Open Access Te Herenga Waka-Victoria University of Wellington
Browse
thesis_access.pdf (9.68 MB)

Investigation of the Biological Effect of eIF4A Reduction and Inhibition

Download (9.68 MB)
thesis
posted on 2021-12-08, 18:13 authored by Richard Little

Translation initiation has been identified as a therapeutic target for many diseases including cancers, Alzheimer’s disease, viral infections and cachexia. One protein involved in this process is the eukaryotic initiation factor 4A (eIF4A), an RNA helicase that is integral for cap-dependent translation initiation. Multiple drugs that inhibit the normal function of eIF4A have been identified, with one currently entering clinical trials. Recent investigations into the effects of eIF4A inhibitor treatment, however, have used concentrations that significantly hinder cell proliferation and survival. However, applications in Alzheimer’s disease, viral infections and cachexia require much lower inhibitor concentrations. Current evidence shows that under these conditions, inhibition of eIF4A leads to disruption of translation of individual transcripts in a manner that is dependent on their sequence and structure. However, the cell-wide effects of eIF4A inhibition at these low concentrations is still not known, and so the mechanisms through which treatments for these diseases will function are not fully elucidated.  Using an expression-based analysis, we investigated the effects of mild perturbation of eIF4A through gene deletion mutations in yeast and low doses of the eIF4A inhibitor pateamine on human cells. With both these approaches we identify a range of expression changes in proteins throughout the proteostatic network, relating to processes such as translation, amino acid production, ribosome biogenesis, protein folding and protein degradation. Processes further removed from translation initiation were also found to be affected but differed between yeast and human cell line models, with energy metabolism being affected in yeast, and telomere maintenance and mRNA metabolism being affected in human cells. We also identified an mRNA 5′ untranslated region sequence that appears to confer a disproportionate reduction in expression only seen in pateamine treatment conditions. Through this approach we identify the key cellular effects of altered eIF4A function and demonstrate differences between reduced eIF4A function and pateamine inhibition.

History

Copyright Date

2020-01-01

Date of Award

2020-01-01

Publisher

Te Herenga Waka—Victoria University of Wellington

Rights License

Author Retains Copyright

Degree Discipline

Cell and Molecular Bioscience

Degree Grantor

Te Herenga Waka—Victoria University of Wellington

Degree Level

Doctoral

Degree Name

Doctor of Philosophy

Victoria University of Wellington Unit

Centre for Biodiscovery

ANZSRC Type Of Activity code

2 STRATEGIC BASIC RESEARCH

Victoria University of Wellington Item Type

Awarded Doctoral Thesis

Language

en_NZ

Victoria University of Wellington School

School of Biological Sciences

Advisors

Teesdale-Spittle, Paul; Peng, Lifeng