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Oxygen sufficiency controls TOP mRNA translation via the TSC-Rheb-mTOR pathway in a 4E-BP-independent manner

Journal of Molecular Cell Biology 2014年第3期8卷 255-266页

作者： Rachel Miloslavski Elad Cohen Adam Avraham Yifat I luz zvi ha.ouka.judith ka.ir Rajini Mudhasani Stephen N. Jones Nadine Cybulski Markus A. Ruegg Ola Larsson Valentina Gandin Arjuna Rajakumar Ivan Topisirovic Oded Meyuhas Department of Biochemistry and Molecular Biology The Institute for Medical Research - Israel-Canada The Hebrew University-Hadassah Medical School Jerusalem 91120 Israel Department of Cell Biology University of Massachusetts Medical School North Worcester MA 01655 USA Biozentrum University of Basel Klingelbergstrasse 70 CH-4056 Basel Switzerland Department of Oncolo'gy-Pathology Karolinska Instituie Stockholm SE-171 76 Sweden Lady Davis Institute for Medical Research Sir Mortimer B. Davis-Jewish General Hospital and Department of Oncology McGill University Montreal QC H3T 1E2 Canada Present address: Migal-Galilee Research Institute Kiryat Shmona 11016 Israel Present address: United States Army Medical Research Institute of Infectious Diseases Frederick MD 21702-5011 USA Present address: ADAM Montreal QC H3N 2C7 Canada

Cells encountering hypoxic stress conserve resources and energy by downregulating the protein synthesis. Here we demonstrate that one mechanism in this response is the translational repression of TOP mRNAs that encode components of the translational apparatus. This mode of regulation involves TSC and Rheb, as knockout of TSC1 or TSC2 or overexpression of Rheb rescued TOP mRNA translation in oxygen-deprived celts. Stress-induced translational repression of these mRNAs closely correlates with the hypophosphorylated state of 4E-BP, a translational repressor. However, a series of 4E-BP loss- and gain-of-function experiments disprove a cause-and- effect relationship between the phosphorylation status of 4E-BP and the translational repression of TOP mRNAs under oxygen or growth factor deprivation. Furthermore, the repressive effect of anoxia is similar to that attained by the very efficient inhibition of mTOR activity by Torin 1, but much more pronounced than roptor or rictor knockouL Likewise, deficiency of raptor or rictor, even though it mildly downregulated basal translation efficiency of TOP mRNAs, failed to suppress the oxygen-mediated translational activation of TOP mRNAs. Finally, co-knockdown of TIA-1 and TIAR, two RNA-binding proteins previously implicated in translational repression of TOP mRNAs in amino acid-starved cells, failed to relieve TOP mRNA translation under other stress conditions. Thus, the nature of the proximal translational regulator of TOP m RNAs remains elusive.

关键词： hypoxia roTOR TOP mRNAs translational control 4E-BP

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The speed of kill of fluralaner(BravectoTM) against Ixodes ricinus ticks on dogs

The speed of kill of fluralaner(BravectoTM) against Ixodes r...

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中国畜牧兽医学会兽医药理毒理学分会第十五次学术讨论会

作者： Christina Wengenmayer Heike Williams Eva Zschiesche Andreas Moritz judith Langenstein Rainer ka Roepke Anja R Heckeroth MSD Animal Health Innovation GmbH Zur Propstei Department of Veterinary Clinical Sciences Clinical PathophysiologyJustus-Liebig-University

Background:Pathogens that are transmitted by ticks to dogs,such as Anaplasma phagocytophilum,Babesia spp.,Borrelia burgdorferi sensu latu,and Ehrlichia canis,are an increasing problem in the *** method to prevent pathogen transmission to dogs is to kill the ticks before transmission ***(Bravecto) is a novel isoxazoline insecticide and acaricide that provides long persistent antiparasitic activity following systemic *** study investigated the speed of kill of fluralaner against Ixodes ricinus ticks on ***:A total of 48 dogs were randomized to 8 groups of 6 dogs and each dog was infested with 50 female and 10 male *** *** days later(day 0),4 groups received a single treatment of 25 mg fluralaner/kg body weight as Bravecto chewable tablets;the dogs in the other 4 groups were left *** control and treatment groups were paired at each time point(4,8,12,or 24 hours after treatment) for assessment of tick-killing *** 4,8,and 12 weeks after treatment,all dogs were re-infested with 50 female *** ticks and subsequently assessed for live or dead ticks at either 4,8,12,or 24 hours after *** was calculated for each assessment time point by comparison of the treatment group with the respective control ***:Tick-killing efficacy was 89.6% at 4 hours,97.9% at 8 hours,and 100% at12 and 24 hours after treatmentEight hours after re-infestation,efficacy was 96.8%,83.5%,and 45.8% at 4,8,and 12 weeks after treatment,*** least 98.1% tick-killing efficacy was demonstrated 12 and 24 hours after re-infestation over the entire 12 week study ***:Fluralaner kills ticks rapidly after treatment at 4 hours,and over its entire 12-week period of efficacy,it achieves an almost complete killing effect within 12 hours after tick *** rapid tick-killing effect together with the long duration of efficacy enables fluralaner to aid in the prevention of tick

关键词： BravectoTM chewable tablets Fluralaner Speed of kill Dog Tick Ixodes ricinus Tick-borne diseases Efficacy

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