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Biochem Biophys Res Commun. 2003 Jan 10;300(2):524-30.

Benzo(c)quinolizinium drugs inhibit degradation of Delta F508-CFTR cytoplasmic domain.

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1
Department of Medical Biochemistry, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, UK.

Abstract

Proteins comprising the first nucleotide-binding- and R-domains of wild-type and Delta F508 cystic fibrosis transmembrane conductance regulator (CFTR) have been synthesised by in vitro transcription/translation. The kinetics and extent of degradation of wild-type and Delta F508 cytoplasmic domain proteins in rabbit reticulocyte lysates, in which proteasome activity was inhibited, were similar, with a half-life of approximately 4h. The results show for the first time, that the benzo(c)quinolizinium compounds, MPB-07 and MPB-91, selectively inhibit degradation of the Delta F508 cytoplasmic domain protein. Studies using protease inhibitors demonstrated that both Delta F508 and wild-type proteins are substrates for cysteine proteases. The studies provide evidence that benzo(c)quinolizinium compounds protect a proteolytic cleavage site by direct binding to the first cytoplasmic domain of Delta F508-CFTR and this is a likely mechanism for increasing Delta F508-CFTR trafficking in intact cells.

PMID:
12504115
[Indexed for MEDLINE]
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