The Mdm2 oncoprotein is an E3 ubiquitin ligase required to maintain the p53 protein at low levels in embryonic and adult tissues. It also contributes to tumor formation by antagonizing p53 tumor suppressor activity when amplified and/or overexpressed. p53-independent role for Mdm2 has been suggested by transfection studies. Among the growing list of putative Mdm2-regulated proteins are several proteins playing a key role in the control of cell proliferation such as pRb, E2F1/DP1, Numb, Smads, Lats2 or IGF-1R. Consistent with the ability of Mdm2 to promote ubiquitylation and proteasome destruction of IGFR-I independently of p53, we show herein that loss of Mdm2 leads to a significant increase in IGF1-R-beta protein levels both in cells lacking or expressing p53. Interestingly, IGF-1 protects cells from DNA-damage-induced apoptosis only in absence of Mdm2. These data therefore further highlight a physiological role for Mdm2 in the control of IGF1 signalling and provide genetic evidence for a p53-independent proapoptotic function of Mdm2.