The mechanisms of regulation of Hdm2 protein level by serum growth factors

Cell cycle progression in response to serum growth factors is dependent on the expression of functional Hdm2 (Mdm2), which inhibits p53-dependent transcription of anti-proliferative genes. In a well characterised non-transformed human fibroblast model, growth factors induce the expression of Hdm2 with rapid kinetics. Here we dissect the mechanistic basis for this critical response. In contrast to previous studies in which components of the growth factor signalling pathways were overexpressed, hdm2 mRNA expression is not induced with immediate-early kinetics in these cells. Rather, the elevated Hdm2 protein levels which follow growth factor stimulation are primarily a consequence of phosphatidylinositol-3 kinase-dependent stabilisation of the Hdm2 protein combined with a global increase in protein synthesis.