IRES-Dependent, Cap-Independent Translation in Multiple Myeloma

Chapter

Abstract

Due to their significant production of immunoglobulin, malignant myeloma plasma cell clones must maintain viability and continually expand while laboring under heightened endoplasmic reticulum (ER) stress. One potential mechanism to accomplish these goals is the use of cap-independent translation mediated by internal ribosomal entry sequences (IRESs). These sequences, found in only a select number of transcripts, facilitate translation that is independent of RNA cap-binding to initiation factors. Thus, the myeloma cell could globally restrain protein translation (e.g., by over-expressed DEPTOR-inhibiting mTOR function) yet allow selected protein translation through IRES activity. This review highlights previous work that supports this hypothesis, namely, that (1) IRESs exist in important transcripts implicated in myeloma progression (i.e., D-cyclin, c-myc, VEGF); (2) there is a myeloma-specific c-myc point mutation that markedly enhances IRES-dependent translation; and (3) IRES function is important in myeloma cell responses, at least when challenged with mTOR inhibitors or stimulated with IL-6.

Keywords

Cellular stress Multiple myeloma Cap-dependent and –independent Internal ribosome entry sequence (IRES) Untranslated region (UTR) mTOR inhibition Codon IRES trans-acting factors Translation initiation factors Apoptosis Endoplasmic reticulum (ER) Unfolded protein response ER-associated protein degradation 

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© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Department of MedicineGreater Los Angeles va Healthcare Center, Ucla School of Medicine and Jonsson Comprehensive Cancer CenterLos AngelesUSA

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