We have identified TRB3, a human homologue of Drosophila tribbles, as a novel transcriptional target of phosphatidylinositol (PI) 3-kinase. TRB3 expression is remarkably reduced in prostate cancer PC-3 cells after inhibition of PI 3-kinase. TRB3 expression is furthermore controlled by nutrient supplies: Both the lack of glucose or amino acids results in a substantial increase in TRB3 protein levels in a PI 3-kinase-dependent manner. This increase is reversed by the addition of fresh nutrients. Stress stimuli, such as osmotic stress, hypoxia or serum starvation do not affect TRB3 expression. Thus, TRB3 may function as a nutrient sensor. Inhibition of TRB3 expression has no effect on growth of PC-3 cells under regular growth conditions. However, in the absence of glucose overexpression of TRB3 in PC-3 cells can interfere with apoptosis and restore growth on extracellular matrix. Taken together, our data point to an important role of TRB3 in sensing reduced nutrient supplies and in providing survival signals during these periods.