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.

Essential Roles of Receptor-Interacting Protein and TRAF2 in Oxidative Stress-Induced Cell Death

Abstract: Oxidative stress refers to the imbalance with enhanced production of reactive oxygen species (ROS) and/or impaired function of the antioxidant system (50). ROS usually include superoxide anions, hydroxyl radicals, and hydrogen peroxide (H2O2) that are capable of reacting with and damaging various molecular targets including DNA, protein, and lipids. It is well known that ROS or oxidative stress plays an important role in various physiological and pathological processes such as aging, inflammation, carcinogenesis, neurodegenerative diseases, and cancer (15, 22). One important aspect of ROS biological effects is their regulatory roles on cell death: ROS can act either as direct activators of cell death or as second messengers in the cell death processes triggered by many other stimuli such as cancer chemotherapeutic agents, UV, ionizing radiation, and tumor necrosis factor (TNF) (6, 19, 45, 48). As direct stimuli, ROS could cause either apoptosis or necrosis, depending on the concentration used and the cell type tested (18, 53, 57). On the other hand, elevated levels of ROS have been detected in many apoptotic conditions, and mitochondria are believed to be the main source of intracellular ROS production (6, 7, 43). However, some important issues regarding the role of ROS and oxidative stress in cell death remain to be further studied. The molecular targets of ROS in cell death are largely elusive. Inconsistent reports often suggest contradictory results regarding the effects of ROS on some key effectors or regulatory molecules such as caspases, nuclear transcription factors NF-κB and activator protein 1, and some cell stress-activated kinases (6, 23, 43, 49). Apparently, the cell signaling pathways regulating ROS-induced cell death remain to be further investigated. In recent years, extensive research on the TNF signaling pathway has greatly advanced our understanding of the cell death mechanisms. It is well known that receptor-interacting protein (RIP), TNF receptor (TNFR)-associated factor 2 (TRAF2), and Fas-associated death domain protein (FADD) are important effector molecules of TNFR1 signaling (4, 8, 38). In response to TNF, TNFR1 is trimerized and recruits TNFR-associated death domain protein (TRADD) as an adaptor molecule. The recruited TRADD interacts with FADD, which then interacts and activates caspase 8 to initiate the apoptotic cell death pathway. On the other hand, TRADD interacts with RIP and TRAF2 that is known to be important in TNF-induced activation of nuclear transcription factor NF-κB and mitogen-activated protein kinases (MAPK) (14). Although it is well established that RIP and TRAF2 mainly act as cell survival factors to protect against TNF-induced apoptosis via NF-κB activation (4, 31, 37), little is known about their involvement in cell death elicited by other stimuli. An earlier study revealed that RIP is required for Fas-induced caspase-independent cell death in primary T cells (26), indicating diversified functions of RIP in the regulation of the cell death process. On the other hand, ROS and oxidative stress are known to be involved in TNF-induced cell death (12, 16, 46). However, currently there is no report concerning whether some of the key TNF signaling molecules such as RIP and TRAF2 serve as the molecular targets of ROS in cell death. In this study, we demonstrate that RIP, TRAF2, and FADD, three key TNF signaling molecules, are important regulators in H2O2-induced cell death. We found that mouse embryonic fibroblasts (MEF) deficient of RIP and TRAF2 are largely resistant, while FADD−/− MEF cells are highly sensitive to H2O2 cytotoxicity, when compared to wild-type (wt) cells. Reconstitution of these proteins significantly restores the responses of these knockout cells to H2O2. Moreover, RIP and TRAF2 form a complex upon H2O2 exposure, most probably through membrane lipid rafts but independently of TNFR1. Lastly, we demonstrate that activation of c-Jun NH2-terminal kinase 1 (JNK1) is the key downstream event responsible for H2O2-induced cell death. Thus, our study reveals a novel cell signaling mechanism that regulates oxidative stress-induced cell death.

Magnetically vectored nanocapsules for tumor penetration and remotely switchable on-demand drug release.

Abstract: Nanocapsules containing intentionally trapped magnetic nanoparticles and defined anticancer drugs have been prepared to provide a powerful magnetic vector under moderate gradient magnetic fields. These nanocapsules can penetrate into the interior of tumors and allow a controlled on-off switchable release of the drug cargo via remote RF field. This smart drug delivery system is compact as all the components can be self-contained in 80-150 nm capsules. In vitro as well as in vivo results indicate that these nanocapsules can be enriched near the mouse breast tumor and are effective in reducing tumor cell growth.

Fructose stimulated de novo lipogenesis is promoted by inflammation.

Abstract: Benign hepatosteatosis, affected by lipid uptake, de novo lipogenesis and fatty acid (FA) oxidation, progresses to non-alcoholic steatohepatitis (NASH) on stress and inflammation. A key macronutrient proposed to increase hepatosteatosis and NASH risk is fructose. Excessive intake of fructose causes intestinal-barrier deterioration and endotoxaemia. However, how fructose triggers these alterations and their roles in hepatosteatosis and NASH pathogenesis remain unknown. Here we show, using mice, that microbiota-derived Toll-like receptor (TLR) agonists promote hepatosteatosis without affecting fructose-1-phosphate (F1P) and cytosolic acetyl-CoA. Activation of mucosal-regenerative gp130 signalling, administration of the YAP-induced matricellular protein CCN1 or expression of the antimicrobial peptide Reg3b (beta) peptide counteract fructose-induced barrier deterioration, which depends on endoplasmic-reticulum stress and subsequent endotoxaemia. Endotoxin engages TLR4 to trigger TNF production by liver macrophages, thereby inducing lipogenic enzymes that convert F1P and acetyl-CoA to FA in both mouse and human hepatocytes.

Allergen-induced peribronchial fibrosis and mucus production mediated by IκB kinase β-dependent genes in airway epithelium

Abstract: In response to inflammation or injury, airway epithelial cells express inducible genes that may contribute to allergen-induced airway remodeling. To determine the contribution of epithelial cell NF-κB activation to the remodeling response, we generated CC10-Cretg/IkkβΔ/Δ mice in which NF-κB signaling through IκB kinase β (IKKβ) is selectively ablated in the airway epithelium by conditional Cre-recombinase expression from the Clara cell (CC10) promoter. Repetitive ovalbumin challenge of mice deficient in airway epithelial IKKβ prevented nuclear translocation of the RelA NF-κB subunit only in airway epithelial cells, resulting in significantly lower peribronchial fibrosis in CC10-Cretg/IkkβΔ/Δ mice compared with littermate controls as assessed by peribronchial trichrome staining and total lung collagen content. Levels of airway mucus, airway eosinophils, and peribronchial CD4+ cells in ovalbumin-challenged mice were also reduced significantly upon airway epithelial Ikkβ ablation. The diminished inflammatory response was associated with reduced expression of NF-κB-regulated chemokines, including eotaxin-1 and thymus- and activation-regulated chemokine, which attract eosinophils and Th2 cells, respectively, into the airway. The number of peribronchial cells expressing TGF-β1, as well as TGF-β1 amounts in bronchoalveolar lavage, were also significantly reduced in mice deficient in airway epithelium IKKβ. Overall, these studies show an important role for NF-κB regulated genes in airway epithelium in allergen-induced airway remodeling, including peribronchial fibrosis and mucus production.

Immunotherapy, Inflammation and Colorectal Cancer

Abstract: Colorectal cancer (CRC) is the third most common cancer type, and third highest in mortality rates among cancer-related deaths in the United States. Originating from intestinal epithelial cells in the colon and rectum, that are impacted by numerous factors including genetics, environment and chronic, lingering inflammation, CRC can be a problematic malignancy to treat when detected at advanced stages. Chemotherapeutic agents serve as the historical first line of defense in the treatment of metastatic CRC. In recent years, however, combinational treatment with targeted therapies, such as vascular endothelial growth factor, or epidermal growth factor receptor inhibitors, has proven to be quite effective in patients with specific CRC subtypes. While scientific and clinical advances have uncovered promising new treatment options, the five-year survival rate for metastatic CRC is still low at about 14%. Current research into the efficacy of immunotherapy, particularly immune checkpoint inhibitor therapy (ICI) in mismatch repair deficient and microsatellite instability high (dMMR-MSI-H) CRC tumors have shown promising results, but its use in other CRC subtypes has been either unsuccessful, or not extensively explored. This Review will focus on the current status of immunotherapies, including ICI, vaccination and adoptive T cell therapy (ATC) in the treatment of CRC and its potential use, not only in dMMR-MSI-H CRC, but also in mismatch repair proficient and microsatellite instability low (pMMR-MSI-L).

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.