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.

MEK kinase 1 is a negative regulator of virus-specific CD8(+) T cells.

Abstract: MEK kinase 1 (MEKK1) is a potent JNK-activating kinase, a regulator of T helper cell differentiation, cytokine production and proliferation in vitro. Using mice deficient for MEKK1 activity (Mekk1ΔKD) exclusively in their hematopoietic system, we show that MEKK1 has a negative regulatory role in the generation of a virus-specific immune response. Mekk1ΔKD mice challenged with vesicular stomatitis virus (VSV) showed a fourfold increase in splenic CD8+ T cell numbers. In contrast, the number of splenic T cells in infected WT mice was only marginally increased. The CD8+ T cell expansion in Mekk1ΔKD mice following VSV infection is virus-specific and the frequency of virus-specific T cells is significantly higher (more than threefold) in Mekk1ΔKD as compared to WT animals. Moreover, the hyper-expansion of T cells seen in Mekk1ΔKD mice after VSV infection is a result of increased proliferation, since a significantly higher percentage of virus-specific Mekk1ΔKD CD8+ T cells incorporated BrdU as compared to virus-specific WT CD8+ T cells. In contrast, similar levels of apoptosis were detected in Mekk1ΔKD and WT T cells following VSV infection. These results strongly suggest that MEKK1 plays a negative regulatory role in the expansion of virus-specific CD8+ T cells in vivo.

Method of inhibiting transcription utilizing nuclear receptors

Abstract: This invention provides a method of inhibiting the transcription of a gene, which is activated by AP-1 or an AP-1 component, comprising binding AP-1 or the component with a nuclear receptor so as to prevent the binding of AP-1 to the gene. The nuclear receptor can be the retinoic acid receptor, glucocorticoid receptor, vitamin D3 receptor, thyroid receptor, or estrogen receptor. Also provided is a composition of matter comprising AP-1 or an AP-1 component bound to a nuclear receptor. These methods and compositions can be used to treat arthritis and cancer.

A novel T-cell trans-activator that recognizes a phorbol ester-inducible element of the interleukin-2 promoter.

Abstract: The interleukin 2 (IL-2) gene promoter is recognized by several cell-type-specific and ubiquitous transcriptional regulators that integrate information transmitted by various signaling systems leading to IL-2 production and T-cell activation. Using a combination of transfection, protein-DNA binding, and in vitro transcription methods, we have discovered the novel T-cell-specific transcriptional activator TCF-1 (for T-Cell Factor-1), which recognizes a T-cell-specific response element (TCE) located within the IL-2 promoter. Although the TCE is similar in sequence to a consensus NF kappa B site, several criteria indicate that TCF-1 is distinct from NF kappa B. However, like NF kappa B, TCF-1 activity is induced by phorbol esters and other T-cell activators.

Elevated A20 promotes TNF-induced and RIPK1-dependent intestinal epithelial cell death

Abstract: Intestinal epithelial cell (IEC) death is a common feature of inflammatory bowel disease (IBD) that triggers inflammation by compromising barrier integrity. In many patients with IBD, epithelial damage and inflammation are TNF-dependent. Elevated TNF production in IBD is accompanied by increased expression of the TNFAIP3 gene, which encodes A20, a negative feedback regulator of NF-κB. A20 in intestinal epithelium from patients with IBD coincided with the presence of cleaved caspase-3, and A20 transgenic (Tg) mice, in which A20 is expressed from an IEC-specific promoter, were highly susceptible to TNF-induced IEC death, intestinal damage, and shock. A20-expressing intestinal organoids were also susceptible to TNF-induced death, demonstrating that enhanced TNF-induced apoptosis was a cell-autonomous property of A20. This effect was dependent on Receptor Interacting Protein Kinase 1 (RIPK1) activity, and A20 was found to associate with the Ripoptosome complex, potentiating its ability to activate caspase-8. A20-potentiated RIPK1-dependent apoptosis did not require the A20 deubiquitinase (DUB) domain and zinc finger 4 (ZnF4), which mediate NF-κB inhibition in fibroblasts, but was strictly dependent on ZnF7 and A20 dimerization. We suggest that A20 dimers bind linear ubiquitin to stabilize the Ripoptosome and potentiate its apoptosis-inducing activity.

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.