IIBBA   05544
INSTITUTO DE INVESTIGACIONES BIOQUIMICAS DE BUENOS AIRES
Unidad Ejecutora - UE
artículos
Título:
A novel hybrid promoter responsive to pathophysiological and pharmacological regulation
Autor/es:
SUBANG MC; FATAH R; BRIGHT C; BLANCO P; BERENSTEIN M; WU Y; PODHAJCER OL; WINYARD PG; CHERNAJOVSKY Y; GOULD DJ
Revista:
JOURNAL OF MOLECULAR MEDICINE (BERLIN, GERMANY)
Editorial:
SPRINGER
Referencias:
Lugar: Berlin; Año: 2011 p. 401 - 411
ISSN:
0946-2716
Resumen:
The aim of this study was to construct a promoter containing DNA motifs
for an endogenous transcription factor associated with inflammation
along with motifs for pharmacological regulation factors. We demonstrate
in transfected cells that expression of a gene of interest is induced
by hypoxic conditions or through pharmacological induction, and also
show pharmacological repression. In vivo studies utilised
electroporation of plasmid to mouse paws, a delivery method shown to be
effective by bioluminescence imaging. For gene therapy, the promoter was
used to drive expression of IL-1Ra in a paw inflammation model with
therapeutic effect observed which was further enhanced when the promoter
was additionally induced with a pharmacological activator. One of the
most important observations from this study was that promoter induction
by hypoxia or inflammation could be prevented by the pharmacological
repressor in the absence of doxycycline. These studies demonstrate that
hybrid promoters enable pharmacological adjustment to the
pathophysiological level of gene expression and, importantly, that they
allow termination of gene expression even in the presence of
pathophysiological stimuli.