@article{miyazawa_bogdan_hashimoto_tsuji_2019, title={Iron-induced transferrin receptor-1 mRNA destabilization: A response to "Neither miR-7-5p nor miR-141-3p is a major mediator of iron-responsive transferrin receptor-1 mRNA degradation"}, volume={25}, ISSN={["1469-9001"]}, DOI={10.1261/rna.073270.119}, abstractNote={We read with great interest the Divergent Views article by Connell and colleagues disputing our recent publication describing a role for two microRNAs in the iron-mediated regulation of transferrin receptor 1 (TfR1) mRNA stability. Our publication sought to shed light on a long-standing question in the field of cellular iron metabolism, and we welcome commentary and critique. However, there are several critical issues contained in the article by Connell and colleagues that require further consideration. We appreciate the opportunity to reply here.}, number={11}, journal={RNA}, author={Miyazawa, Masaki and Bogdan, Alexander R. and Hashimoto, Kazunori and Tsuji, Yoshiaki}, year={2019}, month={Nov}, pages={1416–1420} }
 @article{hashimoto_majumdar_tsuji_2017, title={Nuclear lamins and progerin are dispensable for antioxidant Nrf2 response to arsenic and cadmium}, volume={33}, ISSN={["1873-3913"]}, DOI={10.1016/j.cellsig.2017.02.012}, abstractNote={Lamins are important constituents of the nuclear inner membrane and provide a platform for transcription factors and chromatin. Progerin, a C-terminal truncated lamin A mutant, causes premature aging termed Hutchinson-Gilford Progeria Syndrome (HGPS). Oxidative stress appears to be involved in the pathogenesis of HGPS, although the mechanistic role of progerin remains elusive. Here we examined whether nuclear lamins are important for a cellular antioxidant mechanism, and whether progerin compromises it. We investigated the activation of nuclear factor-E2-related factor 2 (Nrf2) which regulates various antioxidant genes including heme oxygenase-1 (HMOX1), following exposure to sodium arsenite or cadmium chloride in lamin knockdown human cell lines and primary HGPS human fibroblasts. Knocking down lamin A/C, or B, or all nuclear lamins simultaneously in three human cell lines (HaCaT, SW480, and K562) did not impair arsenite- or cadmium-induced activation of Nrf2. Progerin-expressing human primary HGPS fibroblasts showed lower basal levels of HMOX1 and NQO1 expression; however, in response to arsenic stress both normal and HGPS primary fibroblasts showed Nrf2 nuclear accumulation along with upregulation and phosphorylation of p62/SQSTM1 at Ser351, downregulation of Keap1, and comparable expression of an array of downstream Nrf2-regulated antioxidant genes. We also observed new forms of cleaved lamin A, B1 and B2 induced by cadmium stress although their roles in the Nrf2 antioxidant system need further investigation. These results suggest that the nuclear lamins and progerin have marginal roles in the activation of the antioxidant Nrf2 response to arsenic and cadmium.}, journal={CELLULAR SIGNALLING}, author={Hashimoto, Kazunori and Majumdar, Rima and Tsuji, Yoshiaki}, year={2017}, month={May}, pages={69–78} }
 @article{hashimoto_tsuji_2017, title={Arsenic-Induced Activation of the Homeodomain-Interacting Protein Kinase 2 (HIPK2) to cAMP-Response Element Binding Protein (CREB) Axis}, volume={429}, ISSN={["1089-8638"]}, DOI={10.1016/j.jmb.2016.11.015}, abstractNote={Cyclic AMP-response element-binding protein (CREB) plays key transcriptional roles in cell metabolism, proliferation, and survival. Ser133 phosphorylation by protein kinase A (PKA) is a well-characterized CREB activation mechanism. Homeodomain-interacting protein kinase (HIPK) 2, a nuclear serine/threonine kinase, activates CREB through Ser271 phosphorylation; however, the regulatory mechanism remains uncharacterized. Transfection of CREB in HEK293 cells together with the kinase demonstrated that HIPK2 phosphorylated CREB at Ser271 but not Ser133; likewise, PKA phosphorylated CREB at Ser133 but not Ser271, suggesting two distinct CREB regulatory mechanisms by HIPK2 and PKA. In vitro kinase assay revealed that HIPK2, and HIPK1 and HIPK3, directly phosphorylated CREB. Cells exposed to 10 μM sodium arsenite increased the stability of HIPK1 and HIPK2 proteins, leading to CREB activation via Ser271 phosphorylation. Phospho-Ser271 CREB showed facilitated interaction with the TFIID subunit coactivator TAF4 assessed by immunoprecipitation. Furthermore, a focused gene array between cells transfected with CREB alone and CREB plus HIPK2 over empty vector-transfected control displayed 14- and 32-fold upregulation of cyclin A1, respectively, while no upregulation was displayed by HIPK2 alone. These results suggest that the HIPK2-phospho-Ser271 CREB axis is a new arsenic-responsive CREB activation mechanism in parallel with the PKA-phospho-Ser133 CREB axis.}, number={1}, journal={JOURNAL OF MOLECULAR BIOLOGY}, author={Hashimoto, Kazunori and Tsuji, Yoshiaki}, year={2017}, month={Jan}, pages={64–78} }
 @misc{wilson_bogdan_miyazawa_hashimoto_tsuji_2016, title={Siderophores in Iron Metabolism: From Mechanism to Therapy Potential}, volume={22}, ISSN={["1471-499X"]}, DOI={10.1016/j.molmed.2016.10.005}, abstractNote={Iron is an essential nutrient for life. During infection, a fierce battle of iron acquisition occurs between the host and bacterial pathogens. Bacteria acquire iron by secreting siderophores, small ferric iron-binding molecules. In response, host immune cells secrete lipocalin 2 (also known as siderocalin), a siderophore-binding protein, to prevent bacterial reuptake of iron-loaded siderophores. To counter this threat, some bacteria can produce lipocalin 2-resistant siderophores. This review discusses the recently described molecular mechanisms of siderophore iron trafficking between host and bacteria, highlighting the therapeutic potential of exploiting pathogen siderophore machinery for the treatment of antibiotic-resistant bacterial infections. Because the latter reflect a persistent problem in hospital settings, siderophore-targeting or siderophore-based compounds represent a promising avenue to combat such infections.}, number={12}, journal={TRENDS IN MOLECULAR MEDICINE}, author={Wilson, Briana R. and Bogdan, Alexander R. and Miyazawa, Masaki and Hashimoto, Kazunori and Tsuji, Yoshiaki}, year={2016}, month={Dec}, pages={1077–1090} }
 @article{hashimoto_simmons_kajino-sakamoto_tsuji_ninomiya-tsuji_2016, title={TAK1 Regulates the Nrf2 Antioxidant System Through Modulating p62/SQSTM1}, volume={25}, ISSN={["1557-7716"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85002932956&partnerID=MN8TOARS}, DOI={10.1089/ars.2016.6663}, abstractNote={AIMS
Nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) is the master transcriptional regulator of antioxidant gene expression. On increased oxidative stress, an adaptor for Nrf2 degradation, Kelch-like ECH-associated protein 1 (Keap1), is directly modulated by oxidants in the cytoplasm, which results in stabilization and activation of Nrf2. Nrf2 is also constitutively active, to some extent, in the absence of exogenous oxidative stress. We have previously demonstrated that intestinal epithelium-specific TGF-β-activated kinase 1 (TAK1) deletion downregulates the level of Nrf2 protein, resulting in an increase of reactive oxygen species (ROS) in a mouse model. We aim at determining the mechanism by which TAK1 modulates the level of Nrf2.


RESULTS
We found that TAK1 upregulated serine 351 phosphorylation of an autophagic adaptor protein, p62/Sequestosome-1 (SQSTM1), which facilitates interaction between p62/SQSTM1 and Keap1 and subsequent Keap1 degradation. This, ultimately, causes increased Nrf2. Tak1 deficiency reduced the phosphorylation of p62/SQSTM1, resulting in decreased steady-state levels of Nrf2 along with increased Keap1. We also found that this regulation is independent of the canonical redox-mediated Nrf2 activation mechanism. In Tak1-deficient intestinal epithelium, a synthetic phenolic electrophile, butylated hydroxyanisole still effectively upregulated Nrf2 and reduced ROS.


INNOVATION
Our results identify for the first time that TAK1 is a modulator of p62/SQSTM1-dependent Keap1 degradation and maintains the steady state-level of Nrf2.


CONCLUSION
TAK1 regulates Nrf2 through modulation of Keap-p62/SQSTM1 interaction. This regulation is important for homeostatic antioxidant protection in the intestinal epithelium. Antioxid. Redox Signal. 25, 953-964.}, number={17}, journal={ANTIOXIDANTS & REDOX SIGNALING}, author={Hashimoto, Kazunori and Simmons, Alicia N. and Kajino-Sakamoto, Rie and Tsuji, Yoshiaki and Ninomiya-Tsuji, Jun}, year={2016}, month={Dec}, pages={953–964} }
 @misc{bogdan_miyazawa_hashimoto_tsuji_2016, title={Regulators of Iron Homeostasis: New Players in Metabolism, Cell Death, and Disease}, volume={41}, ISSN={["1362-4326"]}, DOI={10.1016/j.tibs.2015.11.012}, abstractNote={Iron is necessary for life, but can also cause cell death. Accordingly, cells evolved a robust, tightly regulated suite of genes for maintaining iron homeostasis. Previous mechanistic studies on iron homeostasis have granted insight into the role of iron in human health and disease. We highlight new regulators of iron metabolism, including iron-trafficking proteins [solute carrier family 39, SLC39, also known as ZRT/IRT-like protein, ZIP; and poly-(rC)-binding protein, PCBP] and a cargo receptor (NCOA4) that is crucial for release of ferritin-bound iron. We also discuss emerging roles of iron in apoptosis and a novel iron-dependent cell death pathway termed 'ferroptosis', the dysregulation of iron metabolism in human pathologies, and the use of iron chelators in cancer therapy.}, number={3}, journal={TRENDS IN BIOCHEMICAL SCIENCES}, author={Bogdan, Alexander R. and Miyazawa, Masaki and Hashimoto, Kazunori and Tsuji, Yoshiaki}, year={2016}, month={Mar}, pages={274–286} }