Mdm2 exerts pro-apoptotic activities by antagonizing insulin-like growth factor-I-mediated survival.
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.
Froment
Pascal
P
Laboratory for Molecular Cancer Biology, VIB-UGent, Gent, Belgium.
Dupont
Joelle
J
Christophe-Marine
Jean
J
D000818:Animals; D002478:Cells, Cultured; D004249:DNA Damage; D006801:Humans; D007150:Immunohistochemistry; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D016159:Tumor Suppressor Protein p53; D007334:Insulin-Like Growth Factor I; D051736:Proto-Oncogene Proteins c-mdm2