Anti- and proapoptotic functions of the RB transcriptional regulator. (Top) During normal cell cycle progression, RB phosphorylation by Cyclin/CDK complexes results in the dissociation of RB and E2F transcription factors and activation of E2F target genes. RB's ability to restrict cell cycle progression is thought to be one of its major tumor-suppressive roles in cells. (Bottom left) When RB is inappropriately inactivated in quiescent cells or cells exiting the cell cycle—for example, by gene mutation, protein degradation, or hyperphosphorylation—activation of E2F in the wrong context may result in the activation of cell death genes (in addition to cell cycle genes), which may help suppress cancer initiation. (Bottom right) In response to certain stresses (e.g., DNA damage or oncogene activation), RB can specifically bind to E2F-1 even in cycling cells and promote the expression of cell death genes, thereby thwarting the expansion of abnormal cells and suppressing cancer development.

Similarities between RB and p53 in the induction of apoptotic cell death. Both p53 (directly) and RB (with E2F1 or via E2F activity) can increase the transcription of proapoptotic genes in the nucleus. Only some of the known targets are shown, with a focus on genes encoding key apoptotic regulators and common targets between p53 and E2F. Components or regulators of the apoptotic machinery at the mitochondria are highlighted in a box. Note that Puma can disrupt the interaction between p53 and Bcl-X_L, thereby allowing p53 to activate Bax and Bak. The new study from indicates that RB can also directly control Bax at the mitochondria, similarly to p53, which can activate Bax and Bak at the mitochondrial membrane to promote apoptotic cell death.