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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: Impaired tumor development correlated with decreased tumor initiation, which is associated with the production of reactive oxygen species, and lower levels of tumorigenesis were correlated with the decreased expression of cyclin D and CDK as well as decreased cell proliferation.
Abstract: c-Jun NH(2)-terminal kinase (JNK) links several cellular processes, including proliferation and survival, and is believed to be involved in carcinogenesis. However, the role of JNK in gastric tumorigenesis is unknown. Immunohistochemical analysis reveals that JNK is frequently activated in human gastric cancer tissue. We investigated whether JNK1, a major JNK isozyme, is involved in chemically induced gastric cancer development. Mice lacking JNK1 exhibited a marked decrease in gastric carcinogenesis induced by N-methyl-N-nitrosourea, relative to their wild-type counterparts. Impaired tumor development correlated with decreased tumor initiation, which is associated with the production of reactive oxygen species. We also found that lower levels of tumorigenesis were correlated with the decreased expression of cyclin D and CDK as well as decreased cell proliferation. Taken together, JNK seems to be involved in both tumor initiation and promotion and may be an attractive target for the prevention of gastric carcinogenesis.

86 citations

Journal ArticleDOI
TL;DR: Extracellular signals regulate gene expression by triggering signal transduction cascades that result in the modulation of transcription factor activity, which is most commonly achieved by changes in the phosphorylation state of nuclear proteins.

86 citations

Journal ArticleDOI
07 Jun 2001-Oncogene
TL;DR: It is shown that inhibitory signals elicited by TSP-1 did not alter the ability of inducers of angiogenesis to activate p42 and p44 mitogen-activated protein kinase (MAPK) but induced a rapid and transient activation of c-Jun N-terminal kinases (JNK), suggesting a critical role for this stress-activated kinase in the inhibition of neovascularization by T SP-1.
Abstract: Thrombospondin-1 (TSP-1) is a potent inhibitor of angiogenesis that acts directly on endothelial cells via the CD36 surface receptor molecule to halt their migration, proliferation, and morphogenesis in vitro and to block neovascularization in vivo. Here we show that inhibitory signals elicited by TSP-1 did not alter the ability of inducers of angiogenesis to activate p42 and p44 mitogen-activated protein kinase (MAPK). Rather, TSP-1 induced a rapid and transient activation of c-Jun N-terminal kinases (JNK). JNK activation by TSP-1 required engagement of CD36, as it was blocked by antagonistic CD36 antibodies and stimulated by short anti-angiogenic peptides derived from TSP-1 that act exclusively via CD36. TSP-1 inhibition of corneal neovascularization induced by bFGF was severely impaired in mice null for JNK-1, pointing to a critical role for this stress-activated kinase in the inhibition of neovascularization by TSP-1.

83 citations

Journal ArticleDOI
TL;DR: In this article, the effects of a mutation occurring in an IP-affected family on IKK activity and NF-κB signaling were characterized and the mutants were expressed in IKKγ-deficient murine embryonic fibroblasts (MEFs) at levels comparable to those of endogenous IKKα and IKKβ in wild-type MEFs.
Abstract: IκB kinase γ (IKKγ) (also known as NEMO, Fip-3, and IKKAP-1) is the essential regulatory component of the IKK complex; it is required for NF-κB activation by various stimuli, including tumor necrosis factor alpha (TNF-α), interleukin 1 (IL-1), phorbol esters, lipopolysaccharides, and double-stranded RNA. IKKγ is encoded by an X-linked gene, deficiencies in which may result in two human genetic disorders, incontinentia pigmenti (IP) and hypohidrotic ectodermal dysplasia with severe immunodeficiency. Subsequent to the linkage of IKKγ deficiency to IP, we biochemically characterized the effects of a mutation occurring in an IP-affected family on IKK activity and NF-κB signaling. This particular mutation results in premature termination, such that the variant IKKγ protein lacks its putative C-terminal Zn finger and, due to decreased mRNA stability, is underexpressed. Correspondingly, IKK and NF-κB activation by TNF-α and, to a lesser extent, IL-1 are reduced. Mutagenesis of the C-terminal region of IKKγ was performed in an attempt to define the role of the putative Zn finger and other potential functional motifs in this region. The mutants were expressed in IKKγ-deficient murine embryonic fibroblasts (MEFs) at levels comparable to those of endogenous IKKγ in wild-type MEFs and were able to associate with IKKα and IKKβ. Substitution of two leucines within a C-terminal leucine zipper motif markedly reduced IKK activation by TNF-α and IL-1. Another point mutation resulting in a cysteine-to-serine substitution within the putative Zn finger motif affected IKK activation by TNF-α but not by IL-1. These results may explain why cells that express these or similar mutant alleles are sensitive to TNF-α-induced apoptosis despite being able to activate NF-κB in response to other stimuli.

81 citations

Journal ArticleDOI
TL;DR: Nuclear IKKbeta acts as an adaptor protein for IkappaBalpha degradation in UV-induced NF-kappaB activation and suppresses anti-apoptotic gene expression and promotesUV-induced cell death.

81 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