41 results on '"Inuzuka, Hiroyuki"'
Search Results
2. USP7-Based Deubiquitinase-Targeting Chimeras Stabilize AMPK.
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Liu, Jing, Hu, Xiaoping, Luo, Kaixiu, Xiong, Yan, Chen, Li, Wang, Zhen, Inuzuka, Hiroyuki, Qian, Chao, Yu, Xufen, Xie, Ling, Muneer, Adil, Zhang, Dingpeng, Paulo, Joao A., Chen, Xian, Jin, Jian, and Wei, Wenyi more...
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- 2024
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3. USP7-Based Deubiquitinase-Targeting Chimeras Stabilize AMPK
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Liu, Jing, Hu, Xiaoping, Luo, Kaixiu, Xiong, Yan, Chen, Li, Wang, Zhen, Inuzuka, Hiroyuki, Qian, Chao, Yu, Xufen, Xie, Ling, Muneer, Adil, Zhang, Dingpeng, Paulo, Joao A., Chen, Xian, Jin, Jian, and Wei, Wenyi more...
- Abstract
Deubiquitinase-targeting chimeras (DUBTACs) have been recently developed to stabilize proteins of interest, which is in contrast to targeted protein degradation (TPD) approaches that degrade disease-causing proteins. However, to date, only the OTUB1 deubiquitinase has been utilized to develop DUBTACs via an OTUB1 covalent ligand, which could unexpectedly compromise the endogenous function of OTUB1 owing to its covalent nature. Here, we show for the first time that deubiquitinase USP7 can be harnessed for DUBTAC development. Based on a noncovalent ligand of USP7, we developed USP7-based DUBTACs that stabilized the ?F508-CFTR mutant protein as effectively as the previously reported OTUB1-based DUBTAC. Importantly, using two different noncovalent ligands of USP7, we developed the first AMPK DUBTACs that appear to selectively stabilize different isoforms of AMPKß, leading to elevated AMPK signaling. Overall, these results highlight that, in addition to OTUB1, USP7 can be leveraged to develop DUBTACs, thus significantly expanding the limited toolbox for targeted protein stabilization and the development of novel AMPK DUBTACs as potential therapeutics. more...
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- 2024
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4. Structurally Specific Z‑DNA Proteolysis Targeting Chimera Enables Targeted Degradation of Adenosine Deaminase Acting on RNA 1.
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Wang, Zhen, Zhang, Dingpeng, Qiu, Xing, Inuzuka, Hiroyuki, Xiong, Yan, Liu, Jing, Chen, Li, Chen, He, Xie, Ling, Kaniskan, H. Ümit, Chen, Xian, Jin, Jian, and Wei, Wenyi
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- 2024
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5. Structurally Specific Z-DNA Proteolysis Targeting Chimera Enables Targeted Degradation of Adenosine Deaminase Acting on RNA 1
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Wang, Zhen, Zhang, Dingpeng, Qiu, Xing, Inuzuka, Hiroyuki, Xiong, Yan, Liu, Jing, Chen, Li, Chen, He, Xie, Ling, Kaniskan, H. Ümit, Chen, Xian, Jin, Jian, and Wei, Wenyi
- Abstract
Given the prevalent advancements in DNA- and RNA-based PROTACs, there remains a significant need for the exploration and expansion of more specific DNA-based tools, thus broadening the scope and repertoire of DNA-based PROTACs. Unlike conventional A- or B-form DNA, Z-form DNA is a configuration that exclusively manifests itself under specific stress conditions and with specific target sequences, which can be recognized by specific reader proteins, such as ADAR1 or ZBP1, to exert downstream biological functions. The core of our innovation lies in the strategic engagement of Z-form DNA with ADAR1 and its degradation is achieved by leveraging a VHL ligand conjugated to Z-form DNA to recruit the E3 ligase. This ingenious construct engendered a series of Z-PROTACs, which we utilized to selectively degrade the Z-DNA-binding protein ADAR1, a molecule that is frequently overexpressed in cancer cells. This meticulously orchestrated approach triggers a cascade of PANoptotic events, notably encompassing apoptosis and necroptosis, by mitigating the blocking effect of ADAR1 on ZBP1, particularly in cancer cells compared with normal cells. Moreover, the Z-PROTAC design exhibits a pronounced predilection for ADAR1, as opposed to other Z-DNA readers, such as ZBP1. As such, Z-PROTAC likely elicits a positive immunological response, subsequently leading to a synergistic augmentation of cancer cell death. In summary, the Z-DNA-based PROTAC (Z-PROTAC) approach introduces a modality generated by the conformational change from B- to Z-form DNA, which harnesses the structural specificity intrinsic to potentiate a selective degradation strategy. This methodology is an inspiring conduit for the advancement of PROTAC-based therapeutic modalities, underscoring its potential for selectivity within the therapeutic landscape of PROTACs to target undruggable proteins. more...
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- 2024
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6. Methylated Nucleotide-Based Proteolysis-Targeting Chimera Enables Targeted Degradation of Methyl-CpG-Binding Protein 2.
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Wang, Zhen, Liu, Jing, Qiu, Xing, Zhang, Dingpeng, Inuzuka, Hiroyuki, Chen, Li, Chen, He, Xie, Ling, Kaniskan, H. Ümit, Chen, Xian, Jin, Jian, and Wei, Wenyi
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- 2023
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7. Prolonged hypoxia alleviates prolyl hydroxylation-mediated suppression of RIPK1 to promote necroptosis and inflammation
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Zhang, Tao, Xu, Daichao, Liu, Jianping, Wang, Min, Duan, Li-Juan, Liu, Min, Meng, Huyan, Zhuang, Yuan, Wang, Huibing, Wang, Yingnan, Lv, Mingming, Zhang, Zhengyi, Hu, Jia, Shi, Linyu, Guo, Rui, Xie, Xingxing, Liu, Hui, Erickson, Emily, Wang, Yaru, Yu, Wenyu, Dang, Fabin, Guan, Dongxian, Jiang, Cong, Dai, Xiaoming, Inuzuka, Hiroyuki, Yan, Peiqiang, Wang, Jingchao, Babuta, Mrigya, Lian, Gewei, Tu, Zhenbo, Miao, Ji, Szabo, Gyongyi, Fong, Guo-Hua, Karnoub, Antoine E., Lee, Yu-Ru, Pan, Lifeng, Kaelin, William G., Yuan, Junying, and Wei, Wenyi more...
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The prolyl hydroxylation of hypoxia-inducible factor 1α (HIF-1α) mediated by the EGLN–pVHL pathway represents a classic signalling mechanism that mediates cellular adaptation under hypoxia. Here we identify RIPK1, a known regulator of cell death mediated by tumour necrosis factor receptor 1 (TNFR1), as a target of EGLN1–pVHL. Prolyl hydroxylation of RIPK1 mediated by EGLN1 promotes the binding of RIPK1 with pVHL to suppress its activation under normoxic conditions. Prolonged hypoxia promotes the activation of RIPK1 kinase by modulating its proline hydroxylation, independent of the TNFα–TNFR1 pathway. As such, inhibiting proline hydroxylation of RIPK1 promotes RIPK1 activation to trigger cell death and inflammation. Hepatocyte-specific Vhldeficiency promoted RIPK1-dependent apoptosis to mediate liver pathology. Our findings illustrate a key role of the EGLN–pVHL pathway in suppressing RIPK1 activation under normoxic conditions to promote cell survival and a model by which hypoxia promotes RIPK1 activation through modulating its proline hydroxylation to mediate cell death and inflammation in human diseases, independent of TNFR1. more...
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- 2023
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8. Chirality-Induced Magnetoresistance Due to Thermally Driven Spin Polarization.
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Kondou, Kouta, Shiga, Masanobu, Sakamoto, Shoya, Inuzuka, Hiroyuki, Nihonyanagi, Atsuko, Araoka, Fumito, Kobayashi, Masaki, Miwa, Shinji, Miyajima, Daigo, and Otani, YoshiChika
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- 2022
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9. Delayed fluorescence from inverted singlet and triplet excited states
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Aizawa, Naoya, Pu, Yong-Jin, Harabuchi, Yu, Nihonyanagi, Atsuko, Ibuka, Ryotaro, Inuzuka, Hiroyuki, Dhara, Barun, Koyama, Yuki, Nakayama, Ken-ichi, Maeda, Satoshi, Araoka, Fumito, and Miyajima, Daigo
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Hund’s multiplicity rule states that a higher spin state has a lower energy for a given electronic configuration1. Rephrasing this rule for molecular excited states predicts a positive energy gap between spin-singlet and spin-triplet excited states, as has been consistent with numerous experimental observations over almost a century. Here we report a fluorescent molecule that disobeys Hund’s rule and has a negative singlet–triplet energy gap of −11 ± 2 meV. The energy inversion of the singlet and triplet excited states results in delayed fluorescence with short time constants of 0.2 μs, which anomalously decrease with decreasing temperature owing to the emissive singlet character of the lowest-energy excited state. Organic light-emitting diodes (OLEDs) using this molecule exhibited a fast transient electroluminescence decay with a peak external quantum efficiency of 17%, demonstrating its potential implications for optoelectronic devices, including displays, lighting and lasers. more...
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- 2022
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10. Functional analysis of the emerging roles for the KISS1/KISS1R signaling pathway in cancer metastasis
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Li, Zhenxi, Liu, Jing, Inuzuka, Hiroyuki, and Wei, Wenyi
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Cancer metastasis, a process that primary tumor cells disseminate to secondary organs, is the most lethal and least effectively treated characteristic of human cancers. Kisspeptins are proteins encoded by the KISS1gene that was originally described as a melanoma metastasis suppressor gene. Then, Kisspeptins were discovered as the natural ligands of the G-protein-coupled receptor 54 (GPR54) that is also called KISS1R. The KISS1/KISS1R signaling is essential to control GnRH secretion during puberty and to establish mammalian reproductive function through the hypothalamic-pituitary-gonadal (HPG) axis. Although KISS1 primarily plays a suppressive role in the metastasis progression in several cancer types, emerging evidence indicates that the physiological effect of KISS1/KISS1R in cancer metastasis is tissue context-dependent and still controversial. Here, we will discuss the epigenetic mechanism involved in the regulation of KISS1gene expression, the context-dependent role of KISS1/KISS1R, prometastasis/anti-metastasis signaling pathways of KISS1/KISS1R, and the perspective anticancer therapeutics via targeting KISS1/KISS1R. more...
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- 2022
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11. PCAF and SIRT1 modulate βTrCP1 protein stability in an acetylation-dependent manner
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Dang, Fabin, Jiang, Cong, Zhang, Tao, Inuzuka, Hiroyuki, and Wei, Wenyi
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- 2021
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12. Skp2 dictates cell cycle-dependent metabolic oscillation between glycolysis and TCA cycle
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Liu, Jing, Peng, Yunhua, Shi, Le, Wan, Lixin, Inuzuka, Hiroyuki, Long, Jiangang, Guo, Jianping, Zhang, Jinfang, Yuan, Min, Zhang, Shuangxi, Wang, Xun, Gao, Jing, Dai, Xiangpeng, Furumoto, Shozo, Jia, Lijun, Pandolfi, Pier Paolo, Asara, John M., Kaelin, William G., Liu, Jiankang, and Wei, Wenyi more...
- Abstract
Whether glucose is predominantly metabolized via oxidative phosphorylation or glycolysis differs between quiescent versus proliferating cells, including tumor cells. However, how glucose metabolism is coordinated with cell cycle in mammalian cells remains elusive. Here, we report that mammalian cells predominantly utilize the tricarboxylic acid (TCA) cycle in G1 phase, but prefer glycolysis in S phase. Mechanistically, coupling cell cycle with metabolism is largely achieved by timely destruction of IDH1/2, key TCA cycle enzymes, in a Skp2-dependent manner. As such, depleting SKP2abolishes cell cycle-dependent fluctuation of IDH1 protein abundance, leading to reduced glycolysis in S phase. Furthermore, elevated Skp2 abundance in prostate cancer cells destabilizes IDH1 to favor glycolysis and subsequent tumorigenesis. Therefore, our study reveals a mechanistic link between two cancer hallmarks, aberrant cell cycle and addiction to glycolysis, and provides the underlying mechanism for the coupling of metabolic fluctuation with periodic cell cycle in mammalian cells. more...
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- 2021
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13. Acetylation-dependent regulation of PD-L1 nuclear translocation dictates the efficacy of anti-PD-1 immunotherapy
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Gao, Yang, Nihira, Naoe Taira, Bu, Xia, Chu, Chen, Zhang, Jinfang, Kolodziejczyk, Aleksandra, Fan, Yizeng, Chan, Ngai Ting, Ma, Leina, Liu, Jing, Wang, Dong, Dai, Xiaoming, Liu, Huadong, Ono, Masaya, Nakanishi, Akira, Inuzuka, Hiroyuki, North, Brian J., Huang, Yu-Han, Sharma, Samanta, Geng, Yan, Xu, Wei, Liu, X. Shirley, Li, Lei, Miki, Yoshio, Sicinski, Piotr, Freeman, Gordon J., and Wei, Wenyi more...
- Abstract
Immunotherapies that target programmed cell death protein 1 (PD-1) and its ligand PD-L1 as well as cytotoxic T-lymphocyte-associated protein 4 (CTLA4) have shown impressive clinical outcomes for multiple tumours. However, only a subset of patients achieves durable responses, suggesting that the mechanisms of the immune checkpoint pathways are not completely understood. Here, we report that PD-L1 translocates from the plasma membrane into the nucleus through interactions with components of the endocytosis and nucleocytoplasmic transport pathways, regulated by p300-mediated acetylation and HDAC2-dependent deacetylation of PD-L1. Moreover, PD-L1 deficiency leads to compromised expression of multiple immune-response-related genes. Genetically or pharmacologically modulating PD-L1 acetylation blocks its nuclear translocation, reprograms the expression of immune-response-related genes and, as a consequence, enhances the anti-tumour response to PD-1 blockade. Thus, our results reveal an acetylation-dependent regulation of PD-L1 nuclear localization that governs immune-response gene expression, and thereby advocate targeting PD-L1 translocation to enhance the efficacy of PD-1/PD-L1 blockade. more...
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- 2020
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14. SCFβ‐TrCP ubiquitinates CHK1 in an AMPK‐dependent manner in response to glucose deprivation.
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Ma, Ying, Cui, Danrui, Xiong, Xiufang, Inuzuka, Hiroyuki, Wei, Wenyi, Sun, Yi, North, Brian J., and Zhao, Yongchao
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The ATR/CHK1 pathway is a key effector of cellular response to DNA damage and therefore is a critical regulator of genomic stability. While the ATR/CHK1 pathway is often inactivated by mutations, CHK1 itself is rarely mutated in human cancers. Thus, cellular levels of CHK1 likely play a key role in the maintenance of genomic stability and preventing tumorigenesis. Glucose deprivation is observed in many solid tumors due to high glycolytic rates of cancer cells and insufficient vascularization, yet cancer cells have devised mechanisms to survive in conditions of low glucose. Although CHK1 degradation through the ubiquitin–proteasome pathway following glucose deprivation has been previously reported, the detailed molecular mechanisms remain elusive. Here, we show that CHK1 is ubiquitinated and degraded upon glucose deprivation by the Skp1‐Cullin‐F‐box (β‐TrCP) E3 ubiquitin ligase. Specifically, CHK1 contains a β‐TrCP recognizable degron domain, which is phosphorylated by AMPK in response to glucose deprivation, allowing for β‐TrCP to recognize CHK1 for subsequent ubiquitination and degradation. Our results provide a novel mechanism by which glucose metabolism regulates a DNA damage effector, and imply that glucose deprivation, which is often found in solid tumor microenvironments, may enhance mutagenesis, clonal expansion, and tumor progression by triggering CHK1 degradation. Glucose deprivation is observed in many solid tumors, and cancer cells have devised mechanisms to survive in conditions of low glucose. Here, we show that CHK1, a critical regulator of genomic stability, is ubiquitinated and degraded upon glucose deprivation by the β‐TrCP E3 ubiquitin ligase. Our results indicate that glucose deprivation may enhance tumorigenesis through inactivation of the CHK1 pathway. [ABSTRACT FROM AUTHOR] more...
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- 2019
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15. Protein neddylation in lung tumorigenesis: Target validation and targeted therapy
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Zheng, Yawen, Inuzuka, Hiroyuki, Wei, Wenyi, and Sun, Yi
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Much akin to ubiquitylation, neddylation is catalyzed by a cascade of three enzymes: E1 NEDD8-activating enzyme, E2 NEDD8-conjugating enzyme (UBE2M or UBE2F), and E3 NEDD8 ligases. The best-known neddylation substrates are the members of cullin family, leading to the activation of Cullin-RING ligases, which regulate a variety of downstream biological processes largely via promoting ubiquitylation and subsequent proteasomal degradation of many key signaling proteins. Notably, neddylation enzymes and components of the Cullin-RING ligases are frequently altered in many human cancers and have been validated as promising cancer targets. As such, drug discovery efforts are underway to target neddylation-Cullin-RING ligases with a few selective small molecule inhibitors being advanced into various phases of clinical trials. This review firstly provides a brief introduction to neddylation, then focuses on lung cancer, and summarizes a wealth of current data showing how neddylation-Cullin-RING ligases are altered and affect the growth and survival of lung cancer cells, lung tumorigenesis, lung tumor microenvironment, and inflammatory response. A few reported small molecule inhibitors of neddylation enzymes as well as their activity against lung cancer cells are also summarized, and future perspectives with an ultimate goal of discovering effective treatment of lung cancer via targeting neddylation-Cullin-RING ligases are proposed. more...
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- 2024
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16. PRMT1 orchestrates with SAMTOR to govern mTORC1 methionine sensing via Arg-methylation of NPRL2.
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Jiang, Cong, Liu, Jing, He, Shaohui, Xu, Wei, Huang, Runzhi, Pan, Weijuan, Li, Xiaolong, Dai, Xiaoming, Guo, Jianping, Zhang, Tao, Inuzuka, Hiroyuki, Wang, Ping, Asara, John M., Xiao, Jianru, and Wei, Wenyi more...
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Methionine is an essential branch of diverse nutrient inputs that dictate mTORC1 activation. In the absence of methionine, SAMTOR binds to GATOR1 and inhibits mTORC1 signaling. However, how mTORC1 is activated upon methionine stimulation remains largely elusive. Here, we report that PRMT1 senses methionine/SAM by utilizing SAM as a cofactor for an enzymatic activity-based regulation of mTORC1 signaling. Under methionine-sufficient conditions, elevated cytosolic SAM releases SAMTOR from GATOR1, which confers the association of PRMT1 with GATOR1. Subsequently, SAM-loaded PRMT1 methylates NPRL2, the catalytic subunit of GATOR1, thereby suppressing its GAP activity and leading to mTORC1 activation. Notably, genetic or pharmacological inhibition of PRMT1 impedes hepatic methionine sensing by mTORC1 and improves insulin sensitivity in aged mice, establishing the role of PRMT1-mediated methionine sensing at physiological levels. Thus, PRMT1 coordinates with SAMTOR to form the methionine-sensing apparatus of mTORC1 signaling. [Display omitted] • PRMT1 senses methionine/SAM levels to mTORC1 • PRMT1 orchestrates methionine sensing in concert with SAMTOR • PRMT1 methylates NPRL2 and inhibits GATOR1 activity • PRMT1-NPRL2-mTORC1 axis confers organismal response to dietary methionine restriction Jiang et al. reveal that PRMT1 senses methionine levels to activate mTORC1 signaling via the inhibition of GATOR1 by taking SAM as a cofactor to facilitate the asymmetric dimethylation of NPRL2, which plays a key role in orchestrating the organismal response to dietary methionine restriction in aged mice. [ABSTRACT FROM AUTHOR] more...
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- 2023
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17. USP2 inhibition prevents infection with ACE2-dependent coronaviruses in vitro and is protective against SARS-CoV-2 in mice
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Dang, Fabin, Bai, Lei, Dong, Jiazhen, Hu, Xiaoping, Wang, Jingchao, Paulo, Joao A., Xiong, Yan, Liang, Xiaowei, Sun, Yishuang, Chen, Yuncai, Guo, Ming, Wang, Xin, Huang, Zhixiang, Inuzuka, Hiroyuki, Chen, Li, Chu, Chen, Liu, Jianping, Zhang, Tao, Rezaeian, Abdol-Hossein, Liu, Jing, Kaniskan, Husnu Ümit, Zhong, Bo, Zhang, Jinfang, Letko, Michael, Jin, Jian, Lan, Ke, and Wei, Wenyi more...
- Abstract
Targeting angiotensin-converting enzyme 2 (ACE2) represents a promising and effective approach to combat not only the COVID-19 pandemic but also potential future pandemics arising from coronaviruses that depend on ACE2 for infection. Here, we report ubiquitin specific peptidase 2 (USP2) as a host-directed antiviral target; we further describe the development of MS102, an orally available USP2 inhibitor with viable antiviral activity against ACE2-dependent coronaviruses. Mechanistically, USP2 serves as a physiological deubiquitinase of ACE2, and targeted inhibition with specific small-molecule inhibitor ML364 leads to a marked and reversible reduction in ACE2 protein abundance, thereby blocking various ACE2-dependent coronaviruses tested. Using human ACE2 transgenic mouse models, we further demonstrate that ML364 efficiently controls disease caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as evidenced by reduced viral loads and ameliorated lung inflammation. Furthermore, we improved the in vivo performance of ML364 in terms of both pharmacokinetics and antiviral activity. The resulting lead compound, MS102, holds promise as an oral therapeutic option for treating infections with coronaviruses that are reliant on ACE2. more...
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- 2023
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18. SCFβ-TRCPE3 ubiquitin ligase targets the tumor suppressor ZNRF3 for ubiquitination and degradation
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Ci, Yanpeng, Li, Xiaoning, Chen, Maorong, Zhong, Jiateng, North, Brian, Inuzuka, Hiroyuki, He, Xi, Li, Yu, Guo, Jianping, and Dai, Xiangpeng
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Wnt signaling has emerged as a major regulator of tissue development by governing the self-renewal and maintenance of stem cells in most tissue types. As a key upstream regulator of the Wnt pathway, the transmembrane E3 ligase ZNRF3 has recently been established to play a role in negative regulation of Wnt signaling by targeting Frizzled (FZD) receptor for ubiquitination and degradation. However, the upstream regulation of ZNRF3, in particular the turnover of ZNRF3, is still unclear. Here we report that ZNRF3 is accumulated in the presence of proteasome inhibitor treatment independent of its E3-ubiquitin ligase activity. Furthermore, the Cullin 1-specific SCF complex containing β-TRCP has been identified to directly interact with and ubiquitinate ZNRF3 thereby regulating its protein stability. Similar with the degradation of β-catenin by β-TRCP, ZNRF3 is ubiquitinated by β-TRCP in both CKI-phosphorylation- and degron-dependent manners. Thus, our findings not only identify a novel substrate for β-TRCP oncogenic regulation, but also highlight the dual regulation of Wnt signaling by β-TRCP in a context-dependent manner where β-TRCP negatively regulates Wnt signaling by targeting β-catenin, and positively regulates Wnt signaling by targeting ZNRF3. more...
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- 2018
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19. Prostate cancer–associated SPOP mutations confer resistance to BET inhibitors through stabilization of BRD4
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Dai, Xiangpeng, Gan, Wenjian, Li, Xiaoning, Wang, Shangqian, Zhang, Wei, Huang, Ling, Liu, Shengwu, Zhong, Qing, Guo, Jianping, Zhang, Jinfang, Chen, Ting, Shimizu, Kouhei, Beca, Francisco, Blattner, Mirjam, Vasudevan, Divya, Buckley, Dennis L, Qi, Jun, Buser, Lorenz, Liu, Pengda, Inuzuka, Hiroyuki, Beck, Andrew H, Wang, Liewei, Wild, Peter J, Garraway, Levi A, Rubin, Mark A, Barbieri, Christopher E, Wong, Kwok-Kin, Muthuswamy, Senthil K, Huang, Jiaoti, Chen, Yu, Bradner, James E, and Wei, Wenyi more...
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The bromodomain and extraterminal (BET) family of proteins comprises four members—BRD2, BRD3, BRD4 and the testis-specific isoform BRDT—that largely function as transcriptional coactivators and play critical roles in various cellular processes, including the cell cycle, apoptosis, migration and invasion. BET proteins enhance the oncogenic functions of major cancer drivers by elevating the expression of these drivers, such as c-Myc in leukemia, or by promoting the transcriptional activities of oncogenic factors, such as AR and ERG in prostate cancer. Pathologically, BET proteins are frequently overexpressed and are clinically linked to various types of human cancer; they are therefore being pursued as attractive therapeutic targets for selective inhibition in patients with cancer. To this end, a number of bromodomain inhibitors, including JQ1 and I-BET, have been developed and have shown promising outcomes in early clinical trials. Although resistance to BET inhibitors has been documented in preclinical models, the molecular mechanisms underlying acquired resistance are largely unknown. Here we report that cullin-3SPOPearmarks BET proteins, including BRD2, BRD3 and BRD4, for ubiquitination-mediated degradation. Pathologically, prostate cancer–associated SPOP mutants fail to interact with and promote the degradation of BET proteins, leading to their elevated abundance in SPOP-mutant prostate cancer. As a result, prostate cancer cell lines and organoids derived from individuals harboring SPOP mutations are more resistant to BET-inhibitor-induced cell growth arrest and apoptosis. Therefore, our results elucidate the tumor-suppressor role of SPOP in prostate cancer in which it acts as a negative regulator of BET protein stability and also provide a molecular mechanism for resistance to BET inhibitors in individuals with prostate cancer bearing SPOP mutations. more...
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- 2017
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20. G1 cyclins link proliferation, pluripotency and differentiation of embryonic stem cells
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Liu, Lijun, Michowski, Wojciech, Inuzuka, Hiroyuki, Shimizu, Kouhei, Nihira, Naoe Taira, Chick, Joel M., Li, Na, Geng, Yan, Meng, Alice Y., Ordureau, Alban, Kołodziejczyk, Aleksandra, Ligon, Keith L., Bronson, Roderick T., Polyak, Kornelia, Harper, J. Wade, Gygi, Steven P., Wei, Wenyi, and Sicinski, Piotr more...
- Abstract
Progression of mammalian cells through the G1 and S phases of the cell cycle is driven by the D-type and E-type cyclins. According to the current models, at least one of these cyclin families must be present to allow cell proliferation. Here, we show that several cell types can proliferate in the absence of all G1 cyclins. However, following ablation of G1 cyclins, embryonic stem (ES) cells attenuated their pluripotent characteristics, with the majority of cells acquiring the trophectodermal cell fate. We established that G1 cyclins, together with their associated cyclin-dependent kinases (CDKs), phosphorylate and stabilize the core pluripotency factors Nanog, Sox2 and Oct4. Treatment of murine ES cells, patient-derived glioblastoma tumour-initiating cells, or triple-negative breast cancer cells with a CDK inhibitor strongly decreased Sox2 and Oct4 levels. Our findings suggest that CDK inhibition might represent an attractive therapeutic strategy by targeting glioblastoma tumour-initiating cells, which depend on Sox2 to maintain their tumorigenic potential. more...
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- 2017
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21. Methylated Nucleotide-Based Proteolysis-Targeting Chimera Enables Targeted Degradation of Methyl-CpG-Binding Protein 2
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Wang, Zhen, Liu, Jing, Qiu, Xing, Zhang, Dingpeng, Inuzuka, Hiroyuki, Chen, Li, Chen, He, Xie, Ling, Kaniskan, H. Ümit, Chen, Xian, Jin, Jian, and Wei, Wenyi
- Abstract
Methyl-CpG-binding protein 2 (MeCP2), a reader of DNA methylation, has been extensively investigated for its function in neurological and neurodevelopmental disorders. Emerging evidence indicates that MeCP2 exerts an oncogenic function in cancer; however, the endeavor to develop a MeCP2-targeted therapy remains a challenge. This work attempts to address it by introducing a methylated nucleotide-based targeting chimera termed methyl-proteolysis-targeting chimera (methyl-PROTAC). The methyl-PROTAC incorporates a methylated cytosine into an oligodeoxynucleotide moiety to recruit MeCP2 for targeted degradation in a von Hippel-Lindau- and proteasome-dependent manner, thus displaying antiproliferative effects in cancer cells reliant on MeCP2 overexpression. This selective cytotoxicity endows methyl-PROTAC with the capacity to selectively eliminate cancer cells that are addicted to the overexpression of the MeCP2 oncoprotein. Furthermore, methyl-PROTAC-mediated MeCP2 degradation induces apoptosis in cancer cells. These findings underscore the therapeutic potential of methyl-PROTAC to degrade undruggable epigenetic regulatory proteins. In summary, the development of methyl-PROTAC introduces an innovative strategy by designing a modified nucleotide-based degradation approach for manipulating epigenetic factors, thereby representing a promising avenue for the advancement of PROTAC-based therapeutics. more...
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- 2023
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22. Chapter 12 Experimental Approaches to Investigate the Proteasomal Degradation Pathways Involved in Regulation of Apoptosis.
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Tseng, Alan, Inuzuka, Hiroyuki, Gao, Daming, Singh, Amrik, and Wei, Wenyi
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Abstract: Ubiquitin‐mediated proteolysis plays a major role in a variety of cellular functions, including cell metabolism, cell cycle progression, cellular response to DNA damage, and programmed cell death. In most cases, the crucial regulators involved in the control of these diverse cellular functions are modified by specific E3 ubiquitin ligases through the attachment of multiple ubiquitin molecules, a signal that triggers the subsequent destruction by the 26S proteasome complex. Recent studies revealed that the proteasomal degradation pathway regulates the cellular apoptosis process on multiple levels. Thus, a better understanding of the molecular mechanisms that underlie the ubiquitination and destruction of these specific regulators of apoptosis will provide us with insight on how apoptosis is properly controlled in normal cells and how tumor cells evade the apoptosis pathways. This chapter provides an overview of the common methods used to examine whether a target protein is ubiquitinated, as well as the protocols to examine how a putative E3 ligase controls the destruction of the target protein. [Copyright &y& Elsevier] more...
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- 2008
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23. SCF-Mediated Cdh1 Degradation Defines a Negative Feedback System that Coordinates Cell-Cycle Progression
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Fukushima, Hidefumi, Ogura, Kohei, Wan, Lixin, Lu, Ying, Li, Victor, Gao, Daming, Liu, Pengda, Lau, Alan W., Wu, Tao, Kirschner, Marc W., Inuzuka, Hiroyuki, and Wei, Wenyi
- Abstract
Proper cell-cycle transitions are driven by waves of ubiquitin-dependent degradation of key regulators by the anaphase-promoting complex (APC) and Skp1-Cullin1-F-box (SCF) E3 ubiquitin ligase complexes. But precisely how APC and SCF activities are coordinated to regulate cell-cycle progression remains largely unclear. We previously showed that APC/Cdh1 earmarks the SCF component Skp2 for degradation. Here, we continue to report that SCFβ-TRCPreciprocally controls APC/Cdh1 activity by governing Cdh1 ubiquitination and subsequent degradation. Furthermore, we define both cyclin A and Plk1, two well-known Cdh1 substrates, as upstream modifying enzymes that promote Cdh1 phosphorylation to trigger Cdh1 ubiquitination and subsequent degradation by SCFβ-TRCP. Thus, our work reveals a negative repression mechanism for SCF to control APC, thereby illustrating an elegant dual repression system between these two E3 ligase complexes to create the ordered cascade of APC and SCF activities governing timely cell-cycle transitions. more...
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- 2013
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24. Cdc20: A Potential Novel Therapeutic Target for Cancer Treatment
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Wang, Zhiwei, Wan, Lixin, Zhong, Jiateng, Inuzuka, Hiroyuki, Liu, Pengda, Sarkar, Fazlul H., and Wei, Wenyi
- Abstract
The Anaphase Promoting Complex (APC) has been characterized to play pivotal roles in regulating the timely cell cycle progression by forming two functionally distinct E3 ubiquitin ligase sub-complexes, APCCdc20 and APCCdh1. Interestingly, recent studies have shown that Cdh1 is functioning as a tumor suppressor whereas Cdc20 may function as an oncoprotein to promote the development and progression of human cancers. In this review, we will discuss the physiological role of Cdc20 and its downstream substrates in vitro and in the transgenic mouse model reminiscent of the pathogenesis of human cancers. Furthermore, we summarize recent findings to indicate that Cdc20 may represent a promising therapeutic target, thus development of Cdc20 inhibitors could be useful for achieving better treatment outcome of cancer patients. more...
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- 2013
25. SCFβ-TRCP suppresses angiogenesis and thyroid cancer cell migration by promoting ubiquitination and destruction of VEGF receptor 2
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Shaik, Shavali, Nucera, Carmelo, Inuzuka, Hiroyuki, Gao, Daming, Garnaas, Maija, Frechette, Gregory, Harris, Lauren, Wan, Lixin, Fukushima, Hidefumi, Husain, Amjad, Nose, Vania, Fadda, Guido, Sadow, Peter M., Goessling, Wolfram, North, Trista, Lawler, Jack, and Wei, Wenyi more...
- Abstract
The incidence of human papillary thyroid cancer (PTC) is increasing and an aggressive subtype of this disease is resistant to treatment with vascular endothelial growth factor receptor 2 (VEGFR2) inhibitor. VEGFR2 promotes angiogenesis by triggering endothelial cell proliferation and migration. However, the molecular mechanisms governing VEGFR2 stability in vivo remain unknown. Additionally, whether VEGFR2 influences PTC cell migration is not clear. We show that the ubiquitin E3 ligase SCFβ-TRCP promotes ubiquitination and destruction of VEGFR2 in a casein kinase I (CKI)–dependent manner. β-TRCP knockdown or CKI inhibition causes accumulation of VEGFR2, resulting in increased activity of signaling pathways downstream of VEGFR2. β-TRCP–depleted endothelial cells exhibit enhanced migration and angiogenesis in vitro. Furthermore, β-TRCP knockdown increased angiogenesis and vessel branching in zebrafish. Importantly, we found an inverse correlation between β-TRCP protein levels and angiogenesis in PTC. We also show that β-TRCP inhibits cell migration and decreases sensitivity to the VEGFR2 inhibitor sorafenib in poorly differentiated PTC cells. These results provide a new biomarker that may aid a rational use of tyrosine kinase inhibitors to treat refractory PTC. more...
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- 2012
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26. SCFFbw7Modulates the NFκB Signaling Pathway by Targeting NFκB2 for Ubiquitination and Destruction
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Fukushima, Hidefumi, Matsumoto, Akinobu, Inuzuka, Hiroyuki, Zhai, Bo, Lau, Alan W., Wan, Lixin, Gao, Daming, Shaik, Shavali, Yuan, Min, Gygi, Steven P., Jimi, Eijiro, Asara, John M., Nakayama, Keiko, Nakayama, Keiichi I., and Wei, Wenyi more...
- Abstract
The NFκB/Rel family of proteins play critical roles in a variety of cellular processes. Thus, their physiological activation is tightly controlled. Recently, the NFκB2/p100 precursor has been characterized as the fourth IκB type of suppressor for NFκB. However, the molecular mechanism(s) underlying regulated destruction of NFκB2 remains largely unknown. Here, we report that, unlike other IκBs, ubiquitination and destruction of NFκB2 are governed by SCFFbw7in a GSK3-dependent manner. In Fbw7−/−cells, elevated expression of NFκB2/p100 leads to a subsequent reduction in NFκB signaling pathways and elevated sensitivity to TNFα-induced cell death. Reintroducing wild-type Fbw7, but not disease-derived mutant forms of Fbw7, rescues NFκB activity. Furthermore, T cell-specific depletion of Fbw7 also leads to reduced NFκB activity and perturbed T cell differentiation. Therefore, our work identifies Fbw7 as a physiological E3 ligase controlling NFκB2′s stability. It further implicates that Fbw7 might exert its tumor-suppressor function by regulating NFκB activity. more...
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- 2012
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27. Cdh1 Regulates Cell Cycle through Modulating the Claspin/Chk1 and the Rb/E2F1 Pathways
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Gao, Daming, Inuzuka, Hiroyuki, Korenjak, Michael, Tseng, Alan, Wu, Tao, Wan, Lixin, Kirschner, Marc, Dyson, Nicholas, and Wei, Wenyi
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APC/Cdh1 is a major cell cycle regulator and its function has been implicated in DNA damage repair; however, its exact role remains unclear. Using affinity purification coupled with mass spectrometry, we identified Claspin as a novel Cdh1-interacting protein and further demonstrated that Claspin is a novel Cdh1 ubiquitin substrate. As a result, inactivation of Cdh1 leads to activation of the Claspin/Chk1 pathway. Previously, we demonstrated that Rb interacts with Cdh1 to influence its ability to degrade Skp2. Here, we report that Cdh1 reciprocally regulates the Rb pathway through competing with E2F1 to bind the hypophosphorylated form of Rb. Although inactivation of Cdh1 in HeLa cells, with defective p53/Rb pathways, led to premature S phase entry, acute depletion of Cdh1 in primary human fibroblasts resulted in premature senescence. Acute loss of many other major tumor suppressors, including PTEN and VHL, also induces premature senescence in a p53- or Rb-dependent manner. Similarly, we showed that inactivation of the p53/Rb pathways by overexpression of SV40 LT-antigen partially reversed Cdh1 depletion–induced growth arrest. Therefore, loss of Cdh1 is only beneficial to cells with abnormal p53 and Rb pathways, which helps explain why Cdh1 loss is not frequently found in many tumors. more...
- Published
- 2009
28. Cdh1 Regulates Cell Cycle through Modulating the Claspin/Chk1 and the Rb/E2F1 Pathways
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Gao, Daming, Inuzuka, Hiroyuki, Korenjak, Michael, Tseng, Alan, Wu, Tao, Wan, Lixin, Kirschner, Marc, Dyson, Nicholas, and Wei, Wenyi
- Abstract
APC/Cdh1 is a major cell cycle regulator and its function has been implicated in DNA damage repair; however, its exact role remains unclear. Using affinity purification coupled with mass spectrometry, we identified Claspin as a novel Cdh1-interacting protein and further demonstrated that Claspin is a novel Cdh1 ubiquitin substrate. As a result, inactivation of Cdh1 leads to activation of the Claspin/Chk1 pathway. Previously, we demonstrated that Rb interacts with Cdh1 to influence its ability to degrade Skp2. Here, we report that Cdh1 reciprocally regulates the Rb pathway through competing with E2F1 to bind the hypophosphorylated form of Rb. Although inactivation of Cdh1 in HeLa cells, with defective p53/Rb pathways, led to premature S phase entry, acute depletion of Cdh1 in primary human fibroblasts resulted in premature senescence. Acute loss of many other major tumor suppressors, including PTEN and VHL, also induces premature senescence in a p53- or Rb-dependent manner. Similarly, we showed that inactivation of the p53/Rb pathways by overexpression of SV40 LT-antigen partially reversed Cdh1 depletion–induced growth arrest. Therefore, loss of Cdh1 is only beneficial to cells with abnormal p53 and Rb pathways, which helps explain why Cdh1 loss is not frequently found in many tumors. more...
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- 2009
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29. Acetylation-dependent regulation of BRAF oncogenic function
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Dai, Xiangpeng, Zhang, Xiaoling, Yin, Qing, Hu, Jia, Guo, Jianping, Gao, Yang, Snell, Aidan H., Inuzuka, Hiroyuki, Wan, Lixin, and Wei, Wenyi
- Abstract
Aberrant BRAF activation, including the BRAFV600Emutation, is frequently observed in human cancers. However, it remains largely elusive whether other types of post-translational modification(s) in addition to phosphorylation and ubiquitination-dependent regulation also modulate BRAF kinase activity. Here, we report that the acetyltransferase p300 activates the BRAF kinase by promoting BRAF K601 acetylation, a process that is antagonized by the deacetylase SIRT1. Notably, K601 acetylation facilitates BRAF dimerization with RAF proteins and KSR1. Furthermore, K601 acetylation promotes melanoma cell proliferation and contributes to BRAFV600Einhibitor resistance in BRAFV600Eharboring melanoma cells. As such, melanoma patient-derived K601E oncogenic mutation mimics K601 acetylation to augment BRAF kinase activity. Our findings, therefore, uncover a layer of BRAF regulation and suggest p300 hyperactivation or SIRT1deficiency as potential biomarkers to determine ERK activation in melanomas. more...
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- 2022
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30. Chirality-Induced Magnetoresistance Due to Thermally Driven Spin Polarization
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Kondou, Kouta, Shiga, Masanobu, Sakamoto, Shoya, Inuzuka, Hiroyuki, Nihonyanagi, Atsuko, Araoka, Fumito, Kobayashi, Masaki, Miwa, Shinji, Miyajima, Daigo, and Otani, YoshiChika
- Abstract
Chirality-induced current-perpendicular-to-plane magnetoresistance (CPP-MR) originates from current-induced spin polarization in molecules. The current-induced spin polarization is widely recognized as a fundamental principle of chiral-induced spin selectivity (CISS). In this study, we investigate chirality-induced current-in-plane magnetoresistance (CIP-MR) in a chiral molecule/ferromagnetic metal bilayer at room temperature. In contrast to CPP-MR, CIP-MR observed in the present study requires no bias charge current through the molecule. The temperature dependence of CIP-MR suggests that thermally driven spontaneous spin polarization in chiral molecules is the key to the observed MR. The novel MR is consistent with recent CISS-related studies, that is, chiral molecules in contact with a metallic surface possess a finite spin polarization. more...
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- 2022
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31. STO-609, a Specific Inhibitor of the Ca2+/Calmodulin-dependent Protein Kinase Kinase*
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Tokumitsu, Hiroshi, Inuzuka, Hiroyuki, Ishikawa, Yumi, Ikeda, Masahiko, Saji, Ikutaro, and Kobayashi, Ryoji
- Abstract
STO-609, a selective inhibitor of Ca2+/calmodulin-dependent protein kinase kinase (CaM-KK) was synthesized, and its inhibitory properties were investigated both in vitroand in vivo. STO-609 inhibits the activities of recombinant CaM-KKα and CaM-KKβ isoforms, with Kivalues of 80 and 15 ng/ml, respectively, and also inhibits their autophosphorylation activities. Comparison of the inhibitory potency of the compound against various protein kinases revealed that STO-609 is highly selective for CaM-KK without any significant effect on the downstream CaM kinases (CaM-KI and -IV), and the IC50value of the compound against CaM-KII is ∼10 μg/ml. STO-609 inhibits constitutively active CaM-KKα (glutathione S-transferase (GST)-CaM-KK-(84–434)) as well as the wild-type enzyme. Kinetic analysis indicates that the compound is a competitive inhibitor of ATP. In transfected HeLa cells, STO-609 suppresses the Ca2+-induced activation of CaM-KIV in a dose-dependent manner. In agreement with this observation, the inhibitor significantly reduces the endogenous activity of CaM-KK in SH-SY5Y neuroblastoma cells at a concentration of 1 μg/ml (∼80% inhibitory rate). Taken together, these results indicate that STO-609 is a selective and cell-permeable inhibitor of CaM-KK and that it may be a useful tool for evaluating the physiological significance of the CaM-KK-mediated pathway in vivoas well as in vitro. more...
- Published
- 2002
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32. Interplay between protein acetylation and ubiquitination controls MCL1 protein stability
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Shimizu, Kouhei, Gi, Min, Suzuki, Shugo, North, Brian J., Watahiki, Asami, Fukumoto, Satoshi, Asara, John M., Tokunaga, Fuminori, Wei, Wenyi, and Inuzuka, Hiroyuki
- Abstract
The anti-apoptotic myeloid cell leukemia 1 (MCL1) protein belongs to the pro-survival BCL2 family and is frequently amplified or elevated in human cancers. MCL1 is highly unstable, with its stability being regulated by phosphorylation and ubiquitination. Here, we identify acetylation as another critical post-translational modification regulating MCL1 protein stability. We demonstrate that the lysine acetyltransferase p300 targets MCL1 at K40 for acetylation, which is counteracted by the deacetylase sirtuin 3 (SIRT3). Mechanistically, acetylation enhances MCL1 interaction with USP9X, resulting in deubiquitination and subsequent MCL1 stabilization. Therefore, ectopic expression of acetylation-mimetic MCL1 promotes apoptosis evasion of cancer cells, enhances colony formation potential, and facilitates xenografted tumor progression. We further demonstrate that elevated MCL1 acetylation sensitizes multiple cancer cells to pharmacological inhibition of USP9X. These findings reveal that acetylation of MCL1 is a critical post-translational modification enhancing its oncogenic function and provide a rationale for developing innovative therapeutic strategies for MCL1-dependent tumors. more...
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- 2021
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33. Differential Regulation of Immediate Early Gene Expression in Preadipocyte Cells through Multiple Signaling Pathways
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Inuzuka, Hiroyuki, Nanbu-Wakao, Rika, Masuho, Yasuhiko, Muramatsu, Masa-aki, Tojo, Hideaki, and Wakao, Hiroshi
- Abstract
Using digoxigenin (DIG)-based differential hybridization, a series of immediate early genes (IEG) was identified following the adipogenic stimulation in 3T3-L1 preadipocyte cells. Most of the known IEGs were identified as well as new members such as zf9 and Stra13. To delineate possible signaling pathways accounting for these gene expression, a subset of specific kinase inhibitors, SB203580, PD98059, rapamycin, LY294002, and Ro-32-0432, which inhibit p38 (HOG), MEK (MAPKK), S6 kinase, PI3 kinase, and protein kinase C (PKC), respectively, were employed. The IEGs were classified into three categories according to their susceptibility to the inhibitors. Expression of the first group (c-fos, jun-B, egr-1, tis11, tis21, thrombospondin-1, erp, thyroid hormone receptor [N-10], cyr61, and zf9) was mainly dependent on PKC and MEK pathways, while that of the second class (gene33 and tis10) exhibited an additional dependence on PI3 kinase pathways. The third one (Id-3, gly96, and Stra13) was characterized in that none of these inhibitors interfered with gene expression. Our results suggest that the induction of IEGs by the adipogenic stimuli is mediated by common as well as distinct signaling pathways. more...
- Published
- 1999
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34. Differential expression of R- and N-cadherin in neural and mesodermal tissues during early chicken development
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Inuzuka, Hiroyuki, Redies, Christoph, and Takeichi, Masatoshi
- Abstract
R-cadherin is a newly identified member of the cadherin family of cell adhesion receptors. The expression of R-cadherin in early chicken embryos was studied using affinity-purified antibodies to this molecule, comparing it with that of N-cadherin. Inununoblot analysis of various organs of 10.5-day embryos showed that R-cadherin is most abundantly expressed in the retina and brain. Immunostaining of the cervical and thoracic regions of embryos revealed that R- and N-cadherin are expressed in all neural tissues. In the neural tube, R-cadherin appears at around stage 21, although N-cadherin expression begins at a much earlier stage. The distribution of R-cadherin in the neural tube differs from that of N-cadherin; for example, some regions of the tube express only R-cadherin, and other regions only N-cadherin. In the peripheral ganglia, these two cadherins are also expressed in different patterns which change during development. Some mesenchymal tissues including the notochord, the myotome, myotubes and perichondria also express these cadherins, again in different patterns. Thus, R- and N-cadherin are differentially expressed in all the tissues examined, and they may contribute to the spatial segregation of heterogeneous cells in a tissue. more...
- Published
- 1991
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35. Author Correction: Sin1 phosphorylation impairs mTORC2 complex integrity and inhibits downstream Akt signalling to suppress tumorigenesis
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Liu, Pengda, Gan, Wenjian, Inuzuka, Hiroyuki, Lazorchak, Adam S., Gao, Daming, Arojo, Omotooke, Liu, Dou, Wan, Lixin, Zhai, Bo, Yu, Yonghao, Yuan, Min, Kim, Byeong Mo, Shaik, Shavali, Menon, Suchithra, Gygi, Steven P., Lee, Tae Ho, Asara, John M., Manning, Brendan D., Blenis, John, Su, Bing, and Wei, Wenyi more...
- Abstract
In the version of this Article originally published, the labels for Rictor and mTOR in the whole cell lysate (WCL) blots were swapped in Fig. 3b and the mTOR blot was placed upside down. Unprocessed blots of mTOR were also missing from Supplementary Fig. 9. The corrected Figs are shown below. In addition, control blots for the mTOR antibody (Cell Signalling Technology #2972) were also missing. These are now provided below, as Fig. 9, and show that the lower band is likely non-specific. more...
- Published
- 2019
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36. Author Correction: Skp2 dictates cell cycle-dependent metabolic oscillation between glycolysis and TCA cycle
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Liu, Jing, Peng, Yunhua, Shi, Le, Wan, Lixin, Inuzuka, Hiroyuki, Long, Jiangang, Guo, Jianping, Zhang, Jinfang, Yuan, Min, Zhang, Shuangxi, Wang, Xun, Gao, Jing, Dai, Xiangpeng, Furumoto, Shozo, Jia, Lijun, Pandolfi, Pier Paolo, Asara, John M., Kaelin, William G., Liu, Jiankang, and Wei, Wenyi more...
- Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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- 2021
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37. Hunting the subset-specific genes of neuroblastoma: Expression profiling and differential screening of the full-length-enriched oligo-capping cDNA libraries
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Ohira, Miki, Shishikura, Tomotane, Kawamoto, Takemasa, Inuzuka, Hiroyuki, Morohashi, Aiko, Takayasu, Hajime, Kageyama, Hajime, Takada, Naoyuki, Takahashi, Masato, Sakiyama, Shigeru, Suzuki, Yutaka, Sugano, Sumio, Kuma, Hidekazu, Nozawa, Iwao, and Nakagawara, Akira more...
- Abstract
Neuroblastoma (NBL) has a distinct nature in different prognostic subgroups. To understand the molecular mechanism of NBL's genesis and biology as well as that of the neural crest development, we constructed full-length-enriched cDNA libraries by an oligo-capping method from two different subsets of primary NBL, one with favorable biology and the other with MYCN amplification. Sequencing analysis of these libraries revealed that the expression profile was markedly different between both subsets. To identify the genes differentially expressed between the subsets, semi-quantitative RT-PCR analyses are proceeding. So far, 54 transcripts have been found to be expressed at high levels in favorable NBLs, and significantly at low levels in unfavorable NBLs. Med. Pediatr. Oncol. 35:547549, 2000. © 2000 Wiley-Liss, Inc. more...
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- 2000
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38. Skp2-dependent reactivation of AKT drives resistance to PI3K inhibitors
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Clement, Emilie, Inuzuka, Hiroyuki, Nihira, Naoe T., Wei, Wenyi, and Toker, Alex
- Abstract
Resistance to PI3K inhibitors in triple-negative breast cancer is mediated by AKT reactivation by the ubiquitin ligase Skp2.
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- 2018
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39. Acetylation-dependent regulation of MDM2 E3 ligase activity dictates its oncogenic function
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Nihira, Naoe T., Ogura, Kohei, Shimizu, Kouhei, North, Brian J., Zhang, Jinfang, Gao, Daming, Inuzuka, Hiroyuki, and Wei, Wenyi
- Abstract
Acetylation of MDM2 promotes its oncogenic function by blocking its self-ubiquitination while enhancing its ubiquitination of the tumor suppressor p53.
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- 2017
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40. The SCFβ-TRCPE3 ubiquitin ligase complex targets Lipin1 for ubiquitination and degradation to promote hepatic lipogenesis
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Shimizu, Kouhei, Fukushima, Hidefumi, Ogura, Kohei, Lien, Evan C., Nihira, Naoe Taira, Zhang, Jinfang, North, Brian J., Guo, Ailan, Nagashima, Katsuyuki, Nakagawa, Tadashi, Hoshikawa, Seira, Watahiki, Asami, Okabe, Koji, Yamada, Aya, Toker, Alex, Asara, John M., Fukumoto, Satoshi, Nakayama, Keiichi I., Nakayama, Keiko, Inuzuka, Hiroyuki, and Wei, Wenyi more...
- Abstract
The targeting of Lipin1 by the SCFβ-TRCPE3 ubiquitin ligase complex enhances lipid synthesis and accumulation in the liver.
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- 2017
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41. Effect of n=1 Buffer Layers on n=2 and n=3 Thin Films of Bi2Sr2Can-1CunOy
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Takahiro Oku, Takahiro Oku, Osamu Ajisaka, Osamu Ajisaka, Hiroyuki Inuzuka, Hiroyuki Inuzuka, Yuuji Horie, Yuuji Horie, Teruaki Nomiyama, Teruaki Nomiyama, and Tomoyuki Miyazaki, Tomoyuki Miyazaki more...
- Abstract
The effect of n=1(2201) buffer layers on n=2(2212) and n=3(2223) thin films of Bi2Sr2Can-1CunOywas investigated to reduce the strain caused by the lattice mismatch between the films and the substrates. The bilayer thin films of 2223/2201 and 2212/2201 were grown epitaxially on SrTiO3(100) substrates by dc sputtering. When the thickness of the buffer layer was 10-25 nm, the superconducting transition temperature increased by ?20 K for 2223/2201 and by ?6 K for 2212/2201. The increase was attributed to the reduction of the strain from the experimental results of the full width at half-maximum of X-ray diffraction peaks, the length along the c-axis and the roughness of the film surface. more...
- Published
- 1998
- Full Text
- View/download PDF
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