Biology subjects

Kanellos, G.

Publications and source records attributed to Kanellos, G..

3 recordsLinked to original sources

bioRxiv2025

The differential mechanisms of eIF4A1-mediated translational activation instructed by distinct RNA features

All mRNAs require eukaryotic translation initiation factor (eIF) 4A1 for translation through its different functions: loading of the pre-initiation complex onto mRNAs and unwinding of RNA structure. eIF4A1 is the catalytic subunit of the cap- binding eIF4F complex and presumed to select the mRNAs for translation through these activities, instructed by signalling pathways driving cell fate. The mechanisms underlying activation of the distinct eIF4A1 functions and establish translational selectivity are unknown. Here, we have unravelled the complexity of mRNA selection by eIF4A1. We have mechanistically characterised the biological and atomic basis of inhibition by gain- and loss-of-function eIF4A1-inhibitors eFT226 and hippuristanol, and used machine learning to model the mRNA features associated with specific inhibition. This uncovered the eIF4A1 function - mRNA sequence relationship: 5UTRs containing C/CG-rich require efficient mRNA loading by eIF4F which is specifically targeted by hippuristanol, while 5UTRs harbouring alternatives starts sites together with AG-rich motifs utilise eIF4A1 for start site selection, specifically perturbed by eFT226. Our model is validated through a massively parallel reporter assay using 5UTRs from a distinct evolutionary origin. This prompted us to examine the conservation between mRNA sequence and eIF4A1 function, and revealed their co- development. Our findings highlight opportunities for novel therapeutic strategies targeting eIF4A1 and for improved design of mRNA-based therapeutics.

cell biology↗

bioRxiv2023

eIF4A1 is essential for reprogramming the translational landscape of Wnt-driven colorectal cancers

Dysregulated translation is a hallmark of cancer. Targeting the translational machinery represents a therapeutic avenue which is being actively explored. eIF4A inhibitors target both eIF4A1, which promotes translation as part of the eIF4F complex, and eIF4A2, which can repress translation via the CCR4-NOT complex. While high eIF4A1 expression is associated with poor patient outcome, the role of eIF4A2 in cancer remains unclear. Furthermore, the on-target toxicity of targeting specific eIF4A paralogues in healthy tissue is under-explored. We show that while loss of either paralogue is tolerated in the wild-type intestine, eIF4A1 is specifically required to support the translational demands of oncogenic Wnt signalling. Intestinal tumourigenesis is suppressed in colorectal cancer models following loss of eIF4A1 but accelerated following loss of eIF4A2, while eIF4A inhibition with eFT226 mimics loss of eIF4A1 in these models.

cancer biology↗

bioRxiv2023

The eIF4A2 negative regulator of mRNA translation promotes extracellular matrix deposition to accelerate hepatocellular carcinoma initiation

Increased protein synthesis supports growth of established tumours. However, how mRNA translation contributes to early tumorigenesis remains unclear. Here we show that following oncogene activation, hepatocytes enter a non-proliferative/senescent-like phase characterized by 5{beta}1 integrin-dependent deposition of fibronectin-rich extracellular matrix (ECM) niches. These niches then promote exit from oncogene-induced senescence to permit progression to proliferating hepatocellular carcinoma (HCC). Removal of eIF4A2, a negative regulator of mRNA translation, boosts the synthesis of membrane/secretory proteins which drives a compensatory increase in the turnover/degradation of membrane proteins including 5{beta}1 integrin. This increased membrane protein degradation, in turn, compromises generation of ECM-rich tumour initiation niches, senescence-exit and progression to proliferating HCC. Consistently, pharmacological inhibition of mRNA translation following eIF4A2 loss restores ECM deposition and reinstates HCC progression. Thus, although inhibition of protein synthesis may be an effective way to reduce tumour biomass and the growth of established tumours, our results highlight how agents which reduce mRNA translation, if administered during early tumorigenesis, may awaken senescent cells and promote tumour progression.

cancer biology↗