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.
Review
Biochemistry & Molecular Biology
Joanna R. Kovalski, Duygu Kuzuoglu-Ozturk, Davide Ruggero
Summary: This review discusses how cancer cells regulate protein expression through translational control and highlights the clinical potential of targeting translation factors as anti-cancer therapies. It also details the interaction between RNA sequence and structural elements, the translational machinery, and RNA-binding proteins in coordinating specific pro-survival and pro-growth programs. Additionally, the review provides an overview of current and emerging technologies for studying selective translational control in cancer cells and the tumor microenvironment.
Review
Cell Biology
Akira Fukao, Takumi Tomohiro, Toshinobu Fujiwara
Summary: Protein synthesis is tightly regulated at each step, with the formation of the eIF4F complex on the 5' cap structure of mRNA being a rate-limiting step. Various cis-elements on mRNA contribute to fine-tune protein expression, recognized and bound by trans-acting factors for regulating translation rate or mRNA stability. This review focuses on the regulation of the eIF4F complex assembly and translation initiation by trans-acting factors through cis-elements on mRNAs.
Article
Oncology
Angela Rubio, Gavin D. Garland, Aristeidis Sfakianos, Robert F. Harvey, Anne E. Willis
Summary: Abnormalities in RNA binding proteins within the canonical translation factor machinery are associated with tumorigenesis and can be targeted for therapeutic purposes.
SEMINARS IN CANCER BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Alec C. Gleason, Ghanashyam Ghadge, Yoshifumi Sonobe, Raymond P. Roos
Summary: Ribosome profiling and mass spectroscopy have identified noncanonical translation initiation codons (TICs) that translate oncogenic proteins. These TICs have flanking nucleotides closely matching the Kozak sequence, and cancer-associated genes have longer 5'UTRs, increasing the likelihood of ribosome binding to noncanonical TICs.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Multidisciplinary Sciences
Pratyusha Bala, Jonathan P. Rennhack, Daulet Aitymbayev, Clare Morris, Sydney M. Moyer, Gina N. Duronio, Paul Doan, Zhixin Li, Xiaoyan Liang, Jason L. Hornick, Matthew B. Yurgelun, William C. Hahn, Nilay S. Sethi
Summary: Cell state plasticity is regulated in adult epithelia to prevent cancer, but its expansion in neoplasia is poorly understood. Mouse models and patient samples revealed that impaired differentiation precedes cancer development, with aberrant transcriptional state marked by Ly6a and reactivation of fetal genes. Genetic inactivation of Sox9 prevents adenoma formation and restores multilineage differentiation. These findings indicate that unabated regenerative activity and developmental reprogramming contribute to the aberrant cell state plasticity preceding cancer development.
Review
Cell Biology
Yudi Liu, Jiuwei Cui, Andrew R. Hoffman, Ji-Fan Hu
Summary: Protein translation is a critical regulatory event involved in various physiological and pathological processes. The eukaryotic translation initiation factor 4G2 (eIF4G2) is important for cap-independent translation initiation via internal ribosome entry sites (IRESs), but recent findings suggest that it plays a role in other translation initiation pathways as well. This review summarizes the role of eIF4G2 in different translation initiation events and its involvement in apoptosis, cell survival, cell differentiation, and embryonic development.
CELL PROLIFERATION
(2023)
Article
Cell Biology
Francesco Monticolo, Emanuela Palomba, Maria Luisa Chiusano
Summary: Programmed cell death, involving complex molecular pathways, leads to changes in ribosomal protein expression and organization, influencing cell fate. The differential expression of ribosomal proteins during programmed cell death induced by acetic acid suggests the relevance of reprogramming translational apparatus in yeast cells. Furthermore, exposure to acetic acid affects genes related to translation processes and rRNA maturation, demonstrating the impact of environmental factors on cell death mechanisms.
CELL DEATH DISCOVERY
(2021)
Review
Oncology
Conggai Huang, Qi Zhao, Xiaoqing Zhou, Ran Huang, Yi Duan, Johannes Haybaeck, Zhihui Yang
Summary: Colorectal diseases pose a threat to human health, particularly inflammatory bowel disease (IBD) and colorectal cancer (CRC). This review highlights the significance of gene expression regulation in the pathogenesis of CRC and suggests that eIFs, eEFs, and eRFs may be potential targets for CRC treatment.
FRONTIERS IN ONCOLOGY
(2022)
Article
Cell Biology
Rachael C. L. Smith, Georgios Kanellos, Nikola Vlahov, Constantinos Alexandrou, Anne E. Willis, John R. P. Knight, Owen J. Sansom
Summary: Cell division, differentiation, and function rely heavily on accurate proteome composition and regulated gene expression. The process of translation, particularly translation initiation, is tightly regulated to control the activity of eIFs and recruit mRNAs to ribosomes. Tumor cells can alter translation initiation mechanisms to promote tumor formation and metastasis.
JOURNAL OF CELL SCIENCE
(2021)
Article
Biochemistry & Molecular Biology
Sonam Kumari, Mohammed Sikander, Shabnam Malik, Manish K. Tripathi, Bilal B. Hafeez, Murali M. Yallapu, Subhash C. Chauhan, Sheema Khan, Meena Jaggi
Summary: Steviol effectively inhibits glucose consumption and metabolism in pancreatic cancer cells, reducing their aggressiveness by inducing apoptosis and cell cycle arrest in the G1/M phase. It also suppresses tumorigenic and metastatic potential by repressing the phosphorylation of mTOR and translation initiation proteins, suggesting potential for development of combination therapeutic strategies for pancreatic cancer treatment.
Article
Biochemistry & Molecular Biology
Evrim Fer, Kaitlyn M. McGrath, Lionel Guy, Adam J. Hockenberry, Betul Kacar
Summary: Protein translation is a fundamental process in all living cells. A study on the evolutionary history of translation machinery factors suggests that the ancestors of these factors may have had similar functions and structures to their modern counterparts. By reconstructing the ancestral sequences and studying the changes in residues and structures, the researchers propose an evolutionary scenario for the origins and diversification of essential translation factors EF-Tu and IF2. Understanding the early evolution of the translation machinery is crucial for characterizing universal constraints and capabilities of cellular evolution.
Article
Oncology
Rajni Kant, Rajesh Kumar Manne, Mohammad Anas, Vasudevarao Penugurti, Tingjin Chen, Bo-Syong Pan, Che-Chia Hsu, Hui-Kuan Lin
Summary: Metabolic reprogramming plays a crucial role in cancer malignancies and therapy resistance. Understanding the mechanisms of cancer metabolic reprogramming may lead to new strategies for cancer targeting.
SEMINARS IN CANCER BIOLOGY
(2022)
Article
Multidisciplinary Sciences
Clemens Hinterleitner, Jasmin Straehle, Elke Malenke, Martina Hinterleitner, Melanie Henning, Marco Seehawer, Tatjana Bilich, Jonas Heitmann, Martina Lutz, Sven Mattern, Sophia Scheuermann, Marius Horger, Stefanie Maurer, Juliane Walz, Falko Fend, Rupert Handgretinger, Christian Seitz, Bettina Weigelin, Stephan Singer, Helmut Salih, Oliver Borst, Hans-Georg Kopp, Lars Zender
Summary: This study demonstrates that platelet-derived PD-L1 can serve as a prognostic and predictive biomarker in non-small cell lung cancer patients, playing a role in tumor immune evasion and affecting T cell function. An algorithm was developed to calculate the adjusted PD-L1 payload of platelets (pPD-L1(Adj.)), which showed superior predictive ability for therapy response compared to standard histological PD-L1 quantification.
NATURE COMMUNICATIONS
(2021)
Editorial Material
Plant Sciences
Maria Kidwai, Priyanka Mishra, Catherine Bellini
Summary: After cell reprogramming, adventitious roots or shoot-borne roots transdifferentiate from cells close to vascular tissues, leading to increased transcriptional activity. Garg et al. recently provided a genome-wide landscape of transcriptional signatures during the early stages of adventitious root initiation in rice and found that conserved transcription factors acquire species-specific function.
TRENDS IN PLANT SCIENCE
(2023)
Article
Medicine, Research & Experimental
Fan Huang, Christophe Goncalves, Margarita Bartish, Joelle Remy-Sarrazin, Mark E. Issa, Brendan Cordeiro, Qianyu Guo, Audrey Emond, Mikhael Attias, William Yang, Dany Plourde, Jie Su, Marina Godoy Gimeno, Yao Zhan, Alba Galan, Tomasz Rzymski, Milena Mazan, Magdalena Masiejczyk, Jacek Faber, Elie Khoury, Alexandre Benoit, Natascha Gagnon, David Dankort, Fabrice Journe, Ghanem E. Ghanem, Connie M. Krawczyk, H. Uri Saragovi, Ciriaco A. Piccirillo, Nahum Sonenberg, Ivan Topisirovic, Christopher E. Rudd, Wilson H. Jr Jr Miller, Sonia del Rincon
Summary: By blocking the MNK1/2-eIF4E axis, the study demonstrated inhibition of melanoma phenotype switching and increased sensitivity to anti-PD-1 immunotherapy in melanoma mouse models. Phospho-eIF4E-deficient melanomas expressed high levels of melanocytic antigens, and genetically ablating phospho-eIF4E reprogrammed the immunosuppressive microenvironment. Dual blockade of MNK1/2-eIF4E and PD-1/PD-L1 immune checkpoint showed efficacy in multiple melanoma models and led to an increase in intratumoral stem-like TCF1(+)PD-1(+)CD8(+) T cells.
JOURNAL OF CLINICAL INVESTIGATION
(2021)
Article
Biochemistry & Molecular Biology
Jennifer Chu, Francis Robert, Jerry Pelletier
Summary: Circular RNA expression vectors are used to identify and characterize RNA sequences with IRES activity, but caution must be taken as trans-spliced products may lead to false-positive signals in screens relying on these vectors for IRES discovery.
Article
Oncology
David Papadopoli, Oro Uchenunu, Ranveer Palia, Nabila Chekkal, Laura Hulea, Ivan Topisirovic, Michael Pollak, Julie St-Pierre
Summary: Studies have shown that the SGLT2 inhibitor canagliflozin can inhibit the proliferation of breast cancer cells by limiting glucose uptake, and this effect is independent of glucose availability and the level of SGLT2 expression. Canagliflozin inhibits cell proliferation by reducing oxygen consumption and glutamine metabolism, which fuel respiration. This represents a previously unexpected mechanism of its potential antineoplastic action.
Article
Multidisciplinary Sciences
Stephanie P. Totten, Young Kyuen Im, Eduardo Cepeda Canedo, Ouafa Najyb, Alice Nguyen, Steven Hebert, Ryuhjin Ahn, Kyle Lewis, Benjamin Lebeau, Rachel La Selva, Valerie Sabourin, Constanza Martinez, Paul Savage, Hellen Kuasne, Daina Avizonis, Nancy Santos Martinez, Catherine Chabot, Adriana Aguilar-Mahecha, Marie-Line Goulet, Matthew Dankner, Michael Witcher, Kevin Petrecca, Mark Basik, Michael Pollak, Ivan Topisirovic, Rongtuan Lin, Peter M. Siegel, Claudia L. Kleinman, Morag Park, Julie St-Pierre, Josie Ursini-Siegel
Summary: Bioenergetic perturbations and oxidative stress play important roles in promoting neoplastic growth, requiring compensatory increase in ROS scavengers. In addition, inflammatory mediators can enhance drug cytotoxicity through STAT1-mediated downregulation of ROS scavengers.
NATURE COMMUNICATIONS
(2021)
Review
Biochemistry & Molecular Biology
Eric P. Kusnadi, Clelia Timpone, Ivan Topisirovic, Ola Larsson, Luc Furic
Summary: Translation of mRNA is a critical step in protein-coding gene expression, and translational buffering plays an important role in regulating gene expression post-transcriptionally. There are three types of translational buffering: compensation, equilibration, and offsetting, each serving to maintain protein levels despite changes in mRNA levels. This mechanism, particularly translational offsetting, is less well understood but may have significant implications in maintaining protein homeostasis and in disease states.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
(2022)
Article
Biochemistry & Molecular Biology
Raul Jobava, Yuanhui Mao, Bo-Jhih Guan, Di Hu, Dawid Krokowski, Chien-Wen Chen, Xin Erica Shu, Evelyn Chukwurah, Jing Wu, Zhaofeng Gao, Leah L. Zagore, William C. Merrick, Aleksandra Trifunovic, Andrew C. Hsieh, Saba Valadkhan, Youwei Zhang, Xin Qi, Eckhard Jankowsky, Ivan Topisirovic, Donny D. Licatalosi, Shu-Bing Qian, Maria Hatzoglou
Summary: Cells enter a transient hibernation-like state under severe hyperosmotic stress, a response known as adaptive pausing response (APR) that limits ATP supply and consumption while preserving cellular function elements. Recovery from severe stress involves ISR signaling that allows cell cycle progression and reversal of mitochondrial fragmentation.
Correction
Biochemistry & Molecular Biology
Bianca J. Lee, Jacob A. Boyer, G. Leslie Burnett, Arun P. Thottumkara, Nidhi Tibrewal, Stacy L. Wilson, Tientien Hsieh, Abby Marquez, Edward G. Lorenzana, James W. Evans, Laura Hulea, Gert Kiss, Hui Liu, Dong Lee, Ola Larsson, Shannon McLaughlan, Ivan Topisirovic, Zhengping Wang, Zhican Wang, Yongyuan Zhao, David Wildes, James B. Aggen, Mallika Singh, Adrian L. Gill, Jacqueline A. M. Smith, Neal Rosen
NATURE CHEMICAL BIOLOGY
(2021)
Article
Cell Biology
Sakie Katsumura, Nadeem Siddiqui, Michael Rock Goldsmith, Jaime H. Cheah, Teppei Fujikawa, Genki Minegishi, Atsushi Yamagata, Yukako Yabuki, Kaoru Kobayashi, Mikako Shirouzu, Takeshi Inagaki, Tim H. -M. Huang, Nicolas Musi, Ivan Topisirovic, Ola Larsson, Masahiro Morita
Summary: This study elucidates how CNOT6L deadenylase switches off hepatokine expression after responding to stimuli, providing a new strategy for treating metabolic syndrome.
Article
Biochemistry & Molecular Biology
Ikrame Lazar, Bertrand Fabre, Yongmei Feng, Ali Khateb, Philippe Frit, Anna Kashina, Tongwu Zhang, Emily Avitan-Hersh, Hyungsoo Kim, Kevin Brown, Ivan Topisirovic, Ze'ev A. Ronai
Summary: ATE1 is overexpressed in NRAS-mutant melanomas and downregulated in BRAF-mutant melanomas. Decreased ATE1 expression reduces the aggressiveness of melanoma cells and affects their response to drugs and serum deprivation. ATE1 may play a role in regulating the function of AXIN1 in melanoma.
Article
Biochemistry & Molecular Biology
Oro Uchenunu, Alexander Zhdanov, Phillipe Hutton, Predrag Jovanovic, Ye Wang, Dmitry E. Andreev, Laura Hulea, David J. Papadopoli, Daina Avizonis, Pavel Baranov, Michael N. Pollak, Dmitri B. Papkovsky, Ivan Topisirovic
Summary: The dysfunction of mitochondrial complex IV due to mutations in genes encoding cytochrome c oxidase subunits and assembly factors leads to metabolic and signaling perturbations in cancer cells. This dysfunction results in increased NAD(+) regenerating reactions, decreased glucose oxidation, reduced levels of amino acids, and hyperactivation of the IGF1R/AKT axis. Additionally, the loss of SCO2 in HCT116 colorectal cancer cells is associated with reduced proliferation and enhanced migration.
Article
Cell Biology
Dawid Krokowski, Raul Jobava, Krzysztof J. Szkop, Chien-Wen Chen, Xu Fu, Sarah Venus, Bo-Jhih Guan, Jing Wu, Zhaofeng Gao, Wioleta Banaszuk, Marek Tchorzewski, Tingwei Mu, Phil Ropelewski, William C. Merrick, Yuanhui Mao, Aksoylu Inci Sevval, Helen Miranda, Shu-Bing Qian, Maria Manifava, Nicholas T. Ktistakis, Anastasios Vourekas, Eckhard Jankowsky, Ivan Topisirovic, Ola Larsson, Maria Hatzoglou
Summary: This study reveals an osmoadaptation mechanism that is independent of the integrated stress response, involving the reprogramming of translation through the coordinated actions of mTOR and the plasma membrane amino acid transporter SNAT2. This mechanism allows for the restriction and subsequent reactivation of protein synthesis during cellular stress.
Article
Cell Biology
Mahmud O. Abdullah, Run X. Zeng, Chelsea L. Margerum, David Papadopoli, Cian Monnin, Kaylee B. Punter, Charles Chu, Mohammad Al-Rofaidi, Naser F. Al-Tannak, Domenica Berardi, Zahra Rattray, Nicholas J. W. Rattray, Sheela A. Abraham, Eeva-Liisa Eskelinen, David G. Watson, Daina Avizonis, Ivan Topisirovic, Edmond Y. W. Chan
Summary: The relationship between nutrient starvation and mitochondrial dynamics is poorly understood. In this study, researchers found that cells undergoing amino acid starvation show mitochondrial fusion as a response to evade mitophagy, and supplementation of glutamine, leucine, and arginine further enhances this mitochondrial fusion. The fusion response is dependent on mitochondrial fusion proteins Mfn1 and Opa1 but independent of MTORC1. Metabolite profiling indicates that the supplementation replenishes amino acid and nucleotide pools, and inhibition of fumarate hydra-tase, glutaminolysis, or inosine monophosphate dehydrogenase blocks the mitochondrial hyperfusion, suggesting the critical roles of the tricarboxylic acid (TCA) cycle and purine biosynthesis in this response. Metabolic tracer analyses support the idea that supplemented glutamine promotes purine biosynthesis by serving as a donor of amine groups. This study provides insights into a metabolic mechanism that directly senses cellular amino acids to control mitochondrial fusion and cell fate.
Article
Biochemistry & Molecular Biology
Hsin-Wei Tseng, Anthony Mota-Sydor, Rania Leventis, Predrag Jovanovic, Ivan Topisirovic, Thomas F. Duchaine
Summary: This study reveals the direct regulation of Pten alternative polyadenylation (APA) by the mammalian cleavage factor I (CFIm) complex, impacting PTEN protein dosage and having widespread effects on APA in transcriptomes. Differential regulation of Pten APA by CFIm59 and CFIm68 is uncovered, with their divergent functions having broad impact on APA in transcriptomes.
NUCLEIC ACIDS RESEARCH
(2022)
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
Multidisciplinary Sciences
Sophie Kaspar, Christian Oertlin, Karolina Szczepanowska, Alexandra Kukat, Katharina Senft, Christina Lucas, Susanne Brodesser, Maria Hatzoglou, Ola Larsson, Ivan Topisirovic, Aleksandra Trifunovic
Summary: This study reveals the complex interplay between three transcription factors regulating mitochondrial stress response, in which CHOP acts as a regulator to attenuate prolonged ISR and prevent unfavorable metabolic alterations. The interaction between CHOP and C/EBP beta is necessary to adjust ATF4 levels and prevent overactivation of the ATF4-regulated transcriptional program, switching ISR from an acute to a chronic state.
