Activated pp60c-Src leads to elevated hypoxia-inducible factor (HIF)-1alpha expression under normoxia.

Hypoxia-inducible factor (HIF)-1 is a master transcription factor, which up-regulates glycolysis, erythropoiesis, and angiogenesis under hypoxia. HIF-1alpha accumulates in normoxic tumor cells, leading to glycolysis under aerobic conditions. This phenomenon, known as the "Warburg effect," is caused by a yet unknown mechanism. Here we show that transformed cells that express constitutively active pp60(c-Src) (Src) express HIF-1alpha protein under normoxia, which results in the expression of multiple HIF-1alpha target genes. We show that this occurrence is due to an enhanced rate of HIF-1alpha protein synthesis and not due to reduced HIF-1alpha degradation. Furthermore, we show that the Src-induced increase in protein synthesis is due to the global increase in the rate of cap-dependent translation and does not involve inhibition of HIF-1alpha degradation.