Key Points
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There is extensive crosstalk between the Rb–E2f and MDM2–p53 pathways, and specifically between the transcription factors E2F1 and p53, which influences vital cellular decisions.
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The abundance and activity of both p53 and E2f are often controlled by the same cancer-associated stimuli. Their common regulators include checkpoint kinases and acetyltransferases, MDM2 and the CDKN2A locus.
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Deregulated E2f, which is often present in human tumours, constitutes an oncogenic stress that activates p53. Specifically, E2f indirectly affects the level and activity of p53 by upregulating the expression of many proteins that stabilize and activate p53. Examples include ARF, ataxia telangiectasia mutated and PIN1.
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E2f and p53 cooperate in restricting tumorigenesis by inducing cell death. Their cooperation in apoptosis is attributed to the ability of E2F1 to activate p53. In addition, they activate many pro-apoptotic genes that may cooperate in apoptosis.
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Protein complexes that contain Rb family members and repressor E2fs mediate p53-induced growth arrest and senescence; the latter is an important in vivo mechanism that contributes to protection against cancer.
Abstract
During tumour development cells sustain mutations that disrupt normal mechanisms controlling proliferation. Remarkably, the Rb–E2f and MDM2–p53 pathways are both defective in most, if not all, human tumours, which underscores the crucial role of these pathways in regulating cell cycle progression and viability. A simple interpretation of the observation that both pathways are deregulated is that they function independently in the control of cell fate. However, a large body of evidence indicates that, in addition to their independent effects on cell fate, there is extensive crosstalk between these two pathways, and specifically between the transcription factors E2F1 and p53, which influences vital cellular decisions. This Review discusses the molecular mechanisms that underlie the intricate interactions between E2f and p53.
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Glossary
- Autophagy
-
A catabolic process involving the degradation of a cell's own components by the lysosomal machinery.
- Replicative senescence
-
A largely irreversible spontaneous proliferative arrest of normal untransformed cells after a limited number of cell divisions. It is often caused by progressive shortening of the telomeres at each round of cell division.
- Premature senescence
-
Senescence that occurs before telomeric shortening. Such premature senescence is often associated with the activation of the tumour suppressors INK4A, ARF, p53 and RB.
- Gain-of-function mutations
-
Mutations that change the gene such that the protein gains a new and abnormal function.
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Polager, S., Ginsberg, D. p53 and E2f: partners in life and death. Nat Rev Cancer 9, 738–748 (2009). https://doi.org/10.1038/nrc2718
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DOI: https://doi.org/10.1038/nrc2718
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A CpG island promoter drives the CXXC5 gene expression
Scientific Reports (2021)
