Michael Karin

Bio: Michael Karin is an academic researcher from University of California, San Diego. The author has contributed to research in topics: IκB kinase & Signal transduction. The author has an hindex of 236, co-authored 704 publications receiving 226485 citations. Previous affiliations of Michael Karin include Sanford-Burnham Institute for Medical Research & University of California, Los Angeles.

IKKβ inhibition prevents fat-induced beta cell dysfunction in vitro and in vivo in rodents.

Abstract: We have previously shown that oxidative stress plays a causal role in beta cell dysfunction induced by fat. Here, we address whether the proinflammatory kinase inhibitor of (nuclear factor) κB kinase β (IKKβ), which is activated by oxidative stress, is also implicated. Fat (oleate or olive oil) was infused intravenously in Wistar rats for 48 h with or without the IKKβ inhibitor salicylate. Thereafter, beta cell function was evaluated in vivo using hyperglycaemic clamps or ex vivo in islets isolated from fat-treated rats. We also exposed rat islets to oleate in culture, with or without salicylate and 4(2′-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline; BMS-345541 (BMS, another inhibitor of IKKβ) and evaluated beta cell function in vitro. Furthermore, oleate was infused in mice treated with BMS and in beta cell-specific Ikkb-null mice. 48 h infusion of fat impaired beta-cell function in vivo, assessed using the disposition index (DI), in rats (saline: 1.41 ± 0.13; oleate: 0.95 ± 0.11; olive oil [OLO]: 0.87 ± 0.15; p < 0.01 for both fats vs saline) and in mice (saline: 2.51 ± 0.39; oleate: 1.20 ± 0.19; p < 0.01 vs saline) and ex vivo (i.e., insulin secretion, units are pmol insulin islet−1 h−1) in rat islets (saline: 1.51 ± 0.13; oleate: 1.03 ± 0.10; OLO: 0.91 ± 0.13; p < 0.001 for both fats vs saline) and the dysfunction was prevented by co-infusion of salicylate in rats (oleate + salicylate: 1.30 ± 0.09; OLO + salicylate: 1.33 ± 0.23) or BMS in mice (oleate + BMS: 2.25 ± 0.42) in vivo and by salicylate in rat islets ex vivo (oleate + salicylate: 1.74 ± 0.31; OLO + salicylate: 1.54 ± 0.29). In cultured islets, 48 h exposure to oleate impaired beta-cell function ([in pmol insulin islet−1 h−1] control: 0.66 ± 0.12; oleate: 0.23 ± 0.03; p < 0.01 vs saline), an effect prevented by both inhibitors (oleate + salicylate: 0.98 ± 0.08; oleate + BMS: 0.50 ± 0.02). Genetic inhibition of IKKβ also prevented fat-induced beta-cell dysfunction ex vivo ([in pmol insulin islet−1 h−1] control saline: 0.16 ± 0.02; control oleate: 0.10 ± 0.02; knockout oleate: 0.17 ± 0.04; p < 0.05 control saline vs. control oleate) and in vivo (DI: control saline: 3.86 ± 0.40; control oleate: 1.95 ± 0.29; knockout oleate: 2.96 ± 0.24; p < 0.01 control saline vs control oleate). Our results demonstrate a causal role for IKKβ in fat-induced beta cell dysfunction in vitro, ex vivo and in vivo.

CUP2 binds in a bipartite manner to upstream activation sequence c in the promoter of the yeast copper metallothionein gene

Abstract: Induction of the copper metallothionein (CUP1) gene of the yeast Saccharomyces cerevisiae is achieved by CUP2, a transcriptional activator protein which has a metal-dependent DNA-binding activity. It is thought that metal binding to CUP2 results in the formation of several looped regions of the protein which then are capable of binding to DNA. CUP2 binds to a site near the CUP1 gene called upstream activation sequence c (UASc), an imperfect inverted repeat. While CUP2 binds to both half-sites of UASc, the upstream half-site appears to be more important for transcriptional activity. A variant of CUP2 called ace1, in which cysteine-11 is replaced by tyrosine, binds to DNA but is incapable of activating transcription. We have used hydroxyl radical footprinting and missing nucleoside analysis to examine the complexes of wild-type CUP2 and the ace1 mutant protein with UASc. Our results indicate that ace1 interacts with a smaller portion of UASc than does CUP2, providing further evidence that the DNA-binding domain of CUP2 is complex, composed of two or more elements that recognize distinct features of UASc. We also show that CUP2 itself binds slightly differently to the two half-sites of UASc. While CUP2 and ace1 bind in a rather similar manner to the downstream half-site, in the upstream half-site CUP2 makes more extensive interactions. Our results suggest that the more crucial role that the upstream half-site plays in transcriptional activation may be due to differences in how CUP2 binds to each of the half-sites of UASc.

Erratum: Inflammation-induced IgA + cells dismantle anti-liver cancer immunity

Abstract: Nature 551, 340–345 (2017); doi:10.1038/nature24302 In this Article, owing to an error during the production process, the text ‘(Iga is also known as Cd79a)’ was erroneously added to the sentence describing the generation of MUP-uPA/Iga−/− and STAM/Iga−/− mice; this should have stated ‘(Iga is also known as Igha)’.

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

REACTIVE OXYGEN SPECIES: Metabolism, Oxidative Stress, and Signal Transduction

Abstract: Several reactive oxygen species (ROS) are continuously produced in plants as byproducts of aerobic metabolism. Depending on the nature of the ROS species, some are highly toxic and rapidly detoxified by various cellular enzymatic and nonenzymatic mechanisms. Whereas plants are surfeited with mechanisms to combat increased ROS levels during abiotic stress conditions, in other circumstances plants appear to purposefully generate ROS as signaling molecules to control various processes including pathogen defense, programmed cell death, and stomatal behavior. This review describes the mechanisms of ROS generation and removal in plants during development and under biotic and abiotic stress conditions. New insights into the complexity and roles that ROS play in plants have come from genetic analyses of ROS detoxifying and signaling mutants. Considering recent ROS-induced genome-wide expression analyses, the possible functions and mechanisms for ROS sensing and signaling in plants are compared with those in animals and yeast.