6 Translation Initiation Via Cellular Internal Ribosome Entry Sites

Internal ribosome entry sites (IRESs) in eukaryotic mRNAs were first discovered in viral mRNAs in 1988 (Jang et al. 1988; Pelletier and Sonenberg 1988; for review, see Chapter 5). The first cellular IRES was documented a few years later in the mRNA encoding the human immunoglobulin heavy-chain binding protein, BiP (Macejak and Sarnow 1991). Since then, several dozen cellular IRESs have been reported, although the authenticity of some of them has been called into question. In this chapter, we undertake the definition and description of cellular IRESs, their modes of regulation, and their biological significance. It has long been known that some cellular proteins continue to be expressed under conditions where cap-dependent translation is severely compromised, such as during poliovirus infection, stress, and mitosis (Sarnow 1989; Johannes and Sarnow 1998; Johannes et al. 1999; Clemens 2001; Qin and Sarnow 2004). Such observations led to the hypothesis that these proteins might be expressed from mRNAs under the control of an IRES. Following this reasoning, microarray analysis of polysomes from poliovirus-infected cells, where the cap-binding complex eIF4F is disrupted by cleavage of eIF4G, indicated that up to 3% of eukaryotic mRNAs might contain IRES elements (Johannes et al. 1999; Qin and Sarnow 2004). The mRNAs suggested to have IRES elements are generally not translated efficiently under normal conditions, and they appear to require downregulation of cap-dependent translation for their expression (Merrick 2004; Qin and Sarnow 2004). Furthermore, many of these mRNAs encode proteins that are known or expected to facilitate recovery from...