pRB induces Sp1 activity by relieving inhibition mediated by MDM2

pRB activates transcription by a poorly understood mechanism that involves relieving negative regulation of the promoter specificity factor Sp1. We sh ow here that MDM2 inhibits Sp1-mediated transcription, that MDM2 binds dire ctly to Sp1 in vitro as well as in vivo, and that MDM2 inhibits the DNA-bin ding activity of Sp1. Forced expression of pRB relieves MDM2-mediated repre ssion, and interaction of pRB with the MDM2-Sp1 complex releases Sp1 and re stores DNA binding. These results suggest a model in which the opposing act ivities of MDM2 and pRB regulate Sp1 DNA-binding and transcriptional activi ty.