Abstract
Hypoxia-induced multidrug resistance 1 (MDR1) gene expression is known to be mediated by c-Jun NH(2)-terminal kinase (JNK) activation. However, the molecular mechanisms underlying this action of JNK remain elusive. On the contrary, there has been increasing evidence for a negative correlation of JNK activity with MDR1 expression under normoxic conditions. Here, we present evidence that the JNK pathway represses MDR1 expression in normoxia and activates MDR1 expression in hypoxia. Our data show that JNK pathway-induced MDR1 repression in normoxia is mediated by increased c-Jun binding to activator protein 1 site, located in the MDR1 promoter, and requires the activity of histone deacetylase 5. In contrast, JNK pathway-induced MDR1 activation in hypoxia is independent of the activator protein 1 site. Rather, this action is dependent on increased hypoxia-inducible factor 1 (HIF1) binding to the hypoxia response element in the MDR1 promoter, which is promoted by the interaction of HIF1alpha with c-Jun in the nucleus and requires the activity of the p300/CBP (CREB-binding protein) coactivator.
Highlights
Tissue hypoxia, a decrease in local oxygen tension (PO2), is a common feature of developing tumors
Jun NH2terminal kinase (JNK) Represses Multidrug resistance 1 (MDR1) Expression in Normoxia and Activates MDR1 Expression in Hypoxia—By Western blot analysis, we found that adenovirus-mediated overexpression of JNK in HOP62 cells reduced P-glycoprotein level in normoxia but enhanced P-glycoprotein level in hypoxia, and hypoxia alone induced a modest increase in P-glycoprotein level (Fig. 1, A and B)
Luciferase reporter assay using the MDR1 promoter further showed that transfection of cells with JNK reduced MDR1 promoter activity in normoxia and enhanced MDR1 promoter activity in hypoxia (Fig. 1D)
Summary
A decrease in local oxygen tension (PO2), is a common feature of developing tumors. Our data show that JNK pathway-induced MDR1 repression in normoxia is mediated by increased c-Jun binding to activator protein 1 site, located in the MDR1 promoter, and requires the activity of histone deacetylase 5.
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