Loss of pRb through genetic mutation results in activation of E2F transcription factors. Deregulated E2Fs can promote cell proliferation through transcription of cell cycle and DNA synthesis genes, but can also induce apoptosis through upregulation of ARF and p53 activity. This control mechanism is lost in the absence of p53. While loss of p53 is rare in RB tumors, amplification of the p53 inhibitors Mdm2 or MdmX (blue) can result in decreased p53 activity, thus inhibiting apoptosis and promoting cell proliferation. Inhibitors of Mdm2 and MdmX, such as nutlin-3 (red), can restore p53 activity to RB tumor cells by preventing association of Mdm2 and MdmX with p53, thus promoting p53-mediated apoptosis. Topotecan (green), another targeted therapy, functions by inhibiting topoisomerase I and creating DNA double-strand breaks, which triggers apoptosis through both p53-dependent and p53-independent pathways (128). Through alternative pathways, deregulated E2F activity resulting from pRb loss can also result in p53-independent apoptosis, as well as escape from senescence and de-differentiation.