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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.


Papers
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Journal ArticleDOI
TL;DR: It is demonstrated that repetitive exposure to tobacco smoke promotes tumor development both in carcinogen-treated mice and in transgenic mice undergoing sporadic K-ras activation in lung epithelial cells.

401 citations

Journal ArticleDOI
08 Oct 2004-Science
TL;DR: It is found that extracellular stimuli also modulate protein turnover by regulating the activity of an E3 ligase by means of its phosphorylation.
Abstract: The turnover of Jun proteins, like that of other transcription factors, is regulated through ubiquitin-dependent proteolysis. Usually, such processes are regulated by extracellular stimuli through phosphorylation of the target protein, which allows recognition by F box-containing E3 ubiquitin ligases. In the case of c-Jun and JunB, we found that extracellular stimuli also modulate protein turnover by regulating the activity of an E3 ligase by means of its phosphorylation. Activation of the Jun amino-terminal kinase (JNK) mitogen-activated protein kinase cascade after T cell stimulation accelerated degradation of c-Jun and JunB through phosphorylation-dependent activation of the E3 ligase Itch. This pathway modulates cytokine production by effector T cells.

400 citations

Journal ArticleDOI
TL;DR: The functions and pathways of JNK in liver physiology and pathology are reviewed and findings from preclinical studies with JNK inhibitors are discussed.

396 citations

Journal ArticleDOI
05 Apr 2007-Nature
TL;DR: It is proposed that tumour-infiltrating RANKL-expressing cells lead to nuclear IKKα activation and inhibition of Maspin transcription, thereby promoting the metastatic phenotype.
Abstract: Experiments in a mouse prostate cancer model have identified a signalling pathway that stimulates the formation of metastases. The pathway is initiated when a protein ligand occupies a receptor known as RANK (receptor activator of nuclear factor κB), and is dependent on the activation and nuclear translocation of IKKα (IκB kinase α). Once in the nucleus, activated IKKα represses maspin gene transcription, whose product is well established as an inhibitor of cell migration and invasion in prostate and breast cancer. RANK may therefore be a general promoter of metastatic behaviour in prostate or mammary carcinoma cells. A previously unknown signalling pathway is shown to enhance the formation of metastases in a mouse model of prostate cancer. This pathway can be activated by RANK ligand that is expressed by inflammatory cells in the tumour and triggers activation of IKKα in the nucleus, where it directly represses the transcription of maspin, a known metastases suppressor. Inflammation enhances tumour promotion through NF-κB-dependent mechanisms1. NF-κB was also proposed to promote metastatogenesis through epithelial–mesenchymal transition2. Yet a mechanistic link between inflammation and metastasis is missing. We identified a role for IκB kinase α (IKKα), activated by receptor activator of NF-κB (RANK/TNFRSF11A), in mammary epithelial proliferation during pregnancy3. Owing to similarities between mammary and prostate epithelia, we examined IKKα involvement in prostate cancer and its progression. Here we show that a mutation that prevents IKKα activation slows down CaP growth and inhibits metastatogenesis in TRAMP mice, which express SV40 T antigen in the prostate epithelium4. Decreased metastasis correlated with elevated expression of the metastasis suppressor Maspin5, the ablation of which restored metastatic activity. IKKα activation by RANK ligand (RANKL/TNFSF11) inhibits Maspin expression in prostate epithelial cells, whereas repression of Maspin transcription requires nuclear translocation of active IKKα. The amount of active nuclear IKKα in mouse and human prostate cancer correlates with metastatic progression, reduced Maspin expression and infiltration of prostate tumours with RANKL-expressing inflammatory cells. We propose that tumour-infiltrating RANKL-expressing cells lead to nuclear IKKα activation and inhibition of Maspin transcription, thereby promoting the metastatic phenotype.

396 citations

Journal ArticleDOI
07 Jul 2000-Cell
TL;DR: Data suggest a regulatory role for multiubiquitin chains that is reversible and does not function to target the acceptor protein for degradation, and the K63R mutant of ubiquitin displays defects in ribosomal function in vivo and in vitro, including a dramatic sensitivity to translational inhibitors.

395 citations


Cited by
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Journal ArticleDOI
04 Mar 2011-Cell
TL;DR: Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer.

51,099 citations

28 Jul 2005
TL;DR: PfPMP1)与感染红细胞、树突状组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�ly.
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。

18,940 citations

Journal ArticleDOI
TL;DR: Attention is focussed on the ROS/RNS-linked pathogenesis of cancer, cardiovascular disease, atherosclerosis, hypertension, ischemia/reperfusion injury, diabetes mellitus, neurodegenerative diseases, rheumatoid arthritis, and ageing.

12,240 citations

Journal ArticleDOI
24 Feb 2006-Cell
TL;DR: New insights into innate immunity are changing the way the way the authors think about pathogenesis and the treatment of infectious diseases, allergy, and autoimmunity.

10,685 citations

Journal ArticleDOI
TL;DR: The mechanisms of ROS generation and removal in plants during development and under biotic and abiotic stress conditions are described and the possible functions and mechanisms for ROS sensing and signaling in plants are compared with those in animals and yeast.
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.

9,908 citations