Exploring Internal Ribosome Entry Sites as Therapeutic Targets

Abstract

Initiation of eukaryotic mRNA translation may proceed via several different routes, each requiring a different subset of factors and relying on different and specific interactions between the mRNA and the ribosome. Two modes predominate: (i) so-called cap-dependent initiation, which requires all canonical initiation factors and is responsible for about 95–97% of all initiation events in eukaryotic cells; and (ii) cap-independent internal initiation, which requires a reduced subset of initiation factors and accounts for up to 5% of the remaining initiation events. Internal initiation relies on the presence of so-called internal ribosome entry site (IRES) elements in the 5′ UTRs of some viral and cellular mRNAs. These elements (often possessing complex secondary and tertiary structures) promote efficient interaction of the mRNA with the 40S ribosome and allow for internal ribosome entry. Internal initiation of translation of specific mRNAs may contribute to development of severe disease and pathological states, such as hepatitis C and cancer. Therefore, this cellular mechanism represents an attractive target for pharmacological modulation. The purpose of this review is to provide insight into current strategies used to target viral and cellular IRESs and discuss the physiological consequences (and potential therapeutic implications) of abrogation/modulation of IRES-mediated translation.

A Unique ISR Program Determines Cellular Responses to Chronic Stress

“…The similar role was proposed for the components of the eIF4F complex (Gandin et al, 2016b). These and other examples point to the existence of translation programs that serve as an alternative to the canonical eIF3-eIF4F-dependent mRNA recruitment to the ribosome (Komar and Hatzoglou, 2015). …”

Mammalian Polycistronic mRNAs and Disease

“…In addition, over-expression or depleted expression of ITAFs could cause a direct dysregulation of the secondary protein that could potentially result in disease. A possible therapeutic strategy could be to use genetic knockdown or drug intervention to restore the balance of ITAF expression [40]. Additionally, a disease state may result in alternative localization or alternative cell-specificity of ITAFs and thereby change regulation of secondary protein expression.…”

Targeting RNA helicases in cancer: The translation trap

“…In response to these stressors, cap-dependent translation is downregulated in order to preserve nutrients and energy[55]. Many genes that are upregulated by cells to cope with stress conditions are translated in an IRES dependent fashion[56], which does not require a 5′ cap structure, the cap-binding protein eIF4E or a free 5′ end. Cellular IRES often have a strong secondary structure that recruits the 40S ribosomes to the translation initiation site, either by binding directly to the ribosome or indirectly by binding canonical translation initiation factors like eIF3 and eIF4G or specific IRES transacting factors (ITAFs)[56](Figure 2).…”

“…Many genes that are upregulated by cells to cope with stress conditions are translated in an IRES dependent fashion[56], which does not require a 5′ cap structure, the cap-binding protein eIF4E or a free 5′ end. Cellular IRES often have a strong secondary structure that recruits the 40S ribosomes to the translation initiation site, either by binding directly to the ribosome or indirectly by binding canonical translation initiation factors like eIF3 and eIF4G or specific IRES transacting factors (ITAFs)[56](Figure 2). Because tumor cells are dependent on factors to maintain cellular homeostasis and survive under stressed conditions, IRES mediated translation has been put forward as a therapeutic target in cancer[56].…”

“…Cellular IRES often have a strong secondary structure that recruits the 40S ribosomes to the translation initiation site, either by binding directly to the ribosome or indirectly by binding canonical translation initiation factors like eIF3 and eIF4G or specific IRES transacting factors (ITAFs)[56](Figure 2). Because tumor cells are dependent on factors to maintain cellular homeostasis and survive under stressed conditions, IRES mediated translation has been put forward as a therapeutic target in cancer[56]. Among the IRES mediated proteins are anti-apoptotic proteins like BCL-2[27], c-IAP1[57] and XIAP[55], growth promoting proteins like MYC [58], EGFR[59] and c-jun[60], cell cycle regulator CDK1[27] and regulators of angiogenesis like HIF-1A[61] and VEGF[62].…”