Ramírez-Valle et al. The results help explain why that eIF is commonly overexpressed in breast cancers.
The same group previously showed that malignancy in human breast cancers is correlated with high levels of eIF4GI, a scaffolding protein within the translation initiation complex. In the new work, the authors block production of this protein to understand its effects on cells. In its absence, overall protein synthesis rates in an epithelial cell line were only partially reduced, but the cells were small and replicated slowly, similar to cells undergoing nutrient starvation.
Like starved cells, those lacking eIF4GI had lethargic mitochondria and thus low ATP levels. In an attempt to boost ATP levels, the cells began to cannibalize their own contents via autophagy.
Some mRNAs were affected more than others by the absence of eIF4GI. By identifying transcripts on polysomes, the group showed that loss of eIF4GI specifically blocked the translation of mRNAs necessary for proliferation and energy production.
These transcript-specific effects might explain how cancer cells with extra eIF4GI thrive in the dense tumor environment, where cells should be starved for oxygen and nutrients. The initiation factor might therefore be a good target for cancer therapeutics.
According to the authors, the findings suggest that translation initiation requires individualized factors for classes of transcripts, much as transcription factors differentially activate promoters. The molecular basis for eIF4GI's preference for certain mRNAs is unknown. Many of the transcripts that depended on eIF4GI were in very low abundance or had additional upstream open reading frames. eIF4GI is known to help load the extra ribosomes needed to translate downstream reading frames.