Article
Pharmacology & Pharmacy
Yongmei Feng, Stefan Grotegut, Predrag Jovanovic, Valentina Gandin, Steven H. Olson, Rabi Murad, Anne Beall, Sharon Colayco, Paul De-Jesus, Sumit Chanda, Brian P. English, Robert H. Singer, Michael Jackson, Ivan Topisirovic, Ze'ev A. Ronai
Summary: This study identified small molecules that can inhibit coronaviruses by disrupting protein synthesis, providing a potential basis for developing novel therapeutic modalities against coronaviruses.
FRONTIERS IN PHARMACOLOGY
(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
Oncology
Lee-or Herzog, Beth Walters, Roberta Buono, J. Scott Lee, Sharmila Mallya, Amos Fung, Honyin Chiu, Nancy Nguyen, Boyang Li, Anthony B. Pinkerton, Michael R. Jackson, Robert J. Schneider, Ze'ev A. Ronai, David A. Fruman
Summary: This study identified that using SBI-756 in lymphoma cells can synergize with Venetoclax to induce apoptosis, enhancing its efficacy. SBI-756 prevents eIF4E-eIF4G1 association and cap-dependent translation, reducing protein synthesis rates and selectively affecting sensitive cells.
BRITISH JOURNAL OF CANCER
(2021)
Article
Biochemistry & Molecular Biology
Benjamin Weiss, George Edward Allen, Joachim Kloehn, Karim Abid, Pascale Jaquier-Gubler, Joseph Alphonsus Curran
Summary: The eIF4E family of initiation factors regulate protein synthesis by binding to mRNA cap structures. Among them, eIF4E3 is recruited to the translation complex after mTOR inhibition by Torin1, reprogramming the translatome to enhance cellular stress resistance. Its interaction with diverse cellular proteins suggests potential additional functions beyond initiation factor roles.
NUCLEIC ACIDS RESEARCH
(2021)
Article
Chemistry, Multidisciplinary
Rongsheng Huang, Takahiro Yamamoto, Eiji Nakata, Toshifumi Ozaki, Kazuhiko Kurozumi, Fanyan Wei, Kazuhito Tomizawa, Atsushi Fujimura
Summary: A tRNA-modifying methylthiotransferase CDKAL1 is found to promote the synthesis of CSC-factor SALL2 by assembling the eIF4F translation initiation complex, thereby maintaining cancer stem cell (CSC) properties. CDKAL1 is upregulated in patients with worse prognoses and is essential for maintaining CSCs in rhabdomyosarcoma (RMS) and common cancers. The translation of a group of mRNAs containing cytosine-rich sequences in the 5' untranslated region (5'UTR) is CDKAL1-dependent.
Article
Cell Biology
Ann Kari Grindheim, Sudarshan S. Patil, Canan G. Nebigil, Laurent Desaubry, Anni Vedeler
Summary: Annexin A2 (AnxA2) plays a critical role in cell transformation, immune response, and resistance to cancer therapy. It acts as a calcium- and lipid-binding protein as well as an mRNA-binding protein, involved in the regulation of certain cytoskeleton-associated mRNAs. A new inhibitor called FL3 can transiently increase the expression of AnxA2 and stimulate short-term transcription/translation of anxA2 mRNA. AnxA2 regulates its own mRNA translation via a feedback mechanism, which can be partially relieved by FL3.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2023)
Article
Multidisciplinary Sciences
Thanh-Trang Vo, Lee-or Herzog, Roberta Buono, Jong-Hoon Scott Lee, Sharmila Mallya, Madeleine R. Duong, Joshua Thao, Moran Gotesman, David A. Fruman
Summary: Research on the mTOR signaling pathway has gained attention in the field of B-ALL and other blood cancers. Selective inhibition of mTOR or its downstream effectors offers alternative strategies that may improve selectivity towards leukemia cells.
SCIENTIFIC REPORTS
(2021)
Article
Biochemistry & Molecular Biology
Xinpu Tang, Yi Pu, Haoning Peng, Kaixiu Li, Sara Faouzi, Tianjian Lu, Dan Pu, Michael Cerezo, Jianguo Xu, Lu Li, Caroline Robert, Shensi Shen
Summary: As a central node of protein synthesis, the cap-binding complex, eukaryotic translation initiation factor 4 F (eIF4F), is involved in cell homeostasis, development and tumorigenesis. A large body of literature exists on the regulation and function of eIF4F in cancer cells, however the intracellular localization patterns of this complex are largely unknown. This study developed an in situ detection method for eIF4F at the single cell level and identified five distinct spatial patterns of the eIF4F translation initiation complex in human melanoma cells. The spatial patterns of eIF4F complexes at the single cell level could distinguish melanoma cells harboring different oncogenic driver mutations, suggesting their potential association with melanoma cell chemoresistance.
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
(2023)
Article
Multidisciplinary Sciences
Yuri Frosi, Yen-Chu Lin, Jiang Shimin, Siti Radhiah Ramlan, Kelly Hew, Alf Henrik Engman, Anil Pillai, Kit Yeung, Yue Xiang Cheng, Tobias Cornvik, Par Nordlund, Megan Goh, Dilraj Lama, Zachary P. Gates, Chandra S. Verma, Dawn Thean, David P. Lane, Ignacio Asial, Christopher J. Brown
Summary: An attractive approach to target intracellular macromolecular interfaces and model putative drug interactions is to design small high-affinity proteins. Here, the authors engineer and optimize an autonomous and disulfide-free human VH domain for intracellular expression, and identify several VH domain binders against eIF4E, a protein commonly hyper-activated in cancer. These VH domains interact with eIF4E at the eIF4G binding site via a distinct structural pose, and their intracellular overexpression reduces cellular proliferation and expression of malignancy-related proteins in cancer cell lines. The linkage of high-diversity in vitro libraries with an intracellularly expressible miniprotein scaffold facilitates the discovery of VH domains suitable for intracellular applications.
NATURE COMMUNICATIONS
(2022)
Article
Biochemistry & Molecular Biology
Mario Servulo Izidoro, Masaaki Sokabe, Nancy Villa, William C. Merrick, Christopher S. Fraser
Summary: This study reveals the mechanism by which eukaryotic initiation factors regulate the binding of eIF4F to mRNA during translation initiation. The researchers found that eIF4E binding to eIF4G generates a high-affinity conformation of the eIF4F complex for RNA, and the nucleotide-bound state of eIF4A further regulates RNA binding. They also observed that the autoinhibitory domain of eIF4G promotes a stable eIF4A-binding state, which is overcome by eIF4E binding. These findings provide insights into the dynamic interaction between eIF4F and mRNA during the scanning process.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Fiona Jenkinson, Kang Wei Tan, Barbara Schopf, Miguel M. Santos, Philip Zegerman
Summary: In eukaryotes, cyclin-dependent kinase (CDK) inhibits helicase loading factors to ensure the exact duplication of the genome. CDK activates origin firing by phosphorylating Sld2 and Sld3, forming a transient intermediate called the pre-initiation complex (pre-IC). In yeast, the CDK phosphorylations of Sld3 and Sld2 are rapidly turned over by the phosphatases PP2A and PP4 during S phase. This dephosphorylation is important for genome-wide origin firing, pre-IC formation, and maintaining Sld3 dephosphorylation in G1 phase. PP2ARts1 specifically targets Sld3 and its dephosphorylation is critical for replication and cell viability.
Article
Biochemistry & Molecular Biology
Hao Li, Shuangshuang Shu, Miaomiao Zhou, Ying Chen, An Xiao, Yuanyuan Ma, Fengxin Zhu, Zheng Hu, Jing Nie
Summary: In this study, researchers found that Numb, an adaptor protein, increases the protein abundance of DEPTOR by inhibiting the ubiquitination mediated by SCF beta-TrCP2, leading to increased autophagy flux. Numb disrupts the interaction between beta-TrCP2 and SKP1 by directly binding with SKP1. In a mouse model of renal fibrosis, Numb expression was significantly increased and depletion of Numb reduced DEPTOR abundance and attenuated autophagy in fibrotic lesions. These findings indicate that Numb plays an important role in regulating autophagy.
CELL DEATH AND DIFFERENTIATION
(2022)
Article
Biochemistry & Molecular Biology
Yuki Kito, Akinobu Matsumoto, Kazuya Ichihara, Chisa Shiraishi, Ronghao Tang, Atsushi Hatano, Masaki Matsumoto, Peixun Han, Shintaro Iwasaki, Keiichi Nakayama
Summary: Translation begins with the binding of the eIF4F complex to the 5' mRNA cap, followed by scanning ribosomes searching for the start codon in the 5' untranslated region. This study shows that the ASC-1 complex (ASCC) associates with scanning ribosomes to regulate translation initiation. Knockdown of ASCC3, a subunit of ASCC, impairs the loading and scanning dynamics of the 43S preinitiation complex, leading to reduced translation efficiency. These findings demonstrate that ASCC not only promotes dissociation of colliding 80S ribosomes but also facilitates efficient translation initiation by scanning ribosomes.
Article
Cell Biology
Xuexiu Zhang, Jianning Yao, Haoling Shi, Bing Gao, Haining Zhou, Yanzhen Zhang, Dongyao Zhao, Shilin Gao, Chunfeng Wang, Lianfeng Zhang
Summary: This study revealed that circ_0026628, a circular RNA originating from SP1 pre-mRNA, was upregulated in colorectal cancer cells and functioned as an endogenous sponge of miR-346 and FUS to enhance SP1 expression, consequently activating the Wnt/β-catenin pathway to promote CRC progression through mechanisms involving cell proliferation, migration, EMT, and stemness.
CELL DEATH & DISEASE
(2021)
Review
Biochemistry & Molecular Biology
Emma Minnee, William James Faller
Summary: Protein synthesis is crucial in all kingdoms of life, and dysregulation can drive cancer development, as seen in colorectal cancer with translational reprogramming. Multiple signaling pathways impact the translation initiation machinery, playing a critical role in regulating gene expression differentially.