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Cloning and Characterization of the Murine and Rat mrp1 Promoter Regions
The ATP-binding cassette transporter multidrug resistance protein 1 (MRP1) confers resistance to a number of clinically important chemotherapeutic agents. The proximal promoter region of MRP1 is GC-rich and contains binding sites for members of the Sp1 family of trans -acting factors that seem to be...
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Published in: | Molecular pharmacology 2003-11, Vol.64 (5), p.1259-1269 |
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Main Authors: | , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | The ATP-binding cassette transporter multidrug resistance protein 1 (MRP1) confers resistance to a number of clinically important
chemotherapeutic agents. The proximal promoter region of MRP1 is GC-rich and contains binding sites for members of the Sp1 family of trans -acting factors that seem to be important for basal expression. As an approach to searching for other elements that may contribute
to expression, we have sequenced and functionally compared the promoters of the murine and rat mrp1 genes with that of the human gene. All three promoters are GC-rich, TATA-less, and CAAT-less. Conservation of sequence between
rodent and human promoters is limited to a proximal region of 100 nucleotides containing binding sites for members of the
Sp1 family and a putative activator protein-1 element. The 5â²-untranslated region (UTR) of human MRP1 contains an insertion of approximately 160 nucleotides comprising a GCC-triplet repeat and a GC-rich tandem repeat that is
absent from the rodent sequences. Transient transfection analyses demonstrated that the conserved GC-boxes of all three genes
are the major determinants of basal activity. Based on electrophoretic mobility shift assays, each GC-box can be bound by
Sp1 or Sp3. Unlike the rodent genes, the human MRP1 5â²UTR also binds Sp1 but not Sp3, and the human promoter retains substantial activity even in the absence of the conserved
GC-boxes. Finally, we show that the tumor suppressor protein p53 can repress the human and rodent promoters by a mechanism
that is independent of the Sp1 elements. |
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ISSN: | 0026-895X 1521-0111 |
DOI: | 10.1124/mol.64.5.1259 |