Ho

Figure 9 Chemical structure of pristinamycin I (PI), inducer of the streptogramin-responsive system. See text for additional details.

the Mph(A) promoter. Upon binding to EM, MphR(A) dissociates from its target DNA sequence, thus allowing transcription of Mph(A) gene (85).

Very similarly to the streptogramin system, Erythromycin ON (Eon) and OFF (E0ff) systems were generated (86). The EOFF system is based on an erythromycin dependent transacti-vator ET1, a fusion between MphR(A) and VP16, which binds to an erythromycin responsive promoter (PETR) consisting of the Mph(A) operator fused to Phsp70min minimal promoter. The EON switch relies on MphR(A)-KRAB fusion binding to an artificial ETR octamer cloned downstream of the SV40 promoter. As expected from the ligand-binding and DNA-binding properties of MphR(A), and similar to the streptogramin systems, the EOFF and EON systems are activated by drug withdrawal and administration, respectively. Also in this case, MphR(A)-KRAB fusion proteins increased the stringency of the EOFF system. Hundreds-fold induction and low basal activity were reported in transient and stable transformants. In addition, both the on and off systems proved capable of regulating Epo expression in an EM dose-dependent manner from intra-peritoneally injected stable transformants carrying the regulatory system and the regulated Epo gene (86).

Both the streptogramin- and the macrolide-responsive systems are still in their infancy and we can predict that, as happened with other systems, they will be progressively improved in terms of inducibility, potency, and drug-responsiveness. In

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