Post-transcriptional control model

A more dramatic prediction of the post-transcriptional control model is also substantiated in Figure 6. Following deinduction of a culture inhibition of RNA synthesis should rescue the repressed mRNA and reactivate enzyme formation. Experiments in accord with this prediction were done in HTC cells (Tomkins et al., 1969,1970 Levinson et al., unpublished), and in cultured fetal hamster cells (Bausserman and Nebert, 1970). The results are in remarkably good agreement. In the experiment using HTC cells (Fig. 6) the inducer was removed from the induced culture, and after specified intervals AMD was added to the deinduced culture. As illustrated, TAT formation was reactivated shortly after addition of the inhibitor. Similar results are obtained when the nucleoside analog mercaptopyridethylbenzimidazole (MPB) was used instead of actinomycin D (Levinson, unpublished Tomkins et al., 1970). 

Fig. 4. A model for the post-transcriptional control of tyrosine aminotransferase mRNA utilization in hepatoma cells. For further details see text and Tomkins et td. (1969).

Lessons from the genetic control of translation of ferritin mRNAS and transferrin receptor mRNA stability can be applied to the control of APP expression by iron. This information will be relevant to Alzheimer s disease pathology after applying these models of post-transcriptional control to APP gene expression. 

Indeed, inhibitors of protein synthesis have been used in the in vivo rabbit [60] and in the rat LangendorfT models [61]. Cycloheximide or actinomycin D did not reverse the PC effect [60]. This is probably due to non-complete inhibition of protein synthesis. The latter study [61] showed that the PC effect was abolished only with cycloheximide, but not with actinomycin D, indicating that PC protection is regulated at the post-transcriptional level. Recent findings [62] have reconfirmed the translational control of protein synthesis in ischemic (but not pharmacological) PC. These are in accord with our findings concerning de novo synthesis of ferritin. 

The pre-genomic era was characterized in some measure by a race to acquire information. The post-genomic era saw a secondary race to identify the transcriptional outputs of mammalian genomes, and the impact of proteomic, and ultimately a metabolomic, revolution is probably still to come. However, at this point in time we do have many of the tools needed to create predictive network models of a cellular system like macrophage activation and transcription control. 

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