Regulation of translation initiation is a central control point in gene expression (172). Interestingly, several oncogenes, growth factors and proteins involved in the regulation of programmed cell death, cell cycle progression and stress response contain IRES elements in their 5' UTRs. Internal initiation escapes many control mechanisms that regulate cap-dependent translation. Thus, a distinguishing hallmark of IRES-mediated translation is that it allows for enhanced or continued protein expression under conditions where normal, cap-dependent translation is shut-off or compromised. For instance, IRES elements were found to be active during irradiation (102), hypoxia (146, 251), angiogenesis (2), apoptosis (252) and amino acid starvation (63). Together, these observations suggest that IRES-mediated translation initiation of certain mRNAs represents a regulatory mechanism that helps the cell cope with transient stress. Moreover, IRES activity may also participate in the maintenance of normal physiological processes such as adequate synthesis of some proteins during cell cycle progression (42, 219, 230).
Since 1966, it has been known that translation is inhibited during mitosis in higher eukaryotes (239). In fact, while cap-dependent translation is prevalent in the G1/S phase, it is inhibited in the G2/M phase (42, 219). Our current understanding of how translation initiation is inhibited at mitosis surmises that it is the result of multiple events that lead to disruption of the eIF4F complex, there by inhibition of cap-dependent translation (219). Two such events are the dephosphorylation of eIF4E and the hypophosphorylation of 4E-BPs at mitosis, which prevent eIF4F function and assembly, respectively (59, 217, 219). In contrast to cap-dependent translation, IRES-mediated translation initiation is independent of the cap and is therefore independent of eIF4F integrity (78). In agreement, the synthesis of some proteins required for the completion of mitosis, such as ornithine decarboxylase (218) and the cdk-like p58PITSLRE (43), is maintained by an IRES-mediated mechanism. Other examples of IRESs that are active during the G2/M phase of the cell cycle are those harbored by the hepatitis C virus (HCV) (103), some members of the picornaviridae (18), HIV-1 (26), the human cysteine-rich61 protein (Cyr61) (220), La (220), nucleosome assembly protein 1-like 1 (NAP1L1) (220), and c-Myc encoding mRNAs (133, 136, 218). These reports all provide important insight into cell cycle-specific modulation of IRES activity and support the notion that unique, IRES-mediated mechanisms of translation initiation are activated during G2/M to specifically translate IRES-containing mRNAs (219, 230). Even though highly attractive, this hypothesis may not be adequate, as a recent report showed that not all IRES containing mRNAs are selectively translated during mitosis (220). This suggests that the switch from cap- to IRES-mediated translation initiation is not mediated exclusively through the increased availability of canonical translation initiation factors due to the inhibition of cap-dependent translation. Therefore, it is plausible to propose that the enrichment in the cytoplasm of the specific factor(s), ITAFs, required for certain IRESs to function during the different phases of the cell cycle, would collectively play a role in modulating IRES activity.
Intriguingly, most of the known ITAFs have a role in nuclear RNA metabolism and are therefore preferentially confined to the cell nucleus. However, these factors are expected to diffuse into the cytoplasm during the G2/M phase of the cell cycle due to nuclear envelope breakdown. This cytopasmic enrichment of specific ITAFs, in part, may be responsible for the increased activity of some IRESs. Consistent with this possibility, ITAF45 (209), heterogeneous nuclear ribonucleoprotein C (hnRNP C) (133) and Unr (259) are enriched in the cytoplasm during the G2/M phase of the cell cycle. The IRES of FMDV requires ITAF45 (209), the c-myc IRES activity is increased by hnRNP C (133), and the cdk-like p58PITSLRE IRES interacts with the Unr protein (259). Additionally, complementary DNA microarray studies show that a number of other factors known to bind or interact with IRESs such as PCBP2, PTB, hnRNP L, eIF3 and La protein are induced during the S and G2/M phases (106).
It is also possible that RNA-binding proteins differentially inhibit the activity of some IRESs. Consistent with this possibility, HuD and HuR _members of the Hu family of RNA-binding proteins known to interact with AU-rich elements and the poly(A) tail_ decrease p27 protein expression by reducing the p27Kip1 IRES activity, while PTB is known to enhance the p27Kip1 IRES activity (9, 37, 143). Interestingly, this interplay of RNA-binding proteins and the p27Kip1 IRES activities occurs in a cell-cycle-dependent fashion (37, 143).
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