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91.
Boc and Gas1 each form distinct Shh receptor complexes with Ptch1 and are required for Shh-mediated cell proliferation 总被引:1,自引:0,他引:1
Izzi L Lévesque M Morin S Laniel D Wilkes BC Mille F Krauss RS McMahon AP Allen BL Charron F 《Developmental cell》2011,20(6):788-801
Hedgehog (Hh) proteins regulate important developmental processes, including cell proliferation and differentiation. Although Patched acts as the main Hh receptor in Drosophila, Hh signaling absolutely requires the additional Hh-binding proteins Ihog and Boi. Here we show that, unexpectedly, cerebellar granule neuron progenitors (CGNPs) lacking Boc and Cdon, the vertebrate orthologs of Ihog and Boi, still proliferate in response to Hh. This is because in their absence, Gas1, an Hh-binding protein not present in Drosophila, mediates Hh signaling. Consistently, only CGNPs lacking all three molecules-Boc, Cdon, and Gas1-have a complete loss of Hh-dependent proliferation. In a complementary manner, we find that a mutated Hh ligand that binds Patched1 but not Boc, Cdon, or Gas1 cannot activate Hh signaling. Together, this demonstrates an absolute requirement for Boc, Cdon, and Gas1 in Hh signaling and reveals a distinct requirement for ligand-binding components that distinguishes the vertebrate and invertebrate Hh receptor systems. 相似文献
92.
Crystal C. Walline Sarita Sehra Amanda J. Fisher Lynette M. Guindon Ian M. Kratzke Jessica B. Montgomery Kelsey P. Lipking Nicole L. Glosson Heather L. Benson George E. Sandusky David S. Wilkes Randy R. Brutkiewicz Mark H. Kaplan Janice S. Blum 《PloS one》2013,8(4)
Pulmonary viral infections can exacerbate or trigger the development of allergic airway diseases via multiple mechanisms depending upon the infectious agent. Respiratory vaccinia virus transmission is well established, yet the effects of allergic airway disease on the host response to intra-pulmonary vaccinia virus infection remain poorly defined. As shown here BALB/c mice with preexisting airway disease infected with vaccinia virus developed more severe pulmonary inflammation, higher lung virus titers and greater weight loss compared with mice inoculated with virus alone. This enhanced viremia was observed despite increased pulmonary recruitment of CD8+ T effectors, greater IFNγ production in the lung, and high serum levels of anti-viral antibodies. Notably, flow cytometric analyses of lung CD8+ T cells revealed a shift in the hierarchy of immunodominant viral epitopes in virus inoculated mice with allergic airway disease compared to mice treated with virus only. Pulmonary IL-10 production by T cells and antigen presenting cells was detected following virus inoculation of animals and increased dramatically in allergic mice exposed to virus. IL-10 modulation of host responses to this respiratory virus infection was greatly influenced by the localized pulmonary microenvironment. Thus, blocking IL-10 signaling in virus-infected mice with allergic airway disease enhanced pulmonary CD4+ T cell production of IFNγ and increased serum anti-viral IgG1 levels. In contrast, pulmonary IFNγ and virus-specific IgG1 levels were reduced in vaccinia virus-treated mice with IL-10 receptor blockade. These observations demonstrate that pre-existing allergic lung disease alters the quality and magnitude of immune responses to respiratory poxviruses through an IL-10-dependent mechanism. 相似文献
93.
Grazyna Weltrowska Thi M.-D. Nguyen Nga N. Chung Brian C. Wilkes Peter W. Schiller 《Bioorganic & medicinal chemistry letters》2013,23(18):5082-5085
Derivatives of peptides of the TIPP (Tyr-Tic-Phe-Phe; Tic = 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) family containing a guanidino (Guan) function in place of the N-terminal amino group were synthesized in an effort to improve their blood–brain barrier permeability. Unexpectedly, N-terminal amidination significantly altered the in vitro opioid activity profiles. Guan-analogues of TIPP-related δ opioid antagonists showed δ partial agonist or mixed δ partial agonist/μ partial agonist activity. Guanidinylation of the mixed μ agonist/δ antagonists H-Dmt-Tic-Phe-Phe-NH2 (DIPP-NH2) and H-Dmt-TicΨ[CH2NH]Phe-Phe-NH2 (DIPP-NH2[Ψ]) converted them to mixed μ agonist/δ agonists. A docking study revealed distinct positioning of DIPP-NH2 and Guan-DIPP-NH2 in the δ receptor binding site. Lys3-analogues of DIPP-NH2 and DIPP-NH2[Ψ] (guanidinylated or non-guanidinylated) turned out to be mixed μ/κ agonists with δ antagonist-, δ partial agonist- or δ full agonist activity. Compounds with some of the observed mixed opioid activity profiles have therapeutic potential as analgesics with reduced side effects or for treatment of cocaine addiction. 相似文献
94.
Homologous recombination in Trypanosoma brucei is used for moving variant surface glycoprotein (VSG) genes into expression sites during immune evasion by antigenic variation. A major route for such VSG switching is gene conversion reactions in which RAD51, a universally conserved recombinase, catalyses homology-directed strand exchange. In any eukaryote, RAD51-directed strand exchange in vivo is mediated by further factors, including RAD51-related proteins termed Rad51 paralogues. These appear to be ubiquitously conserved, although their detailed roles in recombination remain unclear. In T. brucei, four putative RAD51 paralogue genes have been identified by sequence homology. Here we show that all four RAD51 paralogues act in DNA repair, recombination and RAD51 subnuclear dynamics, though not equivalently, while mutation of only one RAD51 paralogue gene significantly impedes VSG switching. We also show that the T. brucei RAD51 paralogues interact, and that the complexes they form may explain the distinct phenotypes of the mutants as well as observed expression interdependency. Finally, we document the Rad51 paralogues that are encoded by a wide range of protists, demonstrating that the Rad51 paralogue repertoire in T. brucei is unusually large among microbial eukaryotes and that one member of the protein family corresponds with a key, conserved eukaryotic Rad51 paralogue. 相似文献
95.
Reininger L Wilkes JM Bourgade H Miranda-Saavedra D Doerig C 《Molecular microbiology》2011,79(1):205-221
Aurora kinases compose a family of conserved Ser/Thr protein kinases playing essential roles in eukaryotic cell division. To date, Aurora homologues remain uncharacterized in the protozoan phylum Apicomplexa. In malaria parasites, the characterization of Aurora kinases may help understand the cell cycle control during erythrocytic schizogony where asynchronous nuclear divisions occur. In this study, we revisited the kinome of Plasmodium falciparum and identified three Aurora-related kinases, Pfark-1, -2, -3. Among these, Pfark-1 is highly conserved in malaria parasites and also appears to be conserved across Apicomplexa. By tagging the endogenous Pfark-1 gene with the green fluorescent protein (GFP) in live parasites, we show that the Pfark-1-GFP protein forms paired dots associated with only a subset of nuclei within individual schizonts. Immunofluorescence analysis using an anti-α-tubulin antibody strongly suggests a recruitment of Pfark-1 at duplicated spindle pole bodies at the entry of the M phase of the cell cycle. Unsuccessful attempts at disrupting the Pfark-1 gene with a knockout construct further indicate that Pfark-1 is required for parasite growth in red blood cells. Our study provides new insights into the cell cycle control of malaria parasites and reports the importance of Aurora kinases as potential targets for new antimalarials. 相似文献
96.
Vinothini Rajeeve Iolanda Vendrell Edmund Wilkes Neil Torbett Pedro R. Cutillas 《Molecular & cellular proteomics : MCP》2014,13(6):1457-1470
The tumor microenvironment plays key roles in cancer biology, but its impact on the regulation of signaling pathway activity in cancer cells has not been systemically investigated. We designed an analytical strategy that allows differential analysis of signaling between cancer and stromal cells present in tumor xenografts. We used this approach to investigate how in vivo growth conditions and PI3K inhibitors regulate pathway activities in both cancer and stromal cell populations. We found that, despite inducing more modest changes in protein expression, in vivo growing conditions extensively rewired protein kinase networks in cancer cells. As a result, different sets of phosphorylation sites were modulated by PI3K inhibitors in cancer cells growing in tumors relative to when these cells were in culture. The p110δ PI3K-selective compound CAL-101 (Idelalisib) did not inhibit markers of PI3K activity in cancer or stromal cells; however, unexpectedly, it induced phosphorylation on SQ motifs in both subpopulations of tumor cells in vivo but not in vitro. Thus, the interaction between cancer cells and the stroma modulated the ability of PI3K inhibitors to induce the activation of apoptosis in solid tumors. Our study provides proof-of-principle of a proteomics workflow for measuring signaling specifically in cancer and stromal cells and for investigating how cancer biochemistry is modulated in vivo.Solid tumors contain a heterogeneous population of cells. Transformed epithelial cells recruit different types of somatic cells to the tumor microenvironment where they influence varying aspects of cancer biology. The role of heterotypic communication between normal stromal cells and transformed cancer cells is well established (1, 2). Different somatic cell types, including fibroblasts, epithelial cells, and cells of the immune system—all of which are found in tumors—promote cancer cell development by means of gap-junction intercellular communication, direct cell-to-cell contacts, and by the release of growth factors, enzymes, and cytokines that act on neighboring malignant cells (3–6).The tumor microenvironment determines the ability of cancer cells to survive in specific organs and their ability to proliferate and metastasize (7–9). Growth factors released from tumor-associated stromal cells also influence how cancer cells respond to drug administration (10). Therefore, the advancement of targeted cancer therapies requires an understanding of how the tumor microenvironment modulates the biochemistry of transformed cancer cells. In addition, targeting the tumor stroma is emerging as an intriguing concept for the development of anti-cancer therapies (11). It is therefore important to investigate specific effects of compounds in clinical development on stromal cells in addition to those exerted toward malignant cancer cells (12).Here we investigated the effects that changes in growing conditions from a two-dimensional cell culture to an in vivo three-dimensional tumor environment had in modulating protein and phosphoprotein expression in human cancer cells. For this, we used mass spectrometry (MS) to specifically measure cancer and stromal proteomes and phosphoproteomes within mouse tumor xenografts.We also investigated the effects that the pharmacological inhibitors of PI3K, namely GDC-0941 or CAL-101, would have on the phosphoproteomes of stromal cells relative to cancer cells in solid tumors. GDC-0941 is an inhibitor with specificity for class I PI3Ks, whereas CAL-101 specificity is restricted to the p110δ isoform of PI3K (13, 14), which in untransformed tissues is mainly found in leukocytes (15). The PI3K signaling pathway is often deregulated in different cancer types (16), including colorectal cancer (17), and both compounds used in this study are in different stages of clinical development (18–20). PI3K signaling has also been implicated in mediating the effects that the microenvironment has on cancer cells (21).We found that in vivo growth conditions had profound effects on phosphoprotein expression, which was reflected on the phosphorylation sites modulated by PI3K inhibitors in vivo relative to in vitro and in their ability to induce apoptotic markers across these two cell culture conditions. 相似文献
97.
BACKGROUND: Methane (CH(4)) uptake by steppe soils is affected by a range of specific factors and is a complex process. Increased stocking rate promotes steppe degradation, with unclear consequences for gas exchanges. To assess the effects of grazing management on CH(4) uptake in desert steppes, we investigated soil-atmosphere CH(4) exchange during the winter-spring transition period. METHODOLOGY/MAIN FINDING: The experiment was conducted at twelve grazing plots denoting four treatments defined along a grazing gradient with three replications: non-grazing (0 sheep/ha, NG), light grazing (0.75 sheep/ha, LG), moderate grazing (1.50 sheep/ha, MG) and heavy grazing (2.25 sheep/ha, HG). Using an automatic cavity ring-down spectrophotometer, we measured CH(4) fluxes from March 1 to April 29 in 2010 and March 2 to April 27 in 2011. According to the status of soil freeze-thaw cycles (positive and negative soil temperatures occurred in alternation), the experiment was divided into periods I and II. Results indicate that mean CH(4) uptake in period I (7.51 μg CH(4)-C m(-2) h(-1)) was significantly lower than uptake in period II (83.07 μg CH(4)-C m(-2) h(-1)). Averaged over 2 years, CH(4) fluxes during the freeze-thaw period were -84.76 μg CH(4)-C m(-2) h(-1) (NG), -88.76 μg CH(4)-C m(-2) h(-1) (LG), -64.77 μg CH(4)-C m(-2) h(-1) (MG) and -28.80 μg CH(4)-C m(-2) h(-1) (HG). CONCLUSIONS/SIGNIFICANCE: CH(4) uptake activity is affected by freeze-thaw cycles and stocking rates. CH(4) uptake is correlated with the moisture content and temperature of soil. MG and HG decreases CH(4) uptake while LG exerts a considerable positive impact on CH(4) uptake during spring freeze-thaw cycles in the northern desert steppe in China. 相似文献
98.
Heather L Benson Hidemi Suzuki Jeremy Lott Amanda Jo Fisher Crystal Walline Kathleen M Heidler Randy Brutkiewicz Janice S Blum David S Wilkes 《Respiratory research》2012,13(1):25
Background
Direct allorecognition, i.e., donor lung-derived dendritic cells (DCs) stimulating recipient-derived T lymphocytes, is believed to be the key mechanism of lung allograft rejection. Myeloid (cDCs) and plasmacytoid (pDCs) are believed to have differential effects on T cell activation. However, the roles of each DC type on T cell activation and rejection pathology post lung transplantation are unknown.Methods
Using transgenic mice and antibody depletion techniques, either or both cell types were depleted in lungs of donor BALB/c mice (H-2d) prior to transplanting into C57BL/6 mice (H-2b), followed by an assessment of rejection pathology, and pDC or cDC-induced proliferation and cytokine production in C57BL/6-derived mediastinal lymph node T cells (CD3+).Results
Depleting either DC type had modest effect on rejection pathology and T cell proliferation. In contrast, T cells from mice that received grafts depleted of both DCs did not proliferate and this was associated with significantly reduced acute rejection scores compared to all other groups. cDCs were potent inducers of IFNγ, whereas both cDCs and pDCs induced IL-10. Both cell types had variable effects on IL-17A production.Conclusion
Collectively, the data show that direct allorecognition by donor lung pDCs and cDCs have differential effects on T cell proliferation and cytokine production. Depletion of both donor lung cDC and pDC could prevent the severity of acute rejection episodes. 相似文献99.
Nuttall ME Lee JC Murdock PR Badger AM Wang FL Laydon JT Hofmann GA Pettman GR Lee JA Parihar A Van Wagenen BC Fox J Gowen M Johnson RK Mattern MR 《Journal of biomolecular screening》1999,4(5):269-278
Xenopus laevis melanophores stably expressing 7-transmembrane G-protein-coupled receptors were established and evaluated, either as a primary screening utility for antagonists of the human calcium receptor, or as a screen to assign function to binding inhibitors of human cannabinoid receptors. Stably or transiently expressing melanophores responded selectively to respective effectors of the human calcium, cannabinoid, and neurokinin-1 receptors. Several selective cannabinoid receptor-binding inhibitors of known potency were characterized as agonists or antagonists of the human peripheral cannabinoid (CB(2)) receptor. The results were consistent with changes in cAMP content of hCB(2)-transfected human embryonic kidney (HEK) cells challenged with the same CB(2)-binding antagonists. A stable melanophore cell line expressing the human calcium receptor was used to screen a compound collection directly for functional antagonists, several of which were confirmed as antagonists in secondary screens by stimulating parathyroid hormone (PTH) secretion from bovine parathyroid cells. The percentage of hits in this cell-based screen was reasonably low (1.2%), indicating minimal interference due to toxic effects and validating melanophores as a primary screening modality. Also described is the development of a novel procedure for cryopreservation and reconstitution of cells retaining functional human receptors. () 相似文献
100.
Clare Fennell Shalon Babbitt Ilaria Russo Jonathan Wilkes Lisa Ranford-Cartwright Daniel E Goldberg Christian Doerig 《Malaria journal》2009,8(1):1-15