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Tetsuya Saito

Bio: Tetsuya Saito is an academic researcher from Niigata University. The author has contributed to research in topics: Autophagy & Medicine. The author has an hindex of 9, co-authored 10 publications receiving 1152 citations. Previous affiliations of Tetsuya Saito include Institute of Medical Science & Juntendo University.

Papers
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Journal ArticleDOI
TL;DR: It is shown that phosphorylation of the autophagy-adaptor protein p62 markedly increases p62's binding affinity for Keap1, an adaptor of the Cul3-ubiquitin E3 ligase complex responsible for degrading Nrf2, and that inhibitors of the interaction between phosphorylated p62 and Keap 1 have potential as therapeutic agents against human HCC.

824 citations

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TL;DR: In this article, the authors reveal the molecular mechanism of p62/Sqstm1-dependent malignant progression, and suggest that molecular targeting of P62/sqstmm1 represents a potential chemotherapeutic approach against hepatocellular carcinoma (HCC).
Abstract: p62/Sqstm1 is a multifunctional protein involved in cell survival, growth and death, that is degraded by autophagy. Amplification of the p62/Sqstm1 gene, and aberrant accumulation and phosphorylation of p62/Sqstm1, have been implicated in tumour development. Herein, we reveal the molecular mechanism of p62/Sqstm1-dependent malignant progression, and suggest that molecular targeting of p62/Sqstm1 represents a potential chemotherapeutic approach against hepatocellular carcinoma (HCC). Phosphorylation of p62/Sqstm1 at Ser349 directs glucose to the glucuronate pathway, and glutamine towards glutathione synthesis through activation of the transcription factor Nrf2. These changes provide HCC cells with tolerance to anti-cancer drugs and proliferation potency. Phosphorylated p62/Sqstm1 accumulates in tumour regions positive for hepatitis C virus (HCV). An inhibitor of phosphorylated p62-dependent Nrf2 activation suppresses the proliferation and anticancer agent tolerance of HCC. Our data indicate that this Nrf2 inhibitor could be used to make cancer cells less resistant to anticancer drugs, especially in HCV-positive HCC patients.

234 citations

Journal ArticleDOI
TL;DR: The molecular mechanisms behind the control p62 exerts over Nrf2, mTORC1, and NF‐κB signaling pathways, their interconnection and how their deregulation contributes to cancer progression are presented.
Abstract: p62 is a stress-inducible protein able to change among binding partners, cellular localizations and form liquid droplet structures in a context-dependent manner. This protein is mainly defined as a cargo receptor for selective autophagy, a process that allows the degradation of detrimental and unnecessary components through the lysosome. Besides this role, its ability to interact with multiple binding partners allows p62 to act as a main regulator of the activation of the Nrf2, mTORC1, and NF-κB signaling pathways, linking p62 to the oxidative defense system, nutrient sensing, and inflammation, respectively. In the present review, we will present the molecular mechanisms behind the control p62 exerts over these pathways, their interconnection and how their deregulation contributes to cancer progression.

154 citations

Journal ArticleDOI
TL;DR: It is shown that autophagy promotes the selective degradation of NCoR1, a repressor of lipid metabolism regulator PPARα, in response to starvation, and thus induces the expression of enzymes involved in lipid oxidation and the production of ketone bodies.
Abstract: Selective autophagy ensures the removal of specific soluble proteins, protein aggregates, damaged mitochondria, and invasive bacteria from cells. Defective autophagy has been directly linked to metabolic disorders. However how selective autophagy regulates metabolism remains largely uncharacterized. Here we show that a deficiency in selective autophagy is associated with suppression of lipid oxidation. Hepatic loss of Atg7 or Atg5 significantly impairs the production of ketone bodies upon fasting, due to decreased expression of enzymes involved in β-oxidation following suppression of transactivation by PPARα. Mechanistically, nuclear receptor co-repressor 1 (NCoR1), which interacts with PPARα to suppress its transactivation, binds to the autophagosomal GABARAP family proteins and is degraded by autophagy. Consequently, loss of autophagy causes accumulation of NCoR1, suppressing PPARα activity and resulting in impaired lipid oxidation. These results suggest that autophagy contributes to PPARα activation upon fasting by promoting degradation of NCoR1 and thus regulates β-oxidation and ketone bodies production.

119 citations

Journal ArticleDOI
TL;DR: In vivo data suggest that cells contain networks of cellular defense mechanisms against defective proteostasis, and both Nrf2 and autophagy serve as in vivo cellular adaptations to impaired proteasome.

94 citations


Cited by
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Journal ArticleDOI
Yu-Jie Li1, Qin Jiang, Guo-Fan Cao, Jin Yao, Biao Yan 
TL;DR: In this manuscript, the relevant progress about the role of autophagy in the pathogenesis of ocular diseases is reviewed and pharmacological manipulation of Autophagy may provide an alternative therapeutic target for some Ocular diseases.
Abstract: Autophagy is an important intracellular degradative process that delivers cytoplasmic proteins to lysosome for degradation. Dysfunction of autophagy is implicated in several human diseases, such as neurodegenerative diseases, infectious diseases, and cancers. Autophagy-related proteins are constitutively expressed in the eye. Increasing studies have revealed that abnormal autophagy is an important pathological feature of several ocular diseases. Pharmacological manipulation of autophagy may provide an alternative therapeutic target for some ocular diseases. In this manuscript, we reviewed the relevant progress about the role of autophagy in the pathogenesis of ocular diseases.

2,571 citations

01 Mar 2017
TL;DR: Recent advances in understanding of mTOR function, regulation, and importance in mammalian physiology are reviewed and how the mTOR-signaling network contributes to human disease is highlighted.
Abstract: The mechanistic target of rapamycin (mTOR) coordinates eukaryotic cell growth and metabolism with environmental inputs, including nutrients and growth factors. Extensive research over the past two decades has established a central role for mTOR in regulating many fundamental cell processes, from protein synthesis to autophagy, and deregulated mTOR signaling is implicated in the progression of cancer and diabetes, as well as the aging process. Here, we review recent advances in our understanding of mTOR function, regulation, and importance in mammalian physiology. We also highlight how the mTOR signaling network contributes to human disease and discuss the current and future prospects for therapeutically targeting mTOR in the clinic.

2,014 citations

Journal ArticleDOI
TL;DR: This review summarizes knowledge about Nrf2 and HO-1 across different phyla suggesting their conservative role as stress-protective and anti-aging factors.
Abstract: The multifunctional regulator nuclear factor erythroid 2-related factor (Nrf2) is considered not only as a cytoprotective factor regulating the expression of genes coding for anti-oxidant, anti-inflammatory and detoxifying proteins, but it is also a powerful modulator of species longevity. The vertebrate Nrf2 belongs to Cap ‘n’ Collar (Cnc) bZIP family of transcription factors and shares a high homology with SKN-1 from Caenorhabditis elegans or CncC found in Drosophila melanogaster. The major characteristics of Nrf2 are to some extent mimicked by Nrf2-dependent genes and their proteins including heme oxygenase-1 (HO-1), which besides removing toxic heme, produces biliverdin, iron ions and carbon monoxide. HO-1 and their products exert beneficial effects through the protection against oxidative injury, regulation of apoptosis, modulation of inflammation as well as contribution to angiogenesis. On the other hand, the disturbances in the proper HO-1 level are associated with the pathogenesis of some age-dependent disorders, including neurodegeneration, cancer or macular degeneration. This review summarizes our knowledge about Nrf2 and HO-1 across different phyla suggesting their conservative role as stress-protective and anti-aging factors.

1,490 citations

Journal ArticleDOI
TL;DR: Observations suggest Nrf2 directs metabolic reprogramming during stress, which would enable the factor to orchestrate adaptive responses to diverse forms of stress.

1,482 citations

Journal ArticleDOI
TL;DR: This review aims at providing novel insight into the regulatory pathways of autophagy in response to glucose and amino acid deprivation, as well as their tight interconnection with metabolic networks and redox homeostasis.
Abstract: Autophagy is a catabolic process aimed at recycling cellular components and damaged organelles in response to diverse conditions of stress, such as nutrient deprivation, viral infection and genotoxic stress. A growing amount of evidence in recent years argues for oxidative stress acting as the converging point of these stimuli, with reactive oxygen species (ROS) and reactive nitrogen species (RNS) being among the main intracellular signal transducers sustaining autophagy. This review aims at providing novel insight into the regulatory pathways of autophagy in response to glucose and amino acid deprivation, as well as their tight interconnection with metabolic networks and redox homeostasis. The role of oxidative and nitrosative stress in autophagy is also discussed in the light of its being harmful for both cellular biomolecules and signal mediator through reversible posttranslational modifications of thiol-containing proteins. The redox-independent relationship between autophagy and antioxidant response, occurring through the p62/Keap1/Nrf2 pathway, is also addressed in order to provide a wide perspective upon the interconnection between autophagy and oxidative stress. Herein, we also attempt to afford an overview of the complex crosstalk between autophagy and DNA damage response (DDR), focusing on the main pathways activated upon ROS and RNS overproduction. Along these lines, the direct and indirect role of autophagy in DDR is dissected in depth.

1,376 citations