Author
Satoru Takahashi
Other affiliations: Hokkaido University, Nihon University, Tohoku University ...read more
Bio: Satoru Takahashi is an academic researcher from University of Tsukuba. The author has contributed to research in topics: MAFB & Medicine. The author has an hindex of 79, co-authored 589 publications receiving 28007 citations. Previous affiliations of Satoru Takahashi include Hokkaido University & Nihon University.
Topics: MAFB, Medicine, Cellular differentiation, Transgene, Transplantation
Papers published on a yearly basis
Papers
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TL;DR: It is demonstrated that Nrf2 is essential for the transcriptional induction of phase II enzymes and the presence of a coordinate transcriptional regulatory mechanism for phase II enzyme genes and the nrf2-deficient mice may prove to be a very useful model for the in vivo analysis of chemical carcinogenesis and resistance to anti-cancer drugs.
3,557 citations
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TL;DR: It is shown that Nrf2 controls the expression of a group of electrophile- and oxidative stress-inducible proteins and activities, which includes heme oxygenase-1, A170, peroxiredoxin MSP23, and cystine membrane transport (system xc −) activity.
1,367 citations
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TL;DR: These experiments show that Keap1 acts upstream of Nrf2 in the cellular response to oxidative and xenobiotic stress, and breeding to NRF2-deficient mice reversed the phenotypic Keap 1 deficiencies.
Abstract: Transcription factor Nrf2 (encoded by Nfe2l2) regulates a battery of detoxifying and antioxidant genes, and Keap1 represses Nrf2 function. When we ablated Keap1, Keap1-deficient mice died postnatally, probably from malnutrition resulting from hyperkeratosis in the esophagus and forestomach. Nrf2 activity affects the expression levels of several squamous epithelial genes. Biochemical data show that, without Keap1, Nrf2 constitutively accumulates in the nucleus to stimulate transcription of cytoprotective genes. Breeding to Nrf2-deficient mice reversed the phenotypic Keap1 deficiencies. These experiments show that Keap1 acts upstream of Nrf2 in the cellular response to oxidative and xenobiotic stress.
802 citations
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TL;DR: regulation of ho‐1 involves a direct sensing of heme levels by Bach1 (by analogy to lac repressor sensitivity to lactose), generating a simple feedback loop whereby the substrate effects repressor–activator antagonism.
Abstract: Heme oxygenase-1 (HO-1) protects cells from various insults including oxidative stress. Transcriptional activators, including the Nrf2/Maf heterodimer, have been the focus of studies on the inducible expression of ho-1. Here we show that a heme-binding factor, Bach1, is a critical physiological repressor of ho-1. Bach1 bound to the multiple Maf recognition elements (MAREs) of ho-1 enhancers with MafK in vitro and repressed their activity in vivo, while heme abrogated this repressor function of Bach1 by inhibiting its binding to the ho-1 enhancers. Gene targeting experiments in mice revealed that, in the absence of Bach1, ho-1 became expressed constitutively at high levels in various tissues under normal physiological conditions. By analyzing bach1/nrf2 compound-deficient mice, we documented antagonistic activities of Bach1 and Nrf2 in several tissues. Chromatin immunoprecipitation revealed that small Maf proteins participate in both repression and activation of ho-1. Thus, regulation of ho-1 involves a direct sensing of heme levels by Bach1 (by analogy to lac repressor sensitivity to lactose), generating a simple feedback loop whereby the substrate effects repressor–activator antagonism.
576 citations
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TL;DR: A unique genetic mechanism of immune escape caused by structural variations (SVs) commonly disrupting the 3' region of the PD-L1 gene is shown, supporting the role of relevant SVs in clonal selection through immune evasion and suggesting that PD-l1 3'-UTR disruption could serve as a genetic marker to identify cancers that actively evade anti-tumour immunity through PD- L1 overexpression.
Abstract: Successful treatment of many patients with advanced cancer using antibodies against programmed cell death 1 (PD-1; also known as PDCD1) and its ligand (PD-L1; also known as CD274) has highlighted the critical importance of PD-1/PD-L1-mediated immune escape in cancer development. However, the genetic basis for the immune escape has not been fully elucidated, with the exception of elevated PD-L1 expression by gene amplification and utilization of an ectopic promoter by translocation, as reported in Hodgkin and other B-cell lymphomas, as well as stomach adenocarcinoma. Here we show a unique genetic mechanism of immune escape caused by structural variations (SVs) commonly disrupting the 3' region of the PD-L1 gene. Widely affecting multiple common human cancer types, including adult T-cell leukaemia/lymphoma (27%), diffuse large B-cell lymphoma (8%), and stomach adenocarcinoma (2%), these SVs invariably lead to a marked elevation of aberrant PD-L1 transcripts that are stabilized by truncation of the 3'-untranslated region (UTR). Disruption of the Pd-l1 3'-UTR in mice enables immune evasion of EG7-OVA tumour cells with elevated Pd-l1 expression in vivo, which is effectively inhibited by Pd-1/Pd-l1 blockade, supporting the role of relevant SVs in clonal selection through immune evasion. Our findings not only unmask a novel regulatory mechanism of PD-L1 expression, but also suggest that PD-L1 3'-UTR disruption could serve as a genetic marker to identify cancers that actively evade anti-tumour immunity through PD-L1 overexpression.
518 citations
Cited by
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3,984 citations
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TL;DR: Observations to date suggest that oxidative stress, chronic inflammation, and cancer are closely linked.
3,922 citations
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TL;DR: This review focuses on the molecular mechanisms through which ROS directly interact with critical signaling molecules to initiate signaling in a broad variety of cellular processes, such as proliferation and survival, ROS homeostasis and antioxidant gene regulation, mitochondrial oxidative stress, apoptosis, and aging.
3,372 citations
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Columbia University1, University of Pittsburgh2, Florey Institute of Neuroscience and Mental Health3, Stanford University4, German Cancer Research Center5, Ludwig Maximilian University of Munich6, Yale University7, Memorial Sloan Kettering Cancer Center8, Dresden University of Technology9, Wistar Institute10, National University of Mar del Plata11, University of Texas Health Science Center at San Antonio12, Guangzhou Medical University13, University of Connecticut Health Center14, Nagoya University15, New York University16, University of Arizona17
TL;DR: The mechanisms underlying ferroptosis are reviewed, connections to other areas of biology and medicine are highlighted, and tools and guidelines for studying this emerging form of regulated cell death are recommended.
3,356 citations
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Utrecht University1, United States Environmental Protection Agency2, Health Canada3, Karolinska Institutet4, Houston Methodist Hospital5, Kaiserslautern University of Technology6, University of Tokyo7, World Health Organization8, National Institute for Health and Welfare9, Umeå University10, National Institutes of Health11, University of Wisconsin-Madison12
TL;DR: Concern was expressed about direct application of the TEF/total toxic equivalency (TEQ) approach to abiotic matrices, such as soil, sediment, etc., for direct application in human risk assessment as the present TEF scheme and TEQ methodology are primarily intended for estimating exposure and risks via oral ingestion.
3,284 citations