FIGURE 1. Role of MDM proteins in retinoblastoma.

a, Under normal conditions, levels of p53 protein are kept low, partly through negative regulation by MDM proteins. MDM2 is an enzyme that tags p53 with a ubiquitin molecule (Ub), thereby promoting p53 degradation. MDMX also interacts physically with p53 and inhibits its gene-regulatory activity. b, Mutation of the retinoblastoma gene (Rb) results in increased production of the p14^ARF protein, which in turn leads to inactivation of MDM2, thus promoting p53 pathway activation. This leads to cell-cycle arrest or cell death, or facilitates DNA repair. c, Increased expression of MDM proteins in the absence of Rb blocks activation of p53, leading to survival of the abnormal cells and tumour progression. Independently of p53, interactions of MDM with other proteins that regulate cell division, survival and differentiation could also promote tumour progression¹³.