Regulation of Gene Expression in Eukaryotes:- Many Eukaryotic mRNAs Are Subject to Translational Repression
Regulation at the level of translation assumes a much more prominent role in eukaryotes than in bacteria and is observed in a range of cellular situations. In contrast to the tight coupling of transcription and translation in bacteria, the transcripts generated in a eukaryotic nucleus must be processed and transported to the cytoplasm before translation. This can impose a significant delay on the appearance of a protein. When a rapid increase in protein production is needed, a translationally repressed mRNA already in the cytoplasm can be activated for translation without delay. Translational regulation may play an especially important role in regulating certain very long eukaryotic genes (a few are measured in the millions of base pairs), for which transcription and mRNA processing can require many hours. Some genes are regulated at both the transcriptional and translational stages, with the latter playing a role in the fine tuning of cellular protein levels. In some anucleate cells, such as reticulocytes (immature erythrocytes), transcriptional control is entirely unavailable and translational control of stored mRNAs becomes essential. As described below, translational controls can also have spatial significance during development, when the reg ulated translation of prepositioned mRNAs creates a local gradient of the protein product. Eukaryotes have at least three main mechanisms of translational regulation.
1. Initiation factors are subject to phosphorylation by a number of protein kinases. The phosphorylated forms are often less active and cause a general depression of translation in the cell.
2. Some proteins bind directly to mRNA and act as translational repressors, many of them binding at specific sites in the 3 untranslated region (3UTR). So positioned, these proteins interact with other translation initiation factors bound to the mRNA or with the 40S ribosomal subunit to prevent translation initiation (Fig. 1).
3. Binding proteins, present in eukaryotes from yeast to mammals, disrupt the interaction between eIF4E and eIF4G . The mammalian versions are known as 4E-BPs (eIF4E binding proteins). When cell growth is slow, these proteins limit translation by binding to the site on eIF4E that normally interacts with eIF4G. When cell growth resumes or increases in response to growth factors or other stimuli, the binding proteins are inactivated by protein kinase dependent phosphorylation.
FIGURE 1 Translational regulation of eukaryotic mRNA. One of the most important mechanisms for translational regulation in eukaryotes involves the binding of translational repressors (RNA-binding proteins) to specific sites in the 3 untranslated region (3UTR) of the mRNA. These proteins interact with eukaryotic initiation factors or with the ribosome to prevent or slow translation.
The variety of translational regulation mechanisms pro vides flexibility, allowing focused repression of a few mRNAs or global regulation of all cellular translation. Translational regulation has been particularly well studied in reticulocytes. One such mechanism in these cells involves eIF2, the initiation factor that binds to the initiator tRNA and conveys it to the ribosome; when Met-tRNA has bound to the P site, the factor eIF2B binds to eIF2, recycling it with the aid of GTP binding and hydrolysis. The maturation of reticulocytes includes destruction of the cell nucleus, leaving behind a plasma membrane packed with hemoglobin. Messenger RNAs deposited in the cytoplasm before the loss of the nucleus allow for the replacement of hemoglobin. When reticulocytes become deficient in iron or heme, the translation of globin mRNAs is repressed. A protein ki nase called HCR (hemin-controlled repressor) is activated, catalyzing the phosphorylation of eIF2. In its phosphorylated form, eIF2 forms a stable complex with eIF2B that sequesters the eIF2, making it unavailable for participation in translation. In this way, the reticulocyte coordinates the synthesis of globin with the avail ability of heme. Many additional examples of translational regulation have been found in studies of the development of multicellular organisms, as discussed in more detail below.
