Article
Oncology
Sho Takahashi, Shusaku Shibutani, Hiroyuki Iwata
Summary: This study investigated the relationship between the localization and phosphorylation of 4E-BP1. The results showed efficient phosphorylation of 4E-BP1 at lysosomes and the plasma membrane, while it was decreased in the nucleus. Additionally, nuclear-localized TORCAR altered cell cycle distribution and reduced cyclin D1 protein levels.
EXPERIMENTAL CELL RESEARCH
(2022)
Article
Biochemistry & Molecular Biology
Su Wu, Gerhard Wagner
Summary: eIF4F plays diverse roles in human cancers, with overexpression of EIF4G1 being more selective than EIF4E, serving as a prognostic indicator in cancer patients. This expression imbalance affects housekeeping pathways and cancer-related pathways, leading to cap-independent initiation due to eIF4G1 hyperphosphorylation. These findings provide a novel model of dysregulated eIF4F function and highlight the clinical relevance of cap-(in)dependent initiation in cancer.
Article
Biochemistry & Molecular Biology
Patrick Senechal, Francis Robert, Regina Cencic, Akiko Yanagiya, Jennifer Chu, Nahum Sonenberg, Marilene Paquet, Jerry Pelletier
Summary: The translation initiation factor eIF4F is crucial for cap-dependent protein synthesis initiation. Different subunits of eIF4F have varying roles in development and tumorigenesis, with some being essential for viability and tumor onset, while others have non-essential functions. This study highlights the complex roles of different eIF4F subunits in gene expression regulation during embryogenesis and tumor development.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2021)
Review
Biochemistry & Molecular Biology
Alice Romagnoli, Mattia D'Agostino, Chiara Ardiccioni, Cristina Maracci, Stefano Motta, Anna La Teana, Daniele Di Marino
Summary: eIF4E plays a central role in controlling mRNA translation, with its interaction with eIF4G and 4E-BPs being crucial for the assembly of the translational machinery. Recent discoveries of non-canonical binding motifs could have implications for the development of new therapeutic strategies targeting eIF4E.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Mehdi Ghram, Gavin Morris, Biljana Culjkovic-Kraljacic, Jean-Clement Mars, Patrick Gendron, Lucy Skrabanek, Maria Victoria Revuelta, Leandro Cerchietti, Monica L. Guzman, Katherine L. B. Borden
Summary: Aberrant splicing, a known contributor to malignancies, is usually attributed to splice-factor mutation. This study, however, discovered a mutation-independent mechanism for extensively reprogramming alternative splicing (AS) in acute myeloid leukemia (AML). The dysregulated expression of eukaryotic translation initiation factor eIF4E was found to increase selective splice-factor production, thereby affecting multiple spliceosome complexes and generating a splicing landscape that supported altered splice-site selection for hundreds of transcripts in AML patients with high-eIF4E expression.
Article
Multidisciplinary Sciences
Yaoxiang Tang, Jiadi Luo, Yang Yang, Sile Liu, Hongmei Zheng, Yuting Zhan, Songqing Fan, Qiuyuan Wen
Summary: In patients with non-small cell lung cancer, the overexpression of phosphorylated eIF4E and 4EBP1 is associated with poor prognosis, suggesting their potential as novel prognostic markers and targeted therapy in lung cancer.
Article
Cell Biology
Rong Li, Dan Huang, Mei Ju, Hong-ying Chen, Chao Luan, Jia-an Zhang, Kun Chen
Summary: The long non-coding RNA (lncRNA) plasmacytoma variant translocation 1 (PVT1) is highly expressed in various cancers and plays an oncogenic role. In this study, we found that PVT1 was upregulated in cutaneous squamous cell carcinoma (cSCC) tissues and cell lines. Knockdown of PVT1 inhibited cell proliferation, induced cell cycle arrest and apoptosis, and suppressed cell migration and invasion in cSCC. Further analysis revealed that 4E-binding protein 1 (4EBP1) is a potential downstream target effector of PVT1, and PVT1 interacts with 4EBP1 in the cytoplasm of cSCC cells. PVT1 combined with 4EBP1 may serve as a potential new therapeutic target for cSCC.
CELL DEATH DISCOVERY
(2023)
Article
Cell Biology
Laura Hauffe, Daniel Picard, Julian Musa, Marc Remke, Thomas G. P. Gruenewald, Barak Rotblat, Guido Reifenberger, Gabriel Leprivier
Summary: Our study confirms the enhanced expression of EIF4EBP1 in malignant gliomas and characterizes the underlying molecular mechanisms. These findings provide important clues for a better understanding of the pathogenesis and progression of gliomas.
CELL DEATH DISCOVERY
(2022)
Review
Cell Biology
Jerry Pelletier, T. Martin Schmeing, Nahum Sonenberg
Summary: This article discusses the significance of adding the 5' cap structure during RNA transcription, the role of cap binding proteins in gene expression regulation, and the recognition mechanism of the cap. Studying the biological properties of the cap and key points of interaction with CBPs is important for guiding drug development.
WILEY INTERDISCIPLINARY REVIEWS-RNA
(2021)
Article
Chemistry, Medicinal
Xintao Gao, Yonglong Jin, Wenyong Zhu, Xiaochen Wu, Jing Wang, Chuanlong Guo
Summary: eIF4E is a central regulator in cancer cell growth, but there are currently no clinically available eIF4E inhibitors. Interfering with eIF4E/eIF4G interactions may provide a new strategy for designing eIF4E inhibitors.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Reem T. Attia, Menna A. Ewida, Eman Khaled, Sherif Ashraf Fahmy, Iten M. Fawzy
Summary: Translation of mRNA is a process used by cancer cells to ensure survival, and this study explores the inhibition of eIF4E to disrupt the translation process. Synthesized GMP analogs showed high potency against breast cancer cells, and compound 4b exhibited the most activity across multiple cell lines. Chitosan-coated niosomes loaded with compound 4b showed enhanced efficacy against cancer cells, and western blot techniques revealed the inhibition of phosphorylated eIF4E expression. The findings suggest the potential use of niosomal nanovesicles as a targeted nanocarrier for cancer therapy.
Article
Plant Sciences
Ruhao Chen, Manhua Yang, Zhen Tu, Fangru Xie, Jiaru Chen, Tao Luo, Xinxi Hu, Bihua Nie, Changzheng He
Summary: Plant viruses depend on host factors for successful infection. One gene, nCBP, is associated with the infection of viruses encoding TGBps. The knockdown of nCBP compromises the accumulation of potato virus S but not that of potato virus M and potato virus X, while the knockdown of nCBP in tobacco suppresses PVX accumulation but not PVM.
FRONTIERS IN PLANT SCIENCE
(2022)
Article
Cell Biology
Yanan Wang, Jiapeng Lei, Song Zhang, Xiaomei Wang, Jiangbo Jin, Yufeng Liu, Mingxi Gan, Yi Yuan, Longhua Sun, Xiaolei Li, Tianyu Han, Jian-Bin Wang
Summary: This study discovered a novel mechanism of 4EBP1 as a cellular glucose sensor in regulating cancer cell death under glucose deprivation conditions. It found that 4EBP1 levels increased in the central region of tumors under nutrient deprivation, and it interacted with STAT3 to induce cell apoptosis.
CELL DEATH & DISEASE
(2022)
Article
Chemistry, Medicinal
Weijun Xu, Srinivasaraghavan Kannan, Chandra S. Verma, Kassoum Nacro
Summary: MNK1/2 are central enzymes activated by ERK or p38 MAP kinases, coordinating cellular signaling and regulating cell proliferation and survival. Overexpression of MNK1/2 and/or eIF4E is associated with diseases including cancer, neurological disorders, autism, and inflammation. There are ongoing efforts to develop potent and selective inhibitors of MNK1/2 in both academia and industry.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Multidisciplinary Sciences
Mateen A. Khan, Pankaj Kumar, Mohd. Akif, Hiroshi Miyoshi
Summary: Phosphorylation of eIFiso4E enhanced the binding rate with VPg, decreased the dissociation rate, and induced an overall conformational change.
Meeting Abstract
Biochemistry & Molecular Biology
Siddharth Sunilkumar, William P. Miller, Allyson Toro, Esma Yerlikaya, Michael D. Dennis
Article
Biochemistry & Molecular Biology
Saketh S. Dinavahi, Yu-Chi Chen, Raghavendra Gowda, Pavan Kumar Dhanyamraju, Kishore Punnath, Dhimant Desai, Arthur Berg, Scot R. Kimball, Shantu Amin, Jin-Ming Yang, Gavin P. Robertson
Summary: This report suggests that modulating cholesterol metabolism through targeting protein translation can be used to treat cancer.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Cell Biology
Paul A. Roberson, Leonard S. Jefferson, Scot R. Kimball
Summary: This study investigated the mechanisms through which leucine and IGF-1 regulate protein synthesis in skeletal muscle via the mTORC1 pathway. The results demonstrated that IGF-1 promoted phosphorylation of AKT, TSC2, and mTOR, while leucine stimulated protein synthesis.
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
(2022)
Article
Oncology
Brandon Labarge, Max Hennessy, Lijun Zhang, David Goldrich, Scott Chartrand, Carson Purnell, Sage Wright, David Goldenberg, James R. Broach
Summary: HPV integration in head and neck cancer correlates with extensive pangenomic structural variation, which may have prognostic implications.
MOLECULAR CANCER RESEARCH
(2022)
Article
Biochemistry & Molecular Biology
Yeon Soo Kim, Priscilla W. Tang, Jaclyn E. Welles, Weihua Pan, Zaineb Javed, Amal Taher Elhaw, Karthikeyan Mythreye, Scot R. Kimball, Nadine Hempel
Summary: During metastasis, cancer cells need to adapt to loss of anchorage and resistance to anoikis. One important adaptation is the increase in antioxidant capacity and restoration of cellular redox balance. In ovarian cancer cells, an early response to detachment, a critical step in metastasis associated with increased oxidative stress, is the increase in mitochondrial superoxide dismutase SOD2 protein expression. This is achieved through the translational regulatory mechanism involving the cytosolic accumulation of the RNA binding protein HuR/ELAVL1 and the activation of mitogen-activated kinase p38.
Article
Endocrinology & Metabolism
William P. Miller, Congzhou M. Sha, Siddharth Sunilkumar, Allyson L. Toro, Ashley M. VanCleave, Scot R. Kimball, Nikolay V. Dokholyan, Michael D. Dennis
Summary: The stress response protein REDD1 is implicated in visual deficits in diabetic patients. Increased REDD1 protein expression in diabetic mice retina was found, which was suppressed by oral antioxidant supplementation. Hyperglycemic conditions enhance REDD1 expression and inhibit its degradation through a redox-sensitive disulfide bond at C150/C157.
Article
Endocrinology & Metabolism
Siddharth Sunilkumar, Esma I. Yerlikaya, Allyson L. Toro, William P. Miller, Han Chen, Kebin Hu, Scot R. Kimball, Michael D. Dennis
Summary: Chronic hyperglycemia promotes the expression of REDD1 in the kidney, leading to oxidative stress and renal injury. Deletion of REDD1 reduces reactive oxygen species and prevents podocyte loss, indicating its role in diabetes-induced renal complications.
Article
Biochemistry & Molecular Biology
Siddharth Sunilkumar, Allyson L. Toro, Christopher M. McCurry, Ashley M. VanCleave, Shaunaci A. Stevens, William P. Miller, Scot R. Kimball, Michael D. Dennis
Summary: The study revealed that REDD1 plays a crucial role in diabetes-induced retinal inflammation by enhancing the activation of the NF-KB signaling pathway to increase the expression of inflammatory cytokines.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Endocrinology & Metabolism
Shaunaci A. Stevens, Maria K. Gonzalez Aguiar, Allyson L. Toro, Esma I. Yerlikaya, Siddharth Sunilkumar, Ashley M. VanCleave, Jessica Pfleger, Elisa A. Bradley, Scot R. Kimball, Michael D. Dennis
Summary: The interplay between endoplasmic reticulum stress and inflammation contributes to cardiovascular disease progression. This study identifies REDD1, a stress response protein, as a missing link that connects the development of endoplasmic reticulum stress with increased production of proinflammatory cytokines in the hearts of obese mice.
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
(2022)
Article
Physiology
Gregory N. Kincheloe, Paul A. Roberson, Allyson L. Toro, Bruce A. Stanley, Anne E. Stanley, Leonard S. Jefferson, Michael D. Dennis, Scot R. Kimball
Summary: The study aimed to test the hypothesis that upregulating protein synthesis can attenuate the loss of muscle mass in disuse atrophy. The results showed that protein synthesis was downregulated in both wild-type and double-knockout mice, but it was higher in fasting double-knockout mice. Surprisingly, muscle atrophy occurred to the same extent in both groups, possibly due to impaired leucine-induced stimulation of protein synthesis and compensatory mechanisms. Proteomic analysis revealed differential translation of mRNA encoding glycolytic enzymes in the two groups of mice.
JOURNAL OF APPLIED PHYSIOLOGY
(2023)
Article
Nutrition & Dietetics
Paul A. Roberson, Gregory N. Kincheloe, Jaclyn E. Welles, Dandan Xu, Mahalia Sam -Clarke, Paul S. MacLean, Charles H. Lang, Leonard S. Jefferson, Scot R. Kimball
Summary: This study confirms the role of Sestrins in glucose-induced mTORC1 activation and reveals the involvement of HK2 in this process in HEK293T cells. The effect of glucose on mTORC1 activation is independent of SESN-GATOR2 interaction and instead associated with alterations in SESNs' association with HK2.
JOURNAL OF NUTRITION
(2023)
Article
Nutrition & Dietetics
Jonathan G. Stine, Jaclyn E. Welles, Shelley Keating, Zeba Hussaini, Christopher Soriano, J. Wes Heinle, Nathaniel Geyer, Vernon M. Chinchilli, Rohit Loomba, Scot R. Kimball
Summary: Exercise can reduce liver fat and improve biomarkers of liver fibrosis in NAFLD by decreasing serum fibroblast growth factor (FGF) 21 levels. This study suggests that the decrease in FGF21 may be a mechanism for the benefits of exercise in improving liver fat and fibrosis.
Article
Endocrinology & Metabolism
Eduardo D. S. Freitas, Katon A. Kras, Lori R. Roust, Elena A. De Filippis, Scot R. Kimball, Matthew Buras, Christos S. Katsanos
Summary: This study aimed to test the hypothesis that expression of insulin-like growth factor 1 (IGF-1) protein and mRNA splice variants is lower in skeletal muscle of humans with obesity who have a lower mixed-muscle protein fractional synthesis rate (MMP-FSR) compared to individuals without obesity. The results showed that individuals with obesity had lower rates of protein synthesis in skeletal muscle, along with lower expression of muscle IGF-1 and IGF-1 receptor proteins, as well as lower mRNA expression of IGF1 splice variants.
Article
Ophthalmology
Esma Yerlikaya, Allyson L. Toro, Siddharth Sunilkumar, Ashley M. VanCleave, Ming Leung, Yuka Imamura Kawasawa, Scot R. Kimball, Michael D. Dennis
Summary: In diabetic retinopathy, neuroglial dysfunction occurs early and Muller glia play a significant role in disease progression. This study investigates the common signaling pathways activated in Muller glia by both type 1 and pre-/type 2 diabetes. The findings suggest that the TREM2/DAP12 receptor-adaptor complex signals via SYK to promote HIF1a stabilization and increased angiogenic cytokine production by Muller glia.
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
(2022)