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Characterization of the basal and carcinogen regulatory elements of the rat mdr1b promoter
Author(s) -
Silverman Jeffrey A.,
Hill Barbara A.
Publication year - 1995
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.2940130109
Subject(s) - biology , microbiology and biotechnology , carcinogen , transcription (linguistics) , promoter , gene , gene expression , transcription factor , regulatory sequence , genetics , linguistics , philosophy
In this report we characterized the transcriptional regulation of the rat mdr1b gene by xenobiotics. The expression of this gene was increased in primary rat hepatocytes and in the H4‐II‐E hepatoma cell line by exposure to carcinogens such as aflatoxin B 1 , N ‐acetoxy‐2‐acetylaminofluorene, and methyl methanesulfonate. Nuclear run‐on experiments indicated that the higher steady‐state levels of mdr1b mRNA were due to an increase in transcription. The 5′‐flanking region of the mdr1b gene was isolated, sequenced, and functionally characterized in transient and stable transfection assays. A single transcription start site was identified for this gene; no alternate start sites were used after induction with aflatoxin B 1 . Deletion analysis of this promoter demonstrated that the sequence between nt −214 and −178 was critical for basal promoter activity. This region did not contain any consensus‐binding sites for previously identified transcription factors. A negative regulatory region was also identified between nt −940 and −250. No specific carcinogen‐responsive element was identified; the xenobiotic response required a large part of the promoter. These data suggest that the carcinogen induction of mdr1b expression is mediated through sequences that overlap or that are identical to the basal promoter element. © 1995 Wiley‐Liss, Inc.