PO2-dependent differential regulation of multidrug resistance 1 gene expression by the c-jun NH2-terminal Kinase pathway

Hypoxia-induced multidrug resistance 1 ( MDR1) gene expression is known to be mediated by c-Jun NH2-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 HIF1 alpha with c-Jun in the nucleus and requires the activity of the p300/CBP ( CREB-binding protein) coactivator.