Article
Biochemistry & Molecular Biology
Sharadha Dayalan Naidu, Plamena R. Angelova, Elena V. Knatko, Chiara Leonardi, Miroslav Novak, Laureano de la Vega, Ian G. Ganley, Andrey Y. Abramov, Albena T. Dinkova-Kostova
Summary: Transcription factor Nrf2 plays a crucial role in maintaining cellular redox homeostasis and mitochondrial health in lung cancer cells with loss-of-function Keap1 mutations.
FREE RADICAL BIOLOGY AND MEDICINE
(2023)
Article
Biology
Yuta Horie, Takafumi Suzuki, Jin Inoue, Tatsuro Iso, Geoffrey Wells, Terry W. Moore, Tsunehiro Mizushima, Albena T. Dinkova-Kostova, Takuma Kasai, Takashi Kamei, Seizo Koshiba, Masayuki Yamamoto
Summary: This study reveals that the dissociation of Keap1 from Nrf2, known as the Hinge-Latch mechanism, is triggered by Keap1-Nrf2 inhibitors and occurs during p62-mediated Nrf2 activation, rather than by electrophilic Nrf2 inducers. Insights gained from this research can be used for the development of Nrf2 activators targeting the Keap1-Nrf2 interaction.
COMMUNICATIONS BIOLOGY
(2021)
Article
Cell Biology
Julia Katharina Charlotte Kress, Christina Jessen, Anita Hufnagel, Werner Schmitz, Thamara Nishida Xavier da Silva, Ancely Ferreira dos Santos, Laura Mosteo, Colin R. Goding, Jose Pedro Friedmann Angeli, Svenja Meierjohann
Summary: The redox regulator NRF2 is activated during oxidative and electrophilic stress and is involved in redox regulation, metabolism, tumor therapy resistance, and immune suppression. This study reveals a previously unrecognized link between the integrated stress response (ISR) and NRF2, mediated by the ISR effector ATF4. NRF2 supports ATF4-induced cells by increasing cystine uptake and upregulating thioredoxin-related genes. These findings highlight the importance of the NRF2 response in cellular resilience.
Article
Biochemistry & Molecular Biology
Roslin J. Adamson, N. Connor Payne, Sergio G. Bartual, Ralph Mazitschek, Alex N. Bullock
Summary: KEAP1 promotes the ubiquitin-dependent degradation of NRF2 by assembling into a CUL3-dependent ubiquitin ligase complex. Oxidative and electrophilic stress inhibit KEAP1, allowing NRF2 to accumulate for stress response gene transactivation. The crystal structure of the BTB and 3-box domains of human KEAP1 in complex with the CUL3 N-terminal domain revealed a heterotetrameric assembly with 2:2 stoichiometry. The developed TRFRET-based assay system and binding profile data provide valuable insights into the KEAP1-CUL3 interaction.
FREE RADICAL BIOLOGY AND MEDICINE
(2023)
Article
Biochemistry & Molecular Biology
Andrew G. Manford, Elijah L. Mena, Karen Y. Shih, Christine L. Gee, Rachael McMinimy, Brenda Martinez-Gonzalez, Rumi Sherriff, Brandon Lew, Madeline Zoltek, Fernando Rodriguez-Perez, Makda Woldesenbet, John Kuriyan, Michael Rape
Summary: Oxidative phosphorylation not only produces ATP, but also generates reactive oxygen species. Cells alleviate reductive stress by ubiquitylating and degrading FNIP1, which relies on zinc as a molecular glue during this process.
Article
Cell Biology
Mengyi Wang, Jingyuan Tang, Shiwu Zhang, Kemiao Pang, Yajun Zhao, Ning Liu, Jiayi Huang, Jiaxin Kang, Shiyun Dong, Hongxia Li, Zhen Tian, Binhong Duan, Fanghao Lu, Weihua Zhang
Summary: In this study, the researchers investigated the effects of hydrogen sulfide (H2S) on diabetic cardiomyopathy (DCM) in mice and cardiomyocytes. They found that exogenous H2S restored its levels in the hearts of diabetic mice and cardiomyocytes exposed to high glucose and palmitate. H2S activated the Nrf2/GPx4/GSH pathway, suppressed ferroptosis, and mitigated mitochondrial apoptosis in db/db mice. The researchers also discovered that H2S facilitated the sulfhydration of Syvn1, which increased the ubiquitination level of Keap1 and promoted Nrf2 nuclear translocation. Overall, exogenous H2S showed potential therapeutic effects on DCM.
CELL DEATH DISCOVERY
(2023)
Article
Biochemistry & Molecular Biology
Shanshan Wang, Taishu Wang, Xuehong Zhang, Shaoxuan Cheng, Chaoqun Chen, Guoheng Yang, Fuqiang Wang, Ruilin Wang, Qingqing Zhang, Dian Yang, Yingqiu Zhang, Shuyan Liu, Hongqiang Qin, Quentin Liu, Han Liu
Summary: This study reveals the tumor-promoting role of USP35 in renal clear cell carcinoma by maintaining NRF2 levels and protecting against apoptosis and ferroptosis.
CELL DEATH AND DIFFERENTIATION
(2023)
Article
Cell Biology
Annina Bindschedler, Jacqueline Schmuckli-Maurer, Rahel Wacker, Nicolas Kramer, Ruth Rehmann, Reto Caldelari, Volker T. Heussler
Summary: NRF2 is activated in Plasmodium-infected hepatocytes, depending on the recruitment of the negative regulator KEAP1 by PV membrane resident p62. Disrupting NRF2 gene leads to reduced parasite survival.
CELLULAR MICROBIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Ping Huang, Fei-Jun Luo, You-Chu Ma, Si-Xian Wang, Jia Huang, Dan-Dan Qin, Fei-Fei Xue, Bi-Yang Liu, Qiang Wu, Xiao-Ling Wang, Gao-Qiang Liu
Summary: A novel antioxidant peptide (GLP4) was identified from Ganoderma lingzhi mycelium, which exhibited both direct and indirect antioxidant activities. GLP4 could enter human umbilical vein endothelial cells (HUVECs) as an exogenous substance and activate the Nrf2/antioxidant response element (ARE) signaling pathway, providing cytoprotective effects against hydrogen peroxide (H2O2)-induced HUVECs.
Review
Biochemistry & Molecular Biology
Uzma Jaffry, Geoff Wells
Summary: The E3 ligase beta-transducin repeat-containing protein (beta TrCP) is a crucial component of the ubiquitin-proteasome system that maintains cellular protein levels in human cells. It targets various substrates for degradation, including factors involved in cellular protection against oxidative damage and tumor suppression. Inhibitors of beta TrCP, such as GS143 and erioflorin, have been identified, along with modified peptides. In this review, the current status of beta TrCP inhibitors is discussed, along with the potential for further inhibitor design and the development of new structures.
BIOCHEMICAL SOCIETY TRANSACTIONS
(2023)
Article
Chemistry, Applied
Yue Wang, Rong Jin, Jiebiao Chen, Jinping Cao, Jianbo Xiao, Xian Li, Chongde Sun
Summary: This study found that flavanones have strong antioxidant activity, while polymethoxyflavones have weaker antioxidant capabilities. Neohesperidin and tangeretin can selectively regulate antioxidant enzyme activity, with tangeretin also maintaining antioxidant enzyme expression in vivo. Tangeretin inhibits NRF2 ubiquitination by inhibiting CUL3, a mechanism verified by CUL3 gene silencing.
Article
Biochemistry & Molecular Biology
Orsolya Bilkei-Gorzo, Tiaan Heunis, Jose Luis Marin-Rubio, Francesca Romana Cianfanelli, Benjamin Bernard Armando Raymond, Joseph Inns, Daniela Fabrikova, Julien Peltier, Fiona Oakley, Ralf Schmid, Anetta Hartlova, Matthias Trost
Summary: This study reveals the importance of phagosomal ubiquitylation and the E3 ubiquitin ligase RNF115 in regulating innate immune functions during bacterial infections.
Article
Biochemistry & Molecular Biology
Hao-Yu Chuang, Li-Yun Hsu, Chih-Ming Pan, Narpati Wesa Pikatan, Vijesh Kumar Yadav, Iat-Hang Fong, Chao-Hsuan Chen, Chi-Tai Yeh, Shao-Chih Chiu
Summary: The overexpression of NEDD4-1 in GBM and TMZ-resistant cells is associated with oncogenicity, tumorigenesis, and chemoresistance. Mechanistically, NEDD4-1 mediates the degradation of PTEN and upregulation of the AKT/NRF2/HO-1 signaling pathway, leading to increased defense against reactive oxygen species and higher resistance against TMZ treatment. Targeting this regulatory axis may help eliminate TMZ-resistant glioblastoma.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Chemistry, Medicinal
Adam G. Bond, Conner Craigon, Kwok-Ho Chan, Andrea Testa, Athanasios Karapetsas, Rotimi Fasimoye, Thomas Macartney, J. Julian Blow, Dario R. Alessi, Alessio Ciulli
Summary: This study describes the design and development of a new protein degradation system utilizing a variant of the Brd4 bromodomain as a degradation tag. The system effectively degrades BromoTagged proteins in a fast, selective manner, showing favorable pharmacokinetic profile in mice. This system expands the arsenal of chemical genetic degradation tools for manipulating protein levels and exploring therapeutic potential in cells and in vivo.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Cell Biology
Martin P. Schwalm, Lena M. Berger, Maximilian N. Meuter, James D. Vasta, Cesear R. Corona, Sandra Roehm, Benedict-Tilman Berger, Frederic Farges, Sebastian M. Beinert, Franziska Preuss, Viktoria Morasch, Vladimir V. Rogov, Sebastian Mathea, Krishna Saxena, Matthew B. Robers, Susanne Mueller, Stefan Knapp
Summary: E3 ligases play a crucial role in regulating protein homeostasis by recruiting substrate proteins to the proteasomal degradation machinery. Recent research has focused on the Baculovirus IAP Repeat (BIR) family of E3 ligases, which contain a structurally conserved but diverse protein interaction domain. The Inhibitors of Apoptosis (IAP) family, which typically have three BIR domains, are promising drug targets. However, there is currently a lack of assay tools to evaluate the selectivity of inhibitors in this target area.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Article
Multidisciplinary Sciences
K. L. Thu, J. Silvester, M. J. Elliott, W. Ba-Alawi, M. H. Duncan, A. C. Elia, A. S. Mer, P. Smirnov, Z. Safikhani, B. Haibe-Kains, T. W. Mak, D. W. Cescon
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2018)
Correction
Multidisciplinary Sciences
Zhaleh Safikhani, Petr Smirnov, Kelsie L. Thu, Jennifer Silvester, Nehme El-Hachem, Rene Quevedo, Mathieu Lupien, Tak W. Mak, David Cescon, Benjamin Haibe-Kains
NATURE COMMUNICATIONS
(2018)
Article
Oncology
Alexander Drilon, Romel Somwar, Biju P. Mangatt, Henrik Edgren, Patrice Desmeules, Anja Ruusulehto, Roger S. Smith, Lukas Delasos, Morana Vojnic, Andrew J. Plodkowski, Joshua Sabari, Kenneth Ng, Joseph Montecalvo, Jason Chang, Huichun Tai, William W. Lockwood, Victor Martinez, Gregory J. Riely, Charles M. Rudin, Mark G. Kris, Maria E. Arcila, Christopher Matheny, Ryma Benayed, Natasha Rekhtman, Marc Ladanyi, Gopinath Ganji
Article
Multidisciplinary Sciences
Victor D. Martinez, Natalie S. Firmino, Erin A. Marshall, Kevin W. Ng, Brennan J. Wadsworth, Christine Anderson, Wan L. Lam, Kevin L. Bennewith
SCIENTIFIC REPORTS
(2018)
Article
Biochemistry & Molecular Biology
Adam P. Sage, Brenda C. Minatel, Erin A. Marshall, Victor D. Martinez, Greg L. Stewart, Katey S. S. Enfield, Wan L. Lam
INTERNATIONAL JOURNAL OF GENOMICS
(2018)
Letter
Multidisciplinary Sciences
Masanori Kawakami, Lisa Maria Mustachio, Lin Zheng, Yulong Chen, Jaime Rodriguez-Canales, Barbara Mino, Jonathan M. Kurie, Jason Roszik, Pamela Andrea Villalobos, Kelsie L. Thu, Jennifer Silvester, David W. Cescon, Ignacio I. Wistuba, Tak W. Mak, Xi Liu, Ethan Dmitrovsky
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2018)
Article
Multidisciplinary Sciences
Shawn P. Kubli, Christian Bassi, Cecilia Roux, Andrew Wakeham, Christoph Gobl, Wenjing Zhou, Soode Moghadas Jafari, Bryan Snow, Lisa Jones, Luis Palomero, Kelsie L. Thu, Luca Cassetta, Daniel Soong, Thorsten Berger, Parameswaran Ramachandran, Shakiba P. Baniasadi, Gordon Duncan, Moshit Lindzen, Yosef Yarden, Carmen Herranz, Conxi Lazaro, Mandy F. Chu, Jillian Haight, Paul Tinto, Jennifer Silvester, David W. Cescon, Anna Petit, Sven Pettersson, Jeffrey W. Pollard, Tak W. Mak, Miguel A. Pujana, Paola Cappello, Chiara Gorrini
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2019)
Article
Oncology
Hannah O'Farrell, Bryant Harbourne, Zimple Kurlawala, Yusuke Inoue, Amy L. Nagelberg, Victor D. Martinez, Daniel Lu, Min Hee Oh, Bradley P. Coe, Kelsie L. Thu, Romel Somwar, Stephen Lam, Wan L. Lam, Arun M. Unni, Levi Beverly, William W. Lockwood
JOURNAL OF THORACIC ONCOLOGY
(2019)
Article
Oncology
Lin Zheng, Zibo Chen, Masanori Kawakami, Yulong Chen, Jason Roszik, Lisa Maria Mustachio, Jonathan M. Kurie, Pamela Villalobos, Wei Lu, Carmen Behrens, Barbara Mino, Luisa M. Solis, Jennifer Silvester, Kelsie L. Thu, David W. Cescon, Jaime Rodriguez-Canales, Ignacio I. Wistuba, Tak W. Mak, Xi Liu, Ethan Dimitrovsky
MOLECULAR CANCER THERAPEUTICS
(2019)
Article
Chemistry, Multidisciplinary
Fatima Brandao, Carla Costa, Maria Joao Bessa, Elise Dumortier, Florence Debacq-Chainiaux, Roland Hubaux, Michel Salmon, Julie Laloy, Miruna S. Stan, Anca Hermenean, Sami Gharbia, Anca Dinischiotu, Anne Bannuscher, Bryan Hellack, Andrea Haase, Sonia Fraga, Joao Paulo Teixeira
Summary: The in vivo pulmonary toxicity of several variants of aSiO(2) NM was investigated, with findings showing increased DNA damage in rat lung cells but no marked in vivo toxicity. Genotoxicity was observed in both instillation and STIS studies, with changes in STIS animals appearing more difficult to revert.
Article
Gastroenterology & Hepatology
Cerise Yuen-Ki Chan, Vincent Wai-Hin Yuen, David Kung-Chun Chiu, Chi-Ching Goh, Kelsie L. Thu, David W. Cescon, Isabel Soria-Bretones, Cheuk-Ting Law, Jacinth Wing-Sum Cheu, Derek Lee, Aki Pui-Wah Tse, Kel Vin Tan, Misty Shuo Zhang, Bowie Po-Yee Wong, Chun-Ming Wong, Pek-Lan Khong, Irene Oi-Lin Ng, Mark R. Bray, Tak Wah Mak, Thomas Chung-Cheung Yau, Carmen Chak-Lui Wong
Summary: This study found that targeting the centrosome regulator PLK4 to activate the cytosolic DNA sensing-mediated immune response effectively suppressed tumor progression in late-stage mouse HCC through cell cycle inhibition and induction of antitumor immunity, presenting a durable suppressive effect.
Article
Multidisciplinary Sciences
Isabel Soria-Bretones, Kelsie L. Thu, Jennifer Silvester, Jennifer Cruickshank, Samah El Ghamrasni, Wail Ba-alawi, Graham C. Fletcher, Reza Kiarash, Mitchell J. Elliott, Jordan J. Chalmers, Andrea C. Elia, Albert Cheng, April A. N. Rose, Mark R. Bray, Benjamin Haibe-Kains, Tak W. Mak, David W. Cescon
Summary: In this study, a panel of CDK4/6i-resistant breast cancer cell lines and patient-derived organoids were developed. It was found that RB1 loss caused mitotic defects and enhanced sensitivity to TTK inhibition, suggesting TTK inhibitor CFI-402257 as a potential therapeutic strategy for CDK4/6i-resistant breast cancer patients.
Article
Pharmacology & Pharmacy
Kushal Joshi, Rajiv Sanwal, Kelsie L. Thu, Scott S. H. Tsai, Warren L. Lee
Summary: This paper presents an in vitro experimental setup using a clinical ultrasound system to study drug delivery mediated by ultrasound and microbubbles (USMB). The results show that optimal drug delivery efficiency can be achieved by adjusting the mechanical index, ultrasound treatment time, and microbubble concentration.
Review
Oncology
Asa P. Y. Lau, Sharon S. Khavkine Binstock, Kelsie L. Thu
Summary: CD47 is a promising immunotherapeutic target in lung cancer, and this review summarizes its roles in tumor biology, its therapeutic potential in non-small cell lung cancer, and the challenges that need to be overcome.
Article
Dermatology
Ah Young Park, Maureen Bourtembourg, Aline Chretien, Roland Hubaux, Celine Lancelot, Michel Salmon, J. Helen Fitton
Summary: The study found that fucoidan has significant effects on gene expression and pathogen adhesion in a model of atopic dermatitis, particularly inhibiting Staphylococcus aureus and Cutibacterium acnes. Therefore, fucoidan may be a useful topical agent for managing atopic dermatitis.