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Principal Investigator: Sarah Elizabeth Walker
Organization: STATE UNIVERSITY OF NEW YORK AT BUFFALO
Fiscal Year: 2024
Award: $333,399
Funding agency: National Institute of General Medical Sciences
SUMMARY:
The level of each protein synthesized in a cell results from both the amount of mRNA available, and
the number of ribosomes that initiate translation of that mRNA. Eukaryotic translation initiation factors
(eIFs) can reprogram which mRNAs are available and translated to produce different levels of the
encoded proteins in response to discrete cellular signals. In fungal species, translational control plays
important roles in host evasion and other pathogenesis mechanisms, and in mammalian species,
altered levels and modifications of eIFs influence cancer progression and other disease states. A
number of protein factors stimulate translation, including the eIF4 factors (4A, B, E, G, and H) that
engage the 5’ cap of mRNA and the small subunit of the ribosome, to promote events prior to start
site recognition. Ample data support roles of the RNA helicase 4A and cofactors 4B and 4G in
unwinding 5’ UTRs to promote translation of structured mRNAs. However, the mRNAs that depend
on 4B activity for translation are distinct from those that rely heavily on 4G, even though both factors
promote 4A activity. Moreover, in striking contrast to protumorigenic 4A and 4G, increased levels of
4B improved survival of patients with aggressive cancers, and preliminary data directly implicated 4B
in opposing metastasis of murine breast cancers. Understanding how 4B mediates translation of
specific transcripts could be important for understanding and predicting metastatic phenotypes.
Finally, posttranslational modifications of the eIF4 factors are known to modulate translation in
mammals, and deregulation is common in disease states. However, it is unclear how modifications of
the eIF4 factors regulate translation in fungal species and how this affects expression of specific
mRNA pools. This proposal takes on these challenges, investing years of experience characterizing
the mechanics of yeast translation initiation and a powerful arsenal of in vitro, genetic, and genome-
wide tools. In order to better understand how mRNAs are selected by ribosomes for translation, the
objective of this work is to understand how 4B achieves translation versus repression of
specific mRNA pools in yeast. Three aims will be pursued: Aim 1. Determine how 4F and 4B
interactions affect translation of 4B hyper and hypo-dependent mRNAs. Aim 2. Elucidate yeast 4B-
RNA binding preferences. Aim 3. Understand how posttranslational modifications (PTMs) of 4F and
4B impact 4B-specific mRNA control. This proposal will use eIF4B as a model to determine how core
translation initiation factors modulate translation versus repression of specific mRNA pools and will
shed light on how robust activity of 4B opposes the metastatic phenotype.
Terms: <5' Untranslated Regions><5'UTR><Acceleration><Address><Affect><Affinity><Assay><Behavior><Binding><Bioassay><Biological Assay><Breast Cancer><C-terminal><Cancer Treatment><Cancers><Cell Body><Cell Communication and Signaling><Cell Function><Cell Physiology><Cell Process><Cell Signaling><Cells><Cellular Expansion><Cellular Function><Cellular Growth><Cellular Physiology><Cellular Process><Complex><Cryo-electron Microscopy><Cryoelectron Microscopy><Cytoplasmic Granules><Data><Dependence><Disease><Disorder><Disseminated Malignant Neoplasm><Early Diagnosis><Early treatment><Electron Cryomicroscopy><Eukaryotic Initiation Factors><Eukaryotic Peptide Initiation Factors><Eukaryotic Translation Initiation Factors><Event><Future><Gel><Generalized Growth><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Growth><In Vitro><Initiation Factors><Intracellular Communication and Signaling><Investments><Knowledge><Link><Malignant Breast Neoplasm><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Mammalia><Mammals><Mechanics><Mediating><Messenger RNA><Metastasis><Metastasize><Metastatic Cancer><Metastatic Lesion><Metastatic Malignant Neoplasm><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Mice><Mice Mammals><Mitotic><Modeling><Modification><Molecular><Molecular Interaction><Murine><Mus><Mutation><Neoplasm Metastasis><Non-Polyadenylated RNA><Outcome><Pathogenesis><Pathway interactions><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Peptide Initiation Factors><Phenotype><Phosphorylation><Play><Post-Translational Modification Protein/Amino Acid Biochemistry><Post-Translational Modifications><Post-Translational Protein Modification><Post-Translational Protein Processing><Posttranslational Modifications><Posttranslational Protein Processing><Protein Biosynthesis><Protein Modification><Protein Phosphorylation><Proteins><Proteome><Putative RNA-Binding Region><RNA><RNA Binding><RNA Binding Domain><RNA Gene Products><RNA Helicase><RNA Recognition Motif><RNA Sequences><RNA bound><RNA vaccine><RNA-based vaccine><RNP Domain><RNP Motif><RNP-1 Signature><Reporter><Repression><Ribo-seq><Ribonucleic Acid><Ribosomal Peptide Biosynthesis><Ribosomal Protein Biosynthesis><Ribosomal Protein Synthesis><Ribosomal Proteins><Ribosomes><Role><Scanning><Secondary Neoplasm><Secondary Tumor><Signal Transduction><Signal Transduction Systems><Signaling><Site><Specificity><Structure><Subcellular Process><Testing><Tissue Growth><Transcript><Translating><Translation Initiation><Translation Initiation Factor><Translational Inhibition><Translational Initiation Factor><Translational Repression><Translations><Work><Yeasts><anti-cancer therapy><biological signal transduction><cancer metastasis><cancer progression><cancer therapy><cancer-directed therapy><cell behavior><cell growth><cellular behavior><cofactor><cryo-EM><cryoEM><cryogenic electron microscopy><eIF-4B><eIF4B><early detection><early therapy><experience><genome mutation><genome scale><genome-wide><genomewide><global gene expression><global transcription profile><granule><human disease><improved><in vitro Assay><in vitro activity><mRNA><mRNA Leader Sequences><mRNA Translation><mRNA capping><mRNA vaccine><mRNA-based vaccine><malignancy><malignant breast tumor><mechanic><mechanical><mutation scanning><mutation screening><neoplasm progression><neoplasm/cancer><neoplastic progression><ontogeny><pathway><patient oriented outcomes><patient prognosis><preference><programs><protein initiation factor eIF-4B><protein synthesis><recruit><response><ribosome footprint profiling><ribosome profiling><social role><synergism><therapeutic target><tool><transcriptome><translation><tumor cell metastasis><tumor progression><tumorigenic>