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Fig. 3. Interactions between Rb, MDMX and p53 during retinoblastoma formation. (A) Biallelic inactivation of the RB1 gene is the initiating oncogenic event in retinoblastoma. As a consequence, the activity of transcription factors of the E2F family is unleashed, leading to increased S-phase entry and induction of ARF expression. ARF is induced in response to oncogenic stress and a direct E2F3a transcription target. ARF functions as an Mdm2 antagonist and therefore activates the p53 pathway. High ARF expression was indeed recently detected in RB1-deficient retinoblasts and, as a consequence, a high proportion of these cells undergo p53-mediated apoptosis. (B) The p53 pathway is suppressed during the formation of retinoblastoma and the majority of tumors inactivate this pathway through selective amplification and/or overexpression of MDMX.
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