Effect of the activated Raf protein kinase on the human multidrug resistance 1 (MDR1) gene promoter.
Cancer Lett
; 98(2): 199-205, 1996 Jan 02.
Article
em En
| MEDLINE
| ID: mdl-8556709
ABSTRACT
Revealing the regulatory mechanism of the multidrug resistance 1 (MDR1) gene is important to gain understanding of MDR in tumor cells. Using MDR1 deletion constructs and the 22W mutant of c-Raf in which the NH2-terminal half has been deleted, we examined the effect of the activated Raf on human MDR1 promoter activity in transient expression assay and stable transfectants of GHE-L cells. A DNA sequence exhibiting strong activation of MDR1 promoter by 22W was located between -197 and -136 containing the upstream heat shock element (HSE) motifs without other regulatory elements, whereas the MDR1 deletion construct containing downstream HSE motif showed a relatively weaker activation by 22W. We observed that the activated Raf significantly potentiated the induction of MDRCAT activity in GHE-L cells by sodium arsenite or heat shock, which stimulates heat shock factor (HSF) binding to HSE. In addition, protein kinase A inhibitor (H-87) blocked the activation of the MDR1 promoter by 22W in GHE-L cells in a dose-dependent manner. From these results, we propose the possibility that Raf- and protein kinase A-dependent pathways control the transcription of MDR1 gene via a mechanism involving the modulation of HSF activity.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Regulação da Expressão Gênica
/
Proteínas Proto-Oncogênicas
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Regiões Promotoras Genéticas
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Proteínas Serina-Treonina Quinases
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Resistência a Múltiplos Medicamentos
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
1996
Tipo de documento:
Article