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Cancer Therapeutics
Science
Both eIF4E and eIF2α are rate limiting components of cap-dependent mRNA translation in eukaryotic cells. The cap-structure at the 5’ end of mRNA is recognized by eIF4F – a complex of eIF4A ~ eIF4E ~ eIF4G. eIF4E is the rate limiting step in the formation of of the eIF4F initiation complex, and is responsible the correct positioning of ribosomal subunits to initiate translation (with mRNA). eIF2α along with GTP and the Met charged initiator tRNA (Met-tRNA) form the Ternary Complex which binds to the 40s ribosomal subunit. These proteins work together to place the initiator tRNA on the AUG start codon and start translation of mRNA into proteins.
A naturally occurring regulatory molecule or binding protein, 4E-BP, binds to the initiation factor eIF4E, preventing its association with eIF4G, thereby preventing the proper association with mRNA and halting translation. Over-expression of 4E-BP reverses cell transformation and inhibits tumor growth.
Inhibition of translation mediated by eIF4E and the Ternary Complex targets pro-oncogenic genes due to differential complexity of their mRNA 5’ UTRs (untranslated regions). Two classes of mRNAs exist based on the length of their respective 5’ UTRs.
- Strong mRNAs have short simple 5' UTRs
- Weak mRNA have long complex 5' UTRs
At least two thirds of weak mRNAs code for proto-oncogenes or proteins that regulate proliferation, angiogenesis, and apoptosis. Since weak mRNAs are highly dependent on a functional translation initiation complex eIF4E/eIF4G and the Ternary Complex, preventing formation of these complexes selectively inhibits genes regulating oncogenesis and tumor progression.