Sequence analysis and functional characterization of the 5'-flanking region of the rat multidrug resistance protein 2 (mrp2) gene

Kauffmann, H.M.; Schrenk, D.

Biochemical and Biophysical Research Communications 245(2): 325-331

1998


ISSN/ISBN: 0006-291X
PMID: 9571149
DOI: 10.1006/bbrc.1998.8340
Accession: 009398636

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Abstract
Gene expression of the canalicular conjugate transporter mrp2 is inducible by treatment with the DNA-damaging agents 2-acetylaminofluorene (50 and 100 muM), and cisplatin (20 muM) in primary rat hepatocytes as well as in the rat hepatoma cell line H4IIE. Furthermore, phenobarbital (1 and 2 mM) induces mrp2 gene expression, probably explaining the increase in bile-salt-independent bile flow caused by phenobarbital, while the cholestatic drug ethinyl estradiol (10-6 M) leads to an increase in mrp2 mRNA but decreases Mrp2 protein level probably via a posttranscriptional mechanism. The 5'-flanking region of the rat mrp2 gene was sequenced and cloned into a luciferase reporter vector. Transient transfection assays with reporter vectors containing unidirectionally deleted 5'-flanking regions using H4IIE cells indicate that two different sequences of 17 and 37 bases comprising a Y-Box and a GC-Box are required for mrp2 gene basal expression. Sequences mediating 2-AAF induction are located within a region 250 bases upstream of the translation start site while the inducing effect of phenobarbital seems to be mediated by another domain located further upstream.

Sequence analysis and functional characterization of the 5'-flanking region of the rat multidrug resistance protein 2 (mrp2) gene