase and with each other to activate Pak. Furthermore, the strong correlation between Pak activation and cooperative transformation suggests that Pak activation is necessary, although not sufficient, for cooperative transformation of Rat-1 fibroblasts by Ras, Rac, and Rho.
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Goi, Takanori, Gabriel Rusanescu, Takeshi Urano, and Larry A. Feig. "Ral-Specific Guanine Nucleotide Exchange Factor Activity Opposes Other Ras Effectors in PC12 Cells by Inhibiting Neurite Outgrowth." Molecular and Cellular Biology 19, no. 3 (March 1, 1999): 1731–41. http://dx.doi.org/10.1128/mcb.19.3.1731.

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ABSTRACT Ras proteins can activate at least three classes of downstream target proteins: Raf kinases, phosphatidylinositol-3 phosphate (PI3) kinase, and Ral-specific guanine nucleotide exchange factors (Ral-GEFs). In NIH 3T3 cells, activated Ral-GEFs contribute to Ras-induced cell proliferation and oncogenic transformation by complementing the activities of Raf and PI3 kinases. In PC12 cells, activated Raf and PI3 kinases mediate Ras-induced cell cycle arrest and differentiation into a neuronal phenotype. Here, we show that in PC12 cells, Ral-GEF activity acts opposite to other Ras effectors. Elevation of Ral-GEF activity induced by transfection of a mutant Ras protein that preferentially activates Ral-GEFs, or by transfection of the catalytic domain of the Ral-GEF Rgr, suppressed cell cycle arrest and neurite outgrowth induced by nerve growth factor (NGF) treatment. In addition, Rgr reduced neurite outgrowth induced by a mutant Ras protein that preferentially activates Raf kinases. Furthermore, inhibition of Ral-GEF activity by expression of a dominant negative Ral mutant accelerated cell cycle arrest and enhanced neurite outgrowth in response to NGF treatment. Ral-GEF activity may function, at least in part, through inhibition of the Rho family GTPases, CDC42 and Rac. In contrast to Ras, which was activated for hours by NGF treatment, Ral was activated for only ∼20 min. These findings suggest that one function of Ral-GEF signaling induced by NGF is to delay the onset of cell cycle arrest and neurite outgrowth induced by other Ras effectors. They also demonstrate that Ras has the potential to promote both antidifferentiation and prodifferentiation signaling pathways through activation of distinct effector proteins. Thus, in some cell types the ratio of activities among Ras effectors and their temporal regulation may be important determinants for cell fate decisions between proliferation and differentiation.
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Reddy, E. Premkumar, Sai Krishna Divakar, Rodrigo Vasquez-Del Carpio, Kaushik Dutta, Stacey J. Baker, Ramana Reddy, and Aneel K. Aggarwal. "Rigosertib Blocks RAS Signaling By Acting As a Small Molecule RAS Mimetic That Binds to the RAS-Binding Domains of RAS Effector Proteins." Blood 124, no. 21 (December 6, 2014): 5616. http://dx.doi.org/10.1182/blood.v124.21.5616.5616.

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Abstract Oncogenic activation of RAS via point mutations occurs in more than 30% of all human cancers, including hematopoietic malignancies such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Investigations to understand the critical biochemical and biological mechanisms of RAS function are at the forefront of cancer research. Studies have shown that RAS interacts with a large number of effector proteins by a highly conserved mechanism that involves the switch region of RAS and the RAS-binding domains (RBDs) of its effector proteins. Because these interactions play an essential role in oncogenic RAS function, inhibiting them constitutes an attractive and important therapeutic approach for myeloid neoplasias and other cancers. Rigosertib is a novel styryl benzyl sulfone, which is in a Phase III clinical trial (ONTIME) for MDS. Here, we delineate the way rigosertib interacts with the RBDs of several RAS effector proteins: RAF, the PI3K family of proteins and RalGDS. To identify residues in the B-RAF RBD that interact with rigosertib, we recorded a series of 15N-1H HSQC spectra of 15N-labeled B-RAF RBD with increasing concentration of rigosertib. Strikingly, the chemical shift perturbations caused by addition of rigosertib are localized to the very region of the B-RAF-RBD implicated in RAS binding, namely the beta1 and beta2 strands and alpha3 helix (Fig 1). Additionally, this cluster of residues with largest chemical shift perturbation contains many of the same residues involved in RAS binding, namely Ile156, Lys164, Arg166, Thr167, Val168, Ala184 and Met187. These key residues are conserved within RAF RBDs, suggesting that rigosertib would bind to similar regions of the A- and c-RAF RBDs. Next, we examined the binding of rigosertib and GTP-RAS to wild type and mutant forms of c-RAF RBD that harbor mutations in residues that mediate binding to rigosertib. Our studies show that all mutations that cause dissociation of GTP-RAS binding also inhibit rigosertib binding to these mutant proteins. Taken together, the chemical shift data and mutagenesis data provide powerful evidence that rigosertib binds the B-RAF RBD at the same location as the RAS switch I region. A consequence of inhibiting RAS binding to RAF appears to be a block in growth factor-induced activation of RAF kinase activity. We also show that a result of this block in RAS/RAF interactions is an inability of RAF proteins to form dimers and activate MEK and ERK. This block in the activation of MEK/ERK pathways can be seen in cells that express wild-type RAS and RAF proteins (HeLa), in cells that express a constitutively active form of oncogenic RAS (HeLa-N-RAS-G12D), and in cells that exhibit amplification of EGF receptors (A431). Rigosertib also inhibits the phosphorylation of c-RAF serine 338, which has been shown to be essential for the activation of its kinase activity and for its association with and activation of PLK-1. Our results showing rigosertib-mediated inhibition of the PLK-1/RAF interaction might help explain the ability of this compound to induce mitotic arrest of human tumor cells and the ability of rigosertib to reduce blast counts in MDS patients (Seetharam et al, Leuk Res 2012). We have also demonstrated the binding of rigosertib to the RBDs of the PI3K family of kinases and RalGDS, both of which constitute important effectors of RAS. A consequence of the interaction of rigosertib with the RBD domains of PI3Ks appears to be a block in growth factor-induced AKT activation. These studies suggest that the disruption of multiple RAS-driven signaling pathways by rigosertib is mediated via rigosertib’s binding to RBDs of RAS effector proteins, leading to their inactivation. Figure 1 Figure 1. Disclosures Reddy: Onconova Therapeutics Inc: Research Funding. Divakar:Onconova Therapeutics Inc: Research Funding. Vasquez-Del Carpio:Onconova Therapeutics Inc: Research Funding. Dutta:Onconova Therapeutics Inc: Research Funding. Baker:Onconova Therapeautics Inc: Consultancy. Reddy:Onconova Therapeutics Inc: Consultancy. Aggarwal:Onconova Therapeutics Inc: Research Funding.
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Ramocki, M. B., S. E. Johnson, M. A. White, C. L. Ashendel, S. F. Konieczny, and E. J. Taparowsky. "Signaling through mitogen-activated protein kinase and Rac/Rho does not duplicate the effects of activated Ras on skeletal myogenesis." Molecular and Cellular Biology 17, no. 7 (July 1997): 3547–55. http://dx.doi.org/10.1128/mcb.17.7.3547.

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The ability of basic helix-loop-helix muscle regulatory factors (MRFs), such as MyoD, to convert nonmuscle cells to a myogenic lineage is regulated by numerous growth factor and oncoprotein signaling pathways. Previous studies have shown that H-Ras 12V inhibits differentiation to a skeletal muscle lineage by disrupting MRF function via a mechanism that is independent of the dimerization, DNA binding, and inherent transcriptional activation properties of the proteins. To investigate the intracellular signaling pathway(s) that mediates the inhibition of MRF-induced myogenesis by oncogenic Ras, we tested two transformation-defective H-Ras 12V effector domain variants for their ability to alter terminal differentiation. H-Ras 12V,35S retains the ability to activate the Raf/MEK/mitogen-activated protein (MAP) kinase cascade, whereas H-Ras 12V,40C is unable to interact directly with Raf-1 yet still influences other signaling intermediates, including Rac and Rho. Expression of each H-Ras 12V variant in C3H10T1/2 cells abrogates MyoD-induced activation of the complete myogenic program, suggesting that MAP kinase-dependent and -independent Ras signaling pathways individually block myogenesis in this model system. However, additional studies with constitutively activated Rac1 and RhoA proteins revealed no negative effects on MyoD-induced myogenesis. Similarly, treatment of Ras-inhibited myoblasts with the MEK1 inhibitor PD98059 revealed that elevated MAP kinase activity is not a significant contributor to the H-Ras 12V effect. These data suggest that an additional Ras pathway, distinct from the well-characterized MAP kinase and Rac/Rho pathways known to be important for the transforming function of activated Ras, is primarily responsible for the inhibition of myogenesis by H-Ras 12V.
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Stang, S., D. Bottorff, and J. C. Stone. "Interaction of activated Ras with Raf-1 alone may be sufficient for transformation of rat2 cells." Molecular and Cellular Biology 17, no. 6 (June 1997): 3047–55. http://dx.doi.org/10.1128/mcb.17.6.3047.

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v-H-ras effector mutants have been assessed for transforming activity and for the ability of the encoded proteins to interact with Raf-1-, B-Raf-, byr2-, ralGDS-, and CDC25-encoded proteins in the yeast two-hybrid system. Transformation was assessed in rat2 cells as well as in a mutant cell line, rv68BUR, that affords a more sensitive transformation assay. Selected mutant Ras proteins were also examined for their ability to interact with an amino-terminal fragment of Raf-1 in vitro. Finally, possible cooperation between different v-H-ras effector mutants and between effector mutants and overexpressed Raf-1 was assessed. Ras transforming activity was shown to correlate best with the ability of the encoded protein to interact with Raf-1. No evidence for cooperation between v-H-ras effector mutants was found. Signaling through the Raf1-MEK-mitogen-activated protein kinase cascade may be the only effector pathway contributing to RAS transformation in these cells.
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Tang, Y., Z. Chen, D. Ambrose, J. Liu, J. B. Gibbs, J. Chernoff, and J. Field. "Kinase-deficient Pak1 mutants inhibit Ras transformation of Rat-1 fibroblasts." Molecular and Cellular Biology 17, no. 8 (August 1997): 4454–64. http://dx.doi.org/10.1128/mcb.17.8.4454.

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Among the mechanisms by which the Ras oncogene induces cellular transformation, Ras activates the mitogen-activated protein kinase (MAPK or ERK) cascade and a related cascade leading to activation of Jun kinase (JNK or SAPK). JNK is additionally regulated by the Ras-related G proteins Rac and Cdc42. Ras also regulates the actin cytoskeleton through an incompletely elucidated Rac-dependent mechanism. A candidate for the physiological effector for both JNK and actin regulation by Rac and Cdc42 is the serine/threonine kinase Pak (p65pak). We show here that expression of a catalytically inactive mutant Pak, Pak1(R299), inhibits Ras transformation of Rat-1 fibroblasts but not of NIH 3T3 cells. Typically, 90 to 95% fewer transformed colonies were observed in cotransfection assays with Rat-1 cells. Pak1(R299) did not inhibit transformation by the Raf oncogene, indicating that inhibition was specific for Ras. Furthermore, Rat-1 cell lines expressing Pak1(R299) were highly resistant to Ras transformation, while cells expressing wild-type Pak1 were efficiently transformed by Ras. Pak1(L83,L86,R299), a mutant that fails to bind either Rac or Cdc42, also inhibited Ras transformation. Rac and Ras activation of JNK was inhibited by Pak1(R299) but not by Pak1(L83,L86,R299). Ras activation of ERK was inhibited by both Pak1(R299) and Pak1(L83,L86,R299), while neither mutant inhibited Raf activation of ERK. These results suggest that Pak1 interacts with components essential for Ras transformation and that inhibition can be uncoupled from JNK but not ERK signaling.
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KELLEY, Grant G., Sarah E. REKS, and Alan V. SMRCKA. "Hormonal regulation of phospholipase Cepsilon through distinct and overlapping pathways involving G12 and Ras family G-proteins." Biochemical Journal 378, no. 1 (February 15, 2004): 129–39. http://dx.doi.org/10.1042/bj20031370.

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PLC∊ (phospholipase C∊) is a novel PLC that has a CDC25 guanine nucleotide exchange factor domain and two RA (Ras-association) domains of which the second (RA2) is critical for Ras activation of the enzyme. In the present studies, we examined hormonal stimulation to elucidate receptor-mediated pathways that functionally regulate PLC∊. We demonstrate that EGF (epidermal growth factor), a receptor tyrosine kinase agonist, and LPA (lysophosphatidic acid), S1P (sphingosine 1-phosphate) and thrombin, GPCR (G-protein-coupled receptor) agonists, stimulate PLC∊ overexpressed in COS-7 cells. EGF stimulated PLC∊ in an RA2-dependent manner through Ras and Rap. In contrast, LPA, S1P and thrombin stimulated PLC∊ by both RA2-independent and -dependent mechanisms. To determine the G-proteins that mediate the effects of these GPCR agonists, we co-expressed constitutively active G-proteins with PLC∊ and found that Gα12, Gα13, Rho, Rac and Ral stimulate PLC∊ in an RA2-independent manner; whereas TC21, Rap1A, Rap2A and Rap2B stimulate PLC∊ in an RA2-dependent manner similar to H-Ras. Of these G-proteins, we show that Gα12/Gα13 and Rap partly mediate the effects of LPA, S1P and thrombin to stimulate PLC∊. In addition, the stimulation by LPA and S1P is also partly sensitive to pertussis toxin. These studies demonstrate diverse hormonal regulation of PLC∊ by distinct and overlapping pathways.
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Dissertations / Theses on the topic "Ras proteins"

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Clyde-Smith, Jodi. "Characterization of ras isoform activation by ras guanine nucleotide exchange factors /." St. Lucia, Qld, 2002. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe16393.pdf.

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Iritani, Brian Masao. "Control of B lymphocyte development by Ras and Raf /." Thesis, Connect to this title online; UW restricted, 1997. http://hdl.handle.net/1773/8322.

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Chan, Yuk-shing, and 陳旭勝. "Expression of RAs-related Nuclear (RAN) protein in breast cancer." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2010. http://hub.hku.hk/bib/B44671003.

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Castillo, Chabeco Boris. "Redox Regulation of Ras Proteins in Dictyostelium discoideum." FIU Digital Commons, 2015. http://digitalcommons.fiu.edu/etd/1864.

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Reactive oxygen species are a normal consequence of life in an aerobic environment. However when they deviate from the narrow permissible range in cells, oxidative damage can occur. Dictyostelium discoideum is a model organism ideal for the study of cell signaling events such as those affected by oxidative stress. It was previously shown that Ras signaling in Dictyostelium is affected by genetic inactivation of the antioxidant enzyme Superoxide dismutase C (SodC) and in vitro data suggests that the NKCD motif of Ras is the redox target of superoxide. The main objective of this project was to determine the mechanism of superoxide mediated Ras regulation in vivo. To accomplish the main objective, we cloned, and in some cases, mutated different Ras proteins and later determined their activity in wild type and sodC- cells. RasC and RasD showed normal activation in sodC- cells, however RasG and RasS displayed high Ras activity. These last two Ras proteins contain the NKC118D motif inside the nucleotide binding region. A mutation of cysteine118 to alanine in RasG rendered the protein less active in sodC- than the wild type RasG protein and a mutation alanine118 to cysteine in RasD conferred redox sensitivity to this small GTPase. Additionally, the propensity of RasG to be targeted by superoxide was evident when the environment of wild type cells was manipulated to induce the internal generation of superoxide through changes in the extracellular ion levels mainly magnesium. Lack of magnesium ions increased the intracellular level of superoxide and severely hampered directional cell migration. Chemotaxis of cells expressing RasG was negatively impacted by the absence of magnesium ions; however rasG- cells did not seem to be affected in their ability to perform chemotaxis. The last experiment implies that RasG is an important mediator of cell signaling during oxidative stress, responsible for preventing cells from continuing their developmental program. Our study suggests that the cysteine residue in the NKCD motif is essential for mediating the redox sensitivity of Ras proteins in Dictyostelium and that RasG is an essential mediator of the response to oxidative stress in this organism.
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Iuga, Adriana. "Solid-state 31P NMR of nucleotide binding proteins." [S.l. : s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=973225238.

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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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Worth, Graham Alan. "The energetics of nucleotide binding to RAS proteins." Thesis, University of Oxford, 1992. http://ora.ox.ac.uk/objects/uuid:44524415-2f2b-4601-998c-56110f332153.

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Ras proteins are a special class of proteins that mediate cell growth signals. Their importance lies in the fact that they are products of a proto-oncogene. This means that under certain conditions the gene that determines its structure is altered and a mutant protein results that is involved in the transformation of normal cells to cancer cells. The actual function by which the protein acts in the signal pathway is not known. However it is known that they act as a switch, undergoing a cycle involving the exchange of guaninosine nucleotides in the binding site. This thesis uses computer simulations to study the energetics of this binding, with the long term aim of developing a drug to inhibit the transforming activity of the oncogenic protein. To begin with, a model of the protein based on a crystal structure is built. Using Molecular dynamics the motion of this model is studied. A possible mechanism by which one half of the nucleotide cycle could be induced is investigated, with the result that phosphorylation of the protein may be involved. The main part of the thesis is then devoted to using the free energy perturbation (FEP) method to calculate the difference in Gibbs binding free energy between the nucleotides in the protein. Using histamine as a model, a method of dealing with charged, flexible molecules is developed; namely the inclusion of a reaction field and comprehensive conformational analysis. The results from the associated calculations are seen to be very close to experimental data. The same procedures are then applied to the much more complex ras: nucleotide system with less successful results, the reason for which is mostly due to the restriction of limited computer resources to tackle such a problem. The conclusion is that given the resources and by using the techniques developed in this thesis, this type of calculation is a feasible way to study such systems.
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Wilkins, Andrew. "The function of Ras proteins in Dictyostelium discoideum." Thesis, University College London (University of London), 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.313544.

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Naim, Adnan. "The Role of G3BPs in the Stress Response Pathway." Thesis, Griffith University, 2016. http://hdl.handle.net/10072/367499.

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The ras-GTPase SH3-domain Binding Proteins (G3BP) are a family of RNA-binding proteins that have been implicated in multiple cellular activities ranging from signal transduction to regulation of messenger RNA (mRNA). G3BPs were named after their interaction with the SH3 domain of Ras-GTPase-activating protein; however recent research did not find this interaction. All three members of the G3BPs family, G3BP1, G3BP2a and G3BP2b, share structural similarities with each other by having four distinct regions (1) the Nuclear Transporting Factor 2, (NTF2) domain at the N-terminal, (2) the acidic and proline-rich domain in the centre, (3) the RNA recognition motif (RRM) and (4) the arginine glycine (RGG)-rich region rich at the C-terminal. The presence of the NTF2 domain in its structure suggests G3BP might play a role in nucleocytoplasmic transportation, which was observed after serum stimulation where G3BP1 was translocated to the nucleus from the cytoplasm. The RNA recognition motif (RRM) region plays a vital role in its interaction with the target RNA. The RGG-rich box is a region rich in arginine and glycine residues, which plays a role assisting RRM in interactions with protein or RNA. G3BP1 is found to be overexpressed in many cancers, including breast cancer, and head and neck tumours, as well as cell lines derived from human lung, prostrate, colon, thyroid and breast cancer. G3BPs have also been implicated in translational control within differentiating neurons, suggesting that G3BP may play several roles in controlling the translational fate of its cargo and that its role may be cell-specific. G3BP1 has also been found in β-integrin- induced adhesion complexes. This information highlights G3BPs as a dynamic protein that is involved in several biological functions.
Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Natural Sciences
Science, Environment, Engineering and Technology
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De, Cristofano Sabrina. "The role of Ras and Kinase Suppressor of Ras 1 (KSR-1) in breast cancer in progression and metastasis /." Thesis, McGill University, 2007. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=112613.

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The Ras signaling cascade is a vital component in the processes that mediate cell survival, growth, differentiation and transformation through activation of MAP kinase (mitogen-activated protein kinase). The recent discovery of a new scaffold of the Ras signaling pathway, Kinase Suppressor of Ras (KSR), is found to be a positive effector of Ras signaling which further contributes to proliferation and transformation in the ERK/MAPK pathway. This thesis describes the roles of Ras and Kinase Suppressor of Ras 1 (KSR-1) in regulating the expression of tumor promoting genes such as urokinase plasminogen activator (uPA) in the development and progression of breast cancer in vitro and in vivo. Ras and KSR increase the proliferative capacity and migration of MDAMB-231 human breast cancer cells in vitro. In contrast, Ras and KSR decrease the invasiveness of MDA-MB-231 human breast cancer cells in vitro. Furthermore, uPA gene expression levels do not correlate with uPA protein expression levels suggesting a possible mutation induced by KSR and/or Ras. In vivo studies reveal that Ras and KSR increase tumor volume in mice, as well as more advanced osteolytic bone metastases. Collectively, these results indicate that Ras and KSR play significant roles in breast cancer development and metastasis.
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Books on the topic "Ras proteins"

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Holmes, L. P. Gtpase protocols: The ras superfamily. [Place of publication not identified]: Humana, 2010.

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Ed, Manser, and Leung Thomas, eds. GTPase protocols: The Ras superfamily. Totowa, N.J: Humana Press, 2002.

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Media, Springer Science+Business, ed. Ras signaling: Methods and protocols. New York: Humana Press, 2014.

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Chen, Luping. Murine CDC25-related proteins: Activators of Ras. Ottawa: National Library of Canada, 1993.

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Carlos, Lacal Juan, and McCormick Frank 1950-, eds. The Ras superfamily of GTPases. Boca Raton: CRC Press, 1993.

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Martin, Zenker, ed. Noonan syndrome and related disorders: A matter of deregulated ras signaling. Basel: Karger, 2009.

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Wittinghofer, Alfred, ed. Ras Superfamily Small G Proteins: Biology and Mechanisms 1. Vienna: Springer Vienna, 2014. http://dx.doi.org/10.1007/978-3-7091-1806-1.

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Wittinghofer, Alfred, ed. Ras Superfamily Small G Proteins: Biology and Mechanisms 2. Cham: Springer International Publishing, 2014. http://dx.doi.org/10.1007/978-3-319-07761-1.

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Ph, Jeanteur, ed. Cytoskeleton and small G proteins. Berlin: Springer, 1999.

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Maria de Lourdes Gutierrez Xicotencatl. Studies on the acylation and processing of p21(ras) proteins. Uxbridge: Brunel University, 1988.

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Book chapters on the topic "Ras proteins"

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Gunzburg, Jean De. "Ras Family Proteins." In RAS Family GTPases, 295–339. Dordrecht: Springer Netherlands, 2006. http://dx.doi.org/10.1007/1-4020-4708-8_13.

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Hancock, J. F., K. Cadwallader, A. I. Magee, C. Newman, T. Giannakouros, E. Fawell, J. Armstrong, H. F. Paterson, and C. J. Marshall. "Prenylation of ras and ras-Related Proteins." In The Superfamily of ras-Related Genes, 15–22. Boston, MA: Springer US, 1991. http://dx.doi.org/10.1007/978-1-4684-6018-6_2.

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Jones, Janet E., and Juan Carlos Lacal. "Ras Proteins as Potential Activators of Protein Kinase C Function." In ras Oncogenes, 105–18. Boston, MA: Springer US, 1989. http://dx.doi.org/10.1007/978-1-4757-1235-3_16.

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Zhou, Yong, and John F. Hancock. "Ras Nanoclusters." In Ras Superfamily Small G Proteins: Biology and Mechanisms 1, 189–210. Vienna: Springer Vienna, 2014. http://dx.doi.org/10.1007/978-3-7091-1806-1_9.

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Tamanoi, Fuyuhiko, Alexander R. Cobitz, Asao Fujiyama, Laurie E. Goodman, and Charles Perou. "Post-Translational Modification of ras Proteins: Palmitoylation and Phosphorylation of Yeast ras Proteins." In ras Oncogenes, 225–33. Boston, MA: Springer US, 1989. http://dx.doi.org/10.1007/978-1-4757-1235-3_29.

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Pizon, V., P. Chardin, I. Lerosey, and A. Tavitian. "The rap Proteins : GTP Binding Proteins Related to p21 ras with a Possible Reversion Effect on ras Transformed Cells." In ras Oncogenes, 83–91. Boston, MA: Springer US, 1989. http://dx.doi.org/10.1007/978-1-4757-1235-3_13.

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Hall, Alan, Jonathan D. H. Morris, Brendan Price, Alison Lloyd, John F. Hancock, Sandra Gardener, Miles D. Houslay, Michael J. O. Wakelam, and Christopher J. Marshall. "The Function of the Mammalian ras Proteins." In ras Oncogenes, 99–104. Boston, MA: Springer US, 1989. http://dx.doi.org/10.1007/978-1-4757-1235-3_15.

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Downward, Julian. "G proteins, Ras and cancer." In Molecular Biology for Oncologists, 63–74. Boston, MA: Springer US, 1996. http://dx.doi.org/10.1007/978-1-4899-3111-5_6.

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Clark, G. J., and C. J. Der. "Oncogenic Activation of Ras Proteins." In GTPases in Biology I, 259–87. Berlin, Heidelberg: Springer Berlin Heidelberg, 1993. http://dx.doi.org/10.1007/978-3-642-78267-1_18.

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Maruta, Hiroshi. "Glutathione S-Transferase/ras Fusion Protein: A Tool for Affinity Chromatography of ras Associated Proteins." In ras Oncogenes, 255–60. Boston, MA: Springer US, 1989. http://dx.doi.org/10.1007/978-1-4757-1235-3_32.

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Conference papers on the topic "Ras proteins"

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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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Yuan, Tina, and Frank McCormick. "Abstract IA05: Regulation of Ras proteins and their effectors." In Abstracts: AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; October 27-30, 2016; San Francisco, CA. American Association for Cancer Research, 2017. http://dx.doi.org/10.1158/1538-7445.transcontrol16-ia05.

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Zheng, Ze-Yi, Chiang-min Cheng, Xin-Rong Fu, Zhou Songyang, and Eric C. Chang. "Abstract 5074: Identification of Ras compartment-specific interacting proteins." 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.am10-5074.

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Denhardt, D. T., Devra Mistretta, and Srilatha Raghuram. "REGULATION OF OSTEOPONTIN TRANSCRIPTION BY A RAS RESPONSE FACTOR." In 3rd International Conference on Osteopontin and SIBLING (Small Integrin-Binding Ligand, N-linked Glycoprotein) Proteins, 2002. TheScientificWorld Ltd, 2002. http://dx.doi.org/10.1100/tsw.2002.327.

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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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Pirogova, Elena, Vuk Vojisavljevic, and Irena Cosic. "Prediction of protein active and/or binding site using time-frequency analysis: Application to ras oncogene proteins." In 2012 ISSNIP Biosignals and Biorobotics Conference: Biosignals and Robotics for Better and Safer Living (BRC). IEEE, 2012. http://dx.doi.org/10.1109/brc.2012.6222173.

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Ratner, Nancy. "Abstract IA10: Signaling through individual Ras proteins in the absence of the Nf1-RASGAP." In Abstracts: AACR Special Conference on RAS Oncogenes: From Biology to Therapy; February 24-27, 2014; Lake Buena Vista, FL. American Association for Cancer Research, 2014. http://dx.doi.org/10.1158/1557-3125.rasonc14-ia10.

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Basu, Srikanta, Sandip K. Basu, Jacqueline Salotti, and Peter F. Johnson. "Abstract 4361: Role of Rab GTPases and endosomal adaptor proteins in oncogenic RAS induced formation of perinuclear signaling complexes (PSCs)." In Proceedings: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.am2018-4361.

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Kim, Ara, and Masahiro Higuchi. "Abstract 1694: Warburg effect increases intracellular oxygen concentration and determines membrane localization of Ras and other prenylated proteins." In Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1538-7445.am2013-1694.

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Mallakin, Ali, Kazushi Inoue, and Martin Guthold. "In-Situ Quantitative Analysis of Tumor Suppressor Protein (hDMP1) Using a Nanomechanical Cantilever Beam." In ASME 2005 International Design Engineering Technical Conferences and Computers and Information in Engineering Conference. ASMEDC, 2005. http://dx.doi.org/10.1115/detc2005-84503.

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This study is focused on testing “immuno-sensors” of micro-cantilever beams for the purpose of future design of high-throughout bioassays. We currently study the aberrant expression, deletion and mutation of hDMP1 (Human DMP1) in human lung cancer. Lung cancer is the leading cause of cancer deaths among men and women in North America. There are four major histological subtypes of human lung cancer: small-cell carcinoma (SCC), adenocarcinoma (AC), squamous cell carcinoma (SCC), and large-cell carcinoma (LCC). The hDMP1 locus is localized on chromosome 7q21, a region frequently deleted as part of the 7q-minus and monosomy 7 abnormalities of acute myeloid leukemia and myelodysplastic syndrome. Recent data demonstrate the critical role of Dmp1 in Ras-Raf-Arf signaling and cellular senescence. In order to study the interactions of hDMP1 gene product and selected tumor markers with BioMEMS devices, protein coating (Antibody) conduct on cantilevers with silicon nitride (SiNx) surfaces. Silicon nitride surface has the potential to provide a good interface for BioMEMS devices, due to enhanced adherence of substances on this surface. The cantilever biosensors coated with hDMP1 antibody were used for the detection of hDMP1 antigen, which is known to be a tumor suppressor protein. Results revealed that the changes in nano-mechanical forces provided sufficient differential torque to bend the cantilever beam upon injection of the antigen. Theoretical models have been developed for the prediction of the vibrational responses of atomic force microscope (AFM) cantilevers before and after antigen/antibody interaction. Exposure of the proteins to micro-cantilever (MC) resulted in un-reversible large stress. Static deflection of micro-cantilever appeared as a result of the surface stresses that are induced by changes upon antibody-antigen interaction. This indicated that the micro-cantilever approach is useful for detecting proteins and tumor markers, and this system is applicable as a model to design miniaturized biosensor systems. We also applied gene micro-array to identify unknown targets for hDMP1 and extend our observation of the complicated process of carcinogenesis.
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Reports on the topic "Ras proteins"

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Heitman, Joseph. Novel Gbeta Mimic Kelch Proteins (Gpb1 and Gpb2 Connect G-Protein Signaling to Ras via Yeast Neurofibromin Homologs Ira1 and Ira2: A Model for Human NF1. Fort Belvoir, VA: Defense Technical Information Center, March 2008. http://dx.doi.org/10.21236/ada483900.

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Heitman, Joseph, and Toshiaki Harashima. Novel Gbeta Mimic Kelch Proteins (Gpb1 and Gpb2 Connect G-Protein Signaling to Ras via Yeast Neurofibromin Homologs Ira1 and Ira2. A Model for Human NF1. Fort Belvoir, VA: Defense Technical Information Center, March 2007. http://dx.doi.org/10.21236/ada479028.

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Heitman, Joseph, and Toshiaki Harashima. Novel Gbeta Mimic Kelch Proteins Gpb1 and Gpb2 Connect G-Protein Signaling to Ras Via Yeast Neurofibromin Homologs Ira 1 and Ira 2: A Model for Human NF1. Fort Belvoir, VA: Defense Technical Information Center, March 2005. http://dx.doi.org/10.21236/ada446943.

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Heitman, Joseph. Novel Gbeta Mimic Kelch Proteins Gpb1 and Gpb2 Connect G-Protein Signaling to Ras via Yeast Neurofibromin Homologs Ira 1 and Ira 2: A Model for Human NF1. Fort Belvoir, VA: Defense Technical Information Center, March 2006. http://dx.doi.org/10.21236/ada469875.

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Yalovsky, Shaul, and Julian Schroeder. The function of protein farnesylation in early events of ABA signal transduction in stomatal guard cells of Arabidopsis. United States Department of Agriculture, January 2002. http://dx.doi.org/10.32747/2002.7695873.bard.

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Loss of function mutations in the farnesyltransferase β subunit gene ERA1 (enhanced response to abscisic acid), cause abscisic acid hypersensitivity in seedlings and in guard cells. This results in slowed water loss of plants in response to drought. Farnesyltransferase (PFT) catalyses the attachment of the 15-carbon isoprenoid farnesyl to conserved cysteine residues located in a conserved C-terminal domain designated CaaX box. PFT is a heterodimeric protein comprised of an a and b sununits. The a subunit is shared between PFT and geranylgeranyltransferase-I (PGGTI) which catalyses the attachemt of the 20-carbon isoprenoid geranylgeranyl to CaaX box proteins in which the last amino acid is almost always leucine and in addition have a polybasic domain proximal to the CaaL box. Preliminary data presented in the proposal showed that increased cytoplasmic Ca2+ concentration in stomal guard cells in response to non-inductive ABA treatements. The goals set in the proposal were to characterize better how PFT (ERA1) affects ABA induced Ca2+ concentrations in guard cells and to identify putative CaaX box proteins which function as negative regulators of ABA signaling and which function is compromised in era1 mutant plants. To achieve these goals we proposed to use camelion Ca2+ sensor protein, high throughput genomic to identify the guard cell transcriptome and test prenylation of candidate proteins. We also proposed to focus our efforts of RAC small GTPases which are prenylated proteins which function in signaling. Our results show that farnesyltransferaseprenylates protein/s that act between the points of ABA perception and the activation of plasma membrane calcium influx channels. A RAC protein designated AtRAC8/AtRop10 also acts in negative regulation of ABA signaling. However, we discovered that this protein is palmitoylated and not prenylated although it contains a C-terminal CXXX motif. We further discovered a unique C-terminal sequence motif required for membrane targeting of palmitoylatedRACs and showed that their function is prenylation independent. A GC/MS based method for expression in plants, purification and analysis of prenyl group was developed. This method would allow highly reliable identification of prenylated protein. Mutants in the shared α subunit of PFT and PGGT-I was identified and characterized and was shown to be ABA hypersensitive but less than era1. This suggested that PFT and PGGT-I have opposing functions in ABA signaling. Our results enhanced the understanding of the role of protein prenylation in ABA signaling and drought resistance in plants with the implications of developing drought resistant plants. The results of our studies were published 4 papers which acknowledge support from BARD.
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Rueda, Fabián L., Jesús A. Polo Olivella, and Jaime A. Cardozo Cerquera. Expresión y purificación de la aSFP recombinante bovina usando fabricas celulares bacterianas. Corporación Colombiana de Investigación Agropecuaria - AGROSAVIA, 2018. http://dx.doi.org/10.21930/agrosavia.poster.2018.17.

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Las proteínas del plasma seminal (PPS) juegan un papel fundamental en los cambios que sufre la célula espermática desde la eyaculación hasta la fecundación del ovocito. En los bovinos, la estructura y función de las PPS han sido descritas en múltiples trabajos y se ha destacado a las espermadhesinas como un grupo de PPS con gran importancia. Por sus características estructurales, las espermadhesinas están relacionadas con la motilidad espermática y con la protección del espermatozoide contra el estrés oxidativo. Se ha determinado que, dentro de la familia de las espermadhesinas, proteínas como la aSFP (acidic Seminal Plasma Protein) tienen una actividad redox importante que brinda protección al espermatozoide frente a las especies reactivas de oxígeno (ROS) y que esta actividad puede ser aprovechada para mejorar la calidad seminal en procesos de criopreservación.
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Walker, Michael, Gill Holcombe, Clare Mills, Chiara Nitride, and Adrian Rogers. Development of Reference Materials for food allergen analysis. Food Standards Agency, June 2023. http://dx.doi.org/10.46756/sci.fsa.hwt621.

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Food hypersensitivity is an increasing problem for many stakeholders with much effort focused on assessment and management of the risks including risk assessment toolkits (for example, the Allergen Bureau (Opens in a new window) Voluntary Incidental Trace Allergen Labelling VITAL®, the iFAAM consortium (Opens in a new window) and the ILSI-Europe Allergen Quantitative Risk Assessment guidance (Opens in a new window)). These toolkits describe the use of action levels and reference doses to assess the risks. A combination of the estimated eliciting dose of allergenic food, (in milligrams as protein) and the amount of food consumed in a single eating occasion can give a threshold or action level as milligrams (as protein) per kilogram (kg) of food) (mg kg-1 as protein) that would provoke an reaction in a given proportion of the allergic population. The eliciting dose is extrapolated from oral food clinical dose-distribution relationships. The results of analysis can be compared to the thresholds or action levels in risk assessment and risk management. Precautionary allergen labelling, well recognized as sub-optimal, could also be improved via an action level approach. Implementation and regulation depend on the ability to measure allergens properly; yet all current analytical approaches exhibit deficiencies, many of which can be addressed by the proper use of appropriate allergen reference materials (RMs). This report describes a pilot project to: 1) Systematically review allergen analytical targets used in ELISA, PCR and MS to allow the creation of a repository of reliable markers and open access verified allergen sequence sets for the studied allergens; 2) Facilitate a guided stakeholder workshop to achieve consensus on priority allergens, physical format of RMs, incurred concentrations and impact of processing; 3) Prepare a RM kit containing (a) a food matrix shown to be devoid of the target allergens, (b) the food matrix incurred with 5 allergens and (c) the raw materials (the allergenic foods); 4) Disseminate to encourage RM use to achieve tangible improvements in allergen analysis, establish a template of best practice for the future and make recommendations for follow up work to complete a set of RMs for the legislated and priority allergens. The RM matrix is based on that used for clinical dose-distribution studies and the raw allergen materials have been characterised by proteomics. The matrix and incurred allergens are industrially relevant to processed foods and the allergen concentrations are clinically relevant in the light of eliciting dose studies. The RM kit has been prepared following a well-established process that includes prescribed homogeneity and stability studies and a formal sign-off procedure of the statements of measurement, in accordance with ISO 17034:2016 ‘General requirements for the competence of reference material producers’ (an updated standard originally ISO GUIDE 34:2009). In October 2020 following detailed external assessment the RM kit was confirmed within the NML scope of ISO 17034 accreditation. ISO 17034:2016 covers the production of all reference materials, including certified reference materials. It is intended as part of the general quality assurance procedures of the reference material producer. LGC formed a consortium which was awarded this project by the FSA following an open competitive tender. The consortium consisted of LGC, the University of Manchester and Romer Laboratories Ltd. The consortium is world leading in (a) the preparation, curation and distribution of RMs in an accredited environment and (b) the characterisation of allergen proteins. Synergy with other concurrent work (for example, by iFAAM, EFSA, ILSI, MoniQA, JRC, and AOAC) has ensured value for money. This report has been compiled from a review of a broad range of data sources including: the scientific literature the tender documents progress reports and minutes of project meetings LGC internal documents and in particular the Material Report[1] UoM reports Romer Lab reports.
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Huber, John Tal, Joshuah Miron, Brent Theurer, Israel Bruckental, and Spencer Swingle. Influence of Ruminal Starch Degradability on Performance of High Producing Dairy Cows. United States Department of Agriculture, January 1994. http://dx.doi.org/10.32747/1994.7568748.bard.

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This research project entitled "Influence of Ruminal Starch Degradability on Performance of High Producing Dairy Cows" had the following objectives: a) Determine effects of feeding varying amounts of ruminally degradable starch (RDS) on efficiency of milk and milk protein production; and 2) Investigate digestive and metabolic mechanisms relating to lactation responses to diets varying in ruminal and total starch degradability. Four lactation studies with high producing cows were conducted in which steam-flaked (~ 75% RDS) was compared with dry-rolled sorghum (~ 50% RDS) grain. All studies demonstrated increased efficiency of conversion of feed to milk (FCM/DMI) and milk protein as amount of RDS in the diet increased by feeding steam-flaked sorghum. As RDS in diets increased, either by increased steam-flaked sorghum, grinding of sorghum, or increasing the proportion of wheat to sorghum, so also did ruminal and total tract digestibilities of starch and neutral-detergent soluble (NDS) carbohydrate. Despite other research by these two groups of workers showing increased non-ammonia N (NAN) flowing from the rumen to the duodenum with higher RDS, only one of the present studies showed such an effect. Post-absorptive studies showed that higher dietary RDS resulted in greater urea recycling, more propionate absorption, a tendency for greater output of glucose by the liver, and increased uptake of alpha-amino nitrogen by the mammary gland. These studies have shown that processing sorghum grain through steam-flaking increases RDS and results in greater yields and efficiency of production of milk and milk protein in high producing dairy cows.
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Droby, Samir, Michael Wisniewski, Ron Porat, and Dumitru Macarisin. Role of Reactive Oxygen Species (ROS) in Tritrophic Interactions in Postharvest Biocontrol Systems. United States Department of Agriculture, December 2012. http://dx.doi.org/10.32747/2012.7594390.bard.

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To elucidate the role of ROS in the tri-trophic interactions in postharvest biocontrol systems a detailed molecular and biochemical investigation was undertaken. The application of the yeast biocontrol agent Metschnikowia fructicola, microarray analysis was performed on grapefruit surface wounds using an Affymetrix Citrus GeneChip. the data indicated that 1007 putative unigenes showed significant expression changes following wounding and yeast application relative to wounded controls. The expression of the genes encoding Respiratory burst oxidase (Rbo), mitogen-activated protein kinase (MAPK) and mitogen-activated protein kinase kinase (MAPKK), G-proteins, chitinase (CHI), phenylalanine ammonia-lyase (PAL), chalcone synthase (CHS) and 4-coumarate-CoA ligase (4CL). In contrast, three genes, peroxidase (POD), superoxide dismutase (SOD) and catalase (CAT), were down-regulated in grapefruit peel tissue treated with yeast cells. The yeast antagonists, Metschnikowia fructicola (strain 277) and Candida oleophila (strain 182) generate relatively high levels of super oxide anion (O2−) following its interaction with wounded fruit surface. Using laser scanning confocal microscopy we observed that the application of M. fructicola and C. oleophila into citrus and apple fruit wounds correlated with an increase in H2O2 accumulation in host tissue. The present data, together with our earlier discovery of the importance of H₂O₂ production in the defense response of citrus flavedo to postharvest pathogens, indicate that the yeast-induced oxidative response in fruit exocarp may be associated with the ability of specific yeast species to serve as biocontrol agents for the management of postharvest diseases. Effect of ROS on yeast cells was also studied. Pretreatment of the yeast, Candida oleophila, with 5 mM H₂O₂ for 30 min (sublethal) increased yeast tolerance to subsequent lethal levels of oxidative stress (50 mM H₂O₂), high temperature (40 °C), and low pH (pH 4). Suppression subtractive hybridization analysis was used to identify genes expressed in yeast in response to sublethal oxidative stress. Transcript levels were confirmed using semi quantitative reverse transcription-PCR. Seven antioxidant genes were up regulated. Pretreatment of the yeast antagonist Candida oleophila with glycine betaine (GB) increases oxidative stress tolerance in the microenvironment of apple wounds. ROS production is greater when yeast antagonists used as biocontrol agents are applied in the wounds. Compared to untreated control yeast cells, GB-treated cells recovered from the oxidative stress environment of apple wounds exhibited less accumulation of ROS and lower levels of oxidative damage to cellular proteins and lipids. Additionally, GB-treated yeast exhibited greater biocontrol activity against Penicillium expansum and Botrytis cinerea, and faster growth in wounds of apple fruits compared to untreated yeast. The expression of major antioxidant genes, including peroxisomal catalase, peroxiredoxin TSA1, and glutathione peroxidase was elevated in the yeast by GB treatment. A mild heat shock (HS) pretreatment (30 min at 40 1C) improved the tolerance of M. fructicola to subsequent high temperature (45 1C, 20–30 min) and oxidative stress (0.4 mol-¹) hydrogen peroxide, 20–60 min). HS-treated yeast cells showed less accumulation of reactive oxygen species (ROS) than non-treated cells in response to both stresses. Additionally, HS-treated yeast exhibited significantly greater (P≥0.0001) biocontrol activity against Penicillium expansum and a significantly faster (Po0.0001) growth rate in wounds of apple fruits stored at 25 1C compared with the performance of untreated yeast cells. Transcription of a trehalose-6-phosphate synthase gene (TPS1) was up regulated in response to HS and trehalose content also increased.
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Eliezer, D. Protein folding and protein metallocluster studies using synchrotron small angler X-ray scattering. Office of Scientific and Technical Information (OSTI), June 1994. http://dx.doi.org/10.2172/10194910.

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