CAP Dependent Vs. Initiation Factor Independent Translation
One caveat to the function of 4EGI-1 and thus the entire class of 4E-BP regulatory proteins is that both the synthetic and naturally occurring molecules are effective at inhibiting only cap-dependent translation, not initiation factor independent translation.
Messenger RNAs (mRNAs) are transcribed from DNA, and serve as templates for the synthesis of proteins by ribosomal translation. Weak mRNAs contain long and highly structured untranslatable regions at their 5’ end. This lengthy region makes it difficult for enzymes to determine where transcription should begin. As a result, initiation factor proteins are required for translation of the message into protein. These weak mRNAs, or mRNAs that carry the code for proteins involved in the development of cancer cells, require cap-dependent translation which necessitates the cellular involvement of the eIFs. Examples of weak mRNAs include those that code for proliferation-related, and anti-apoptotic proteins. Strong mRNAs, in contrast, are translated with much less cellular machinery such as eIFs and generally code for biologically necessary proteins, such as those needed for the essential metabolic processes of a cell. Therapies such as the use of 4EGI-1 against cancer cells can thus be created such that their biologic targets include only the initiation factors involved in the production of weak mRNA’s.
Cap-dependent translation involves a series of steps that join the small and large ribosomal subunits at the start codon of mRNA. The initiation factor complex eIF4F is dependent upon the presence of a 5’ mRNA cap upstream from the start codon in order to initiate translation.4
Initiation factor independent translation does not require the association of initiation factors with the 5’ cap of mRNA. As an alternative, the associated ribosomal units are moved to the start location by Internal Ribosome Entry Site trans acting factors (ITAF)s. It has been found that several cellular proteins that respond to apoptotic signals are translated in this fashion.5
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