line with this prediction is the recent report that the performance of both systems can be dramatically improved by introducing minor modifications to the molecular architecture of their target promoters (87).
An attractive feature of both systems is that they are activated by clinically licensed compound, which may facilitate their use, especially for short-term applications. As for the Tet system, the ON configurations have greater potential for gene therapy applications, but additional work in preclinical models will be required to more precisely evaluate the positive and, possibly, negative features of both systems.
IV. DIMERIZER-REGULATED SYSTEM A. General Principles
The initial concept of using chemical dimerizers of proteinprotein interaction in order to activate biological processes is due to the pioneering work of S. Schreiber and G. Crabtree (88,89). However, its further evolution and adaptations to a variety of applications, including transcriptional activation, is due mainly to the activity of the ARIAD Gene Therapeutics Inc. group. Several recent reviews have nicely summarized the work in this area (90-92).
The foundation of this system is the use of chemical dimer-izers, small chemical entities with two distinct binding surfaces for identical or different polypeptides (89,92). The prototype molecule utilized for this purpose, FK1012, is a homodimer of the immunosuppressant drug FK506. It bears two identical, high-affinity, protein-binding surfaces for FKBP12, a 12-kDa cytoplasmic protein (88,89). FK1012 as
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