Our understanding of gene expression and regulation has undergone tremendous strides over the past several decades due to the successes of many laboratories in elucidating the control of transcription. But of course, the control of gene expression in mammalian cells extends to many levels beyond transcription and occurs in the nucleus and cytoplasm. For example, in the nucleus, pre-mRNA molecules undergo modifications involving the addition of a 5! cap structure and for most, the addition of a 3! poly (A) tract. These two modifications improve the translation and stability of mRNAs. Some genes encode alternative polyadenylation sites, the choice of which can determine the sequence of the 3! noncoding region of the mRNA. Many premRNA molecules must also be processed by the splicing machinery to remove introns. In some cases, pre-mRNAs transcribed from a single gene are alternatively spliced to create multiple mRNA species with differing exon compositions. Clearly, this can affect the coding and/or noncoding regions of mRNAs. Additionally, mRNA coding sequences can be altered by RNA editing processes, such as site-specific base modification of a C to a U (which introduces a stop codon in some mRNAs). Messenger RNA molecules must then be actively transported to the cytoplasm. In the cytoplasm, mRNA degradation processes contribute to establishing suitable steady-state levels, which in turn impact protein levels. Protein levels are the result of the differences in their rates of synthesis by translation versus their rates of degradation. Translation of mRNAs can be regulated in several ways. For example, multiple AUGs in the 5! noncoding region, short upstream open reading frames (uORFs), and structured 5! noncoding regions can severely limit translation of the downstream protein coding region. These controls are often found in the mRNAs of protooncogenes and other genes important for cellular growth and differentiation. Messenger RNAs, such as those encoding proteins important for cell growth, can also contain internal ribosome entry sites (IRES), which as the name implies, permits initiating ribosomes to begin translation internally without prior scanning of the 5! noncoding region. Messenger RNAs can also contain cis-acting sequences that control their translation rates. These control sequences include A+ U–rich elements (AREs) in the 3! noncoding region and 5! terminal oligopyrimidine tracts (5!-TOPs). AREs are found in many mRNAs encoding proteins important for cell growth and immune function; 5!-TOPs are found in mRNAs encoding components of the translational machinery. For protein molecules themselves, posttranslational modifications may be required for proper functioning of the protein. Additionally, a protein’s function may require that it be localized in the proper intracellular compartment or that it be secreted. Clearly, posttranscriptional processes can contribute significantly both to the abundance of a protein and the timing of its expression, and they can provide multiple regulatory points to control each of these parameters. Alterations in the expression of some transcription factors, cytokines, growth factors, and signal transduction components can lead to cellular transformation (for a review, see reference 1). Loss of posttranscriptional controls for the syntheses of these proteins contributes to their inappropriate expression, leading to eventual transformation (for a review, see reference 2).

Several discoveries over the past several years have increased our appreciation of the roles that controlling mRNA degradation and translation can have for normal immune function and cell growth. Shaw and Kamen (3) and …