Lack of control by immediate early response genes in the oxygen regulation of erythropoietin gene expression.

This study sought to investigate the role of immediate early genes in the stimulation of erythropoietin (EPO) gene expression by hypoxia. To this end freshly isolated rat hepatocytes were exposed to either normoxia (20% oxygen) or to hypoxia (1% oxygen) and the mRNA levels of the early genes c-fos, c-jun, c-myc and EGR-1 were monitored together with EPO mRNA. Isolation of the cells from the livers strongly stimulated the expression of c-fos, c-jun, c-myc and of EGR-1, whilst EPO gene expression remained unchanged. Exposure of the isolated hepatocytes to hypoxia did not further change early gene expression when compared with cells kept under normoxic conditions. EPO mRNA increased time dependently with a delay of 1 h after onset of hypoxia. These findings suggest that even strong activation of early gene expression has no influence on EPO gene expression, whilst activation of EPO gene expression during hypoxia can happen without change of early gene expression. It appears, therefore, as if immediate early genes are not causally involved in the sequence of events by which hypoxia stimulates EPO gene expression.