d-amino acid oxidase promotes cellular senescence via the production of reactive oxygen species

Nagano, Tohru; Yamao, Shunsuke; Terachi, Anju; Yarimizu, Hidetora; Itoh, Hisashi; Katasho, Ryoko; Kawai, Kazuki; Nakashima, Akio; Iwasaki, Tetsushi; Kikkawa, Ushio; Kamada, Shinji

doi:10.26508/lsa.201800045

Cited by 20 publications

(18 citation statements)

References 54 publications

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“…The cells were treated with etoposide (Sigma Aldrich, St Louis, MO) or bleomycin (Wako) to induce DNA double-strand breaks. For senescence induction, U2OS and Hs68 cells were treated with 2- and 0.5-μM etoposide, respectively, or 2-μM bleomycin for 48 h and cultured in the medium without the drugs for additional 5 days to develop senescent phenotypes ( 6 , 7 , 8 , 37 ). Transfection with expression vectors was carried out using Effectene Transfection Reagent (Qiagen, Venlo, Netherlands) according to the manufacturer’s instruction.…”

Section: Methodsmentioning

confidence: 99%

“…Although LY6D is often used as a surface marker for leukocyte subset identification because of its lineage-specific expression, the physiological function of LY6D is poorly understood. We have recently identified LY6D to be upregulated specifically in senescent cells by comparing the transcriptome between senescent and apoptotic cells and shown that the upregulation of LY6D is dependent on p53, a crucial transcription factor for the initiation and maintenance of senescence ( 6 , 7 , 8 ). However, it is still unknown whether LY6D functionally contributes to the senescence process because our previous study has shown that ectopic expression of LY6D in osteosarcoma U2OS cells had little effect on senescence induction as determined by colony-forming assay and by senescence-associated β-galactosidase (SA-β-Gal) staining, an established marker of senescence.…”

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confidence: 99%

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LY6D-induced macropinocytosis as a survival mechanism of senescent cells

Nagano

Iwasaki

Onishi

et al. 2021

Journal of Biological Chemistry

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Although senescent cells display various morphological changes including vacuole formation, it is still unclear how these processes are regulated. We have recently identified the gene, lymphocyte antigen 6 complex, locus D (LY6D), to be upregulated specifically in senescent cells. LY6D is a glycosylphosphatidylinositol (GPI)-anchored cell surface protein whose function remains unknown. Here, we analyzed the functional relationship between LY6D and the senescence processes. We found that overexpression of LY6D induced vacuole formation, and knockdown of LY6D suppressed the senescence-associated vacuole formation. The LY6D-induced vacuoles were derived from macropinocytosis, a distinct form of endocytosis. Furthermore, Src family kinases and Ras were found to be recruited to membrane lipid rafts in an LY6D-dependent manner, and inhibition of their activity impaired the LY6D-induced macropinocytosis. Finally, reduction of senescent cell survival induced by glutamine deprivation was recovered by albumin supplementation to the culture media in an LY6D-dependent manner. Since macropinocytosis acts as an amino acid supply route, these results suggest that LY6D-mediated macropinocytosis contributes to senescent cell survival through the incorporation of extracellular nutrients.

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

LY6D-induced macropinocytosis as a survival mechanism of senescent cells

Nagano

Iwasaki

Onishi

et al. 2021

Journal of Biological Chemistry

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“…The major source of ROS originates from mitochondrial production [3], mainly due to complexes I and III function in the respiratory chain [4][5][6]. However, other non-mitochondrial enzymes and protein complexes also produce ROS: among these are nicotinamide adenine dinucleotide phosphate oxidase (NOX) and nitric oxide synthases (NOSs) [7], xanthine oxidase [8,9], the α-ketoglutarate dehydrogenase complex [10,11], including dihydrolipoamide dehydrogenase [12][13][14][15], and d-amino acid oxidases [16][17][18]. Nitric oxide (NO), for instance, produced from sources such as endothelial NOS, contributes to vascular homeostasis, whereas under conditions of oxidative stress such as inflammation, NO interaction with other ROS potentiates cellular damage.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA and ROS Crosstalk in Cardiac and Pulmonary Diseases

Climent

Viggiani

Lin

et al. 2020

IJMS

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Reactive oxygen species (ROS) affect many cellular functions and the proper redox balance between ROS and antioxidants contributes substantially to the physiological welfare of the cell. During pathological conditions, an altered redox equilibrium leads to increased production of ROS that in turn may cause oxidative damage. MicroRNAs (miRNAs) regulate gene expression at the post-transcriptional level contributing to all major cellular processes, including oxidative stress and cell death. Several miRNAs are expressed in response to ROS to mediate oxidative stress. Conversely, oxidative stress may lead to the upregulation of miRNAs that control mechanisms to buffer the damage induced by ROS. This review focuses on the complex crosstalk between miRNAs and ROS in diseases of the cardiac (i.e., cardiac hypertrophy, heart failure, myocardial infarction, ischemia/reperfusion injury, diabetic cardiomyopathy) and pulmonary (i.e., idiopathic pulmonary fibrosis, acute lung injury/acute respiratory distress syndrome, asthma, chronic obstructive pulmonary disease, lung cancer) compartments. Of note, miR-34a, miR-144, miR-421, miR-129, miR-181c, miR-16, miR-31, miR-155, miR-21, and miR-1/206 were found to play a role during oxidative stress in both heart and lung pathologies. This review comprehensively summarizes current knowledge in the field.

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“…Some reports have shown that ROS accumulation induces DNA damage, resulting in cell cycle arrest. Cellular senescence is a permanent cell cycle arrest induced by stress, including oxidative stress and DNA damage [32,33]. Other studies showed that premature cellular senescence caused by oxidative stress in DP compromised the interaction between the epithelium and DP cells, and the above phenomenon was observed mainly in androgenetic alopecia patients [34,35].…”

Section: Discussionmentioning

confidence: 99%

The local hypothalamic–pituitary–adrenal axis in cultured human dermal papilla cells

Lee

Nam

Kang

et al. 2020

BMC Mol and Cell Biol

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Background Stress is an important cause of skin disease, including hair loss. The hormonal response to stress is due to the HPA axis, which comprises hormones such as corticotropin releasing factor (CRF), adrenocorticotropic hormone (ACTH), and cortisol. Many reports have shown that CRF, a crucial stress hormone, inhibits hair growth and induces hair loss. However, the underlying mechanisms are still unclear. The aim of this study was to examine the effect of CRF on human dermal papilla cells (DPCs) as well as hair follicles and to investigate whether the HPA axis was established in cultured human DPCs. Results CRF inhibited hair shaft elongation and induced early catagen transition in human hair follicles. Hair follicle cells, both human DPCs and human ORSCs, expressed CRF and its receptors and responded to CRF. CRF inhibited the proliferation of human DPCs through cell cycle arrest at G2/M phase and induced the accumulation of reactive oxygen species (ROS). Anagen-related cytokine levels were downregulated in CRF-treated human DPCs. Interestingly, increases in proopiomelanocortin (POMC), ACTH, and cortisol were induced by CRF in human DPCs, and antagonists for the CRF receptor blocked the effects of this hormone. Conclusion The results of this study showed that stress can cause hair loss by acting through stress hormones. Additionally, these results suggested that a fully functional HPA axis exists in human DPCs and that CRF directly affects human DPCs as well as human hair follicles under stress conditions.

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d-amino acid oxidase promotes cellular senescence via the production of reactive oxygen species

Abstract: This study reveals a novel role of d-amino acid oxidase in promoting cellular senescence induced by genotoxic stresses via enzymatic generation of reactive oxygen species.

Cited by 20 publications

References 54 publications

LY6D-induced macropinocytosis as a survival mechanism of senescent cells

LY6D-induced macropinocytosis as a survival mechanism of senescent cells

MicroRNA and ROS Crosstalk in Cardiac and Pulmonary Diseases

The local hypothalamic–pituitary–adrenal axis in cultured human dermal papilla cells

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