Heat shock and arsenite increase expression of the multidrug resistance (MDR1) gene in human renal carcinoma cells.
The multidrug transporter, initially identified as a multidrug efflux pump responsible for resistance of cultured cells to natural product cytotoxic drugs, is normally expressed on the apical membranes of excretory epithelial cells in the liver, kidney, and intestine. This localization suggests that the multidrug transporter may have a normal physiological role in transporting cytotoxic compounds or metabolites. In the liver, hepatectomy or treatment with chemical carcinogens increases expression of the MDR1 gene which encodes the multidrug transporter. To evaluate conditions which increase MDR1 gene expression, we have investigated the induction of the MDR1 gene by physical and chemical environmental insults in the renal adenocarcinoma cell line HTB-46. There are two strong heat shock consensus elements in the major MDR1 gene promoter. Exposure of HTB-46 cells to heat shock, sodium arsenite, or cadmium chloride led to a 7- to 8-fold increase in MDR1 mRNA levels. MDR1 RNA levels did not change following glucose starvation or treatment with 2-deoxyglucose and the calcium ionophore A23187, conditions which are known to activate the expression of another family of stress proteins, the glucose-regulated proteins. The levels of the multidrug transporter, P-glycoprotein, as measured by immunoprecipitation, were also increased after heat shock and sodium arsenite treatment. This increase in the level of the multidrug transporter in HTB-46 cells correlated with a transient increase in resistance to vinblastine following heat shock and arsenite treatment. These results suggest that the MDR1 gene is regulatable by environmental stress.
Chin
K V
KV
Laboratory of Molecular Biology, National Cancer Institute, Bethesda, Maryland 20892.
Tanaka
S
S
Darlington
G
G
Pastan
I
I
Gottesman
M M
MM
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000230:Adenocarcinoma / Q000235:genetics*; D001151:Arsenic / Q000494:pharmacology*; D018053:Arsenites; D001483:Base Sequence; D002104:Cadmium / Q000494:pharmacology; D019256:Cadmium Chloride; D000001:Calcimycin / Q000494:pharmacology; D003847:Deoxyglucose / Q000494:pharmacology; D004351:Drug Resistance / Q000235:genetics*; D015870:Gene Expression / Q000187:drug effects*; D006360:Heat-Shock Proteins / Q000235:genetics; D006358:Hot Temperature; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018053:Arsenites; D006360:Heat-Shock Proteins; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D002104:Cadmium; D000001:Calcimycin; D003847:Deoxyglucose; D019256:Cadmium Chloride; C015001:arsenite; D001151:Arsenic