Globin synthesis translational control

Eukaryotes potentially have many more opportunities for control of gene expression than do bacteria. For example, the cell could take advantage of control at the level of the processing of primary transcripts. It is known that RNA is not transported across the nuclear membrane until all introns are excised. A more subtle form of control could involve alternative modes of splicing a particular transcript. There are now examples known where this occurs to yield different mRNA molecules. Perhaps one of the best-known examples of yet another level of control in eukaryotes is that of translational control of globin synthesis. 

Globin is synthesized in reticulocytes (see Chap. 1, Prob. 1.1). which have no nucleus and therefore cannot utilize transcriptional and other potential modes of control. Control of globin synthesis from the pool of globin-enriched mRNA is geared to the concentration of hemin (Fe(III)-protoporphyrin]. which has the ability to inactivate a translational inhibitor of protein synthesis. The inhibitor is a protein kinase that phosphorylates and inactivates one of the initiation factors involved in initiation of translation. When the concentration of hemin is high, it binds to a regulatory subunit of the kinase and. as a result, initiation of globin synthesis can proceed. 

The rabbit reticulocyte, which synthesizes about 90 of its protein as hemoglobin, offers one of the best examples of translational control of protein synthesis in animal cells. In the complete absence of a nucleus (which is extruded from the cell during its maturation) it coordinates the production of the a and R chains of globin, both with each other and with the supply of heme. However, the exact mechanism of this translational control is not yet fully understood, and only a partial description of what appears to be a surprisingly complex process can be given below. 

Gross, M., 1974, Control of globin synthesis by hemin An intermediate form of the translational repressor in rabbit reticulocyte lysates, Biochim. Biophys. Acta 366 319. 

Gross, M., and Rabinovitz, M., 1972a, Control of globin synthesis in cell-free preparations of reticulocytes by formation of a translational repressor that is inactivated by haemin, Proc. Natl. Acad. Sci. USA 69 1565. 

Here we wish to consider the role of hemin in translational control of globin synthesis. The subject of hemin control has been considered in further detail by Lodish (1976), Nienhaus and Benz (1977), Revel and Groner (1978), and Safer and Anderson (1978). The main phenotypic protein of reticulocytes is hemoglobin, which accounts for about 90%... 

Fig. 9. Hypothesis on the control of hemoglobin synthesis in chick embryo blastoderm by control of the synthesis of ALA-synthetase. In the nucleus a repressor protein (I) blocks transcription, and a 5jS-H steroid acts as a derepressor, permitting the structural gene (II) to code for the mRNA of ALA-synthetase. In the cytoplasm the information in the mRNA is translated into the enzyme ALA-synthetase (E,) which migrates into the mitochondrion where ALA (III) is made and finally converted by other enzymes (E2-E7) to heme (IV). Heme controls the synthesis of globin either by acting at the initiating site or by permitting proper folding of the globin.

A structural polypeptide in the form of surface tubules has also been implicated in shut-off (Mbuy et al., 1982). Exposure of HEp-2 cells to high concentrations of surface tubules (equivalent to 10 par-ticles/cell) resulted in a striking inhibition of protein synthesis. Under similar conditions of infection, host RNA and DNA synthesis were not inhibited. The translation of globin mRNA in a messenger-dependent reticulocyte lysate was also inhibited by these surface tubules. These workers performed a series of control experiments, including the use of specific antibodies for surface tubules, to show that shut-off by these tubules was specific. However, these tubules were obtained by extraction with a non-ionic detergent (Nonidet P40), and it is well known that this and similar detergents (Triton X) remain firmly bound to proteins and require extensive dialysis or other pro-... 

The difiFerentiation of erythroid cells, the induction of hemoglobin synthesis, and the switch from embryonic and fetal to adult hemoglobin synthesis, may be explicable in terms of control at the level of transcription of genes. Processes such as the coordination of synthesis of heme and globin and of assembly of a and j8 chains, which are operative during stages of erythroid cell development in which no RNA is synthesized, are more likely to be explicable in terms of translation. 

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