V. Jerome et R. Muller, A synthetic leucine zipper-based dimerization system for combining multiple promoter specificities, GENE THER, 8(9), 2001, pp. 725-729
One of the biggest challenges facing gene therapy is the development of Vec
tors that direct the activity of therapeutic genes specifically to the site
s of disease. To achieve this goal, the restriction of transgene transcript
ion via synthetic promoters that are endowed with multiple specificities re
presents a particularly promising strategy. Towards this end, we have devel
oped a generally applicable strategy (DCTF system) where a synthetic promot
er is driven by an artificial heterodimeric transcription factor whose DNA-
binding and transactivating subunits are expressed from two promoters with
different selectivity. A crucial determinant of the DCTF system is the hete
rodimerization interface that should provide for a high affinity interactio
n without interference by endogenous proteins. Here, we describe such a dim
erization system based on engineered Fos and Jun leucine zippers. We show t
he usefulness of this system for the combination of cell type-specific and
cell cycle-regulated transcription and demonstrate its functionality in an
in vivo setting.