Extensive p53 and E2F1 Cross-talk Within Intrinsic Apoptotic Circuitry
Common Upstream Regulators of E2F1 and p53
I. Checkpoint Kinases and acetylation
Both p53 and E2F1 protein levels stabilize with parallel kinetics in response to the same stimuli, such as DNA damage. Stabilization occurs through post-translational modifications imposed to interfere with protein turnover. In response to DNA damage, ataxia telangiectasia mutated (ATM) and the checkpoint kinases (CHK1 and CHK2) phosphorylate both E2F1 and p53 to stabilize protein levels. Human tumors with inactivating TP53 mutations (gene encoding p53) can still achieve p53-independent apoptosis as CHK1/2 phosphorylate and stabilize E2F1 which activates p73.
Protein levels are also stabilized through DNA damage-induced acetylation by the acetyltransferases CBP/p300 and PCAF/GCN5. DNA-damage-induced acetylation of p53 by p300 and PCAF regulates p53 DNA binding and transactivation, while p300 and PCAF acetylation of E2F1 biases it towards activation of pro-apoptotic targets such as p73. Antagonistic to DNA-damage activated acetyltransferases, the NAD-dependent deacetylase SIRT1 interacts with and inhibits the transcriptional and apoptotic activities of both p53 and E2F1, even in the context of DNA damage.
The E3 ubiquitin ligase MDM2 also regulates both p53 and E2F1. MDM2 directly binds to and inhibits p53 transcriptional activity, ubiquitinates p53 to target it for proteosomal degredation, and inhibits TP53 mRNA translation. In addition to the p53 axis, MDM2 targets the pRB-E2F axis by directly binding pRB, E2F1, and DP1 to promote G1-S phase transition. MDM2 interaction with E2F1 or DP1 stimulates transcription E2F1 target genes involved in cell cycle progression, thus serving as a co-activator with target specificity for the entire transcriptional complex. MDM2 binds the F-box protein SKP2 to prevent it from targeting E2F1 for degradation. MDM2 promotes degredation of pRB in a proteosome-dependentubiquitin-independent manner. In summary, MDM2 degrades the E2F repressor pRB while stabilizing E2F1 levels and ensuring specif
II.
I. Checkpoint Kinases and acetylation
Both p53 and E2F1 protein levels stabilize with parallel kinetics in response to the same stimuli, such as DNA damage. Stabilization occurs through post-translational modifications imposed to interfere with protein turnover. In response to DNA damage, ataxia telangiectasia mutated (ATM) and the checkpoint kinases (CHK1 and CHK2) phosphorylate both E2F1 and p53 to stabilize protein levels. Human tumors with inactivating TP53 mutations (gene encoding p53) can still achieve p53-independent apoptosis as CHK1/2 phosphorylate and stabilize E2F1 which activates p73.
Protein levels are also stabilized through DNA damage-induced acetylation by the acetyltransferases CBP/p300 and PCAF/GCN5. DNA-damage-induced acetylation of p53 by p300 and PCAF regulates p53 DNA binding and transactivation, while p300 and PCAF acetylation of E2F1 biases it towards activation of pro-apoptotic targets such as p73. Antagonistic to DNA-damage activated acetyltransferases, the NAD-dependent deacetylase SIRT1 interacts with and inhibits the transcriptional and apoptotic activities of both p53 and E2F1, even in the context of DNA damage.
The E3 ubiquitin ligase MDM2 also regulates both p53 and E2F1. MDM2 directly binds to and inhibits p53 transcriptional activity, ubiquitinates p53 to target it for proteosomal degredation, and inhibits TP53 mRNA translation. In addition to the p53 axis, MDM2 targets the pRB-E2F axis by directly binding pRB, E2F1, and DP1 to promote G1-S phase transition. MDM2 interaction with E2F1 or DP1 stimulates transcription E2F1 target genes involved in cell cycle progression, thus serving as a co-activator with target specificity for the entire transcriptional complex. MDM2 binds the F-box protein SKP2 to prevent it from targeting E2F1 for degradation. MDM2 promotes degredation of pRB in a proteosome-dependentubiquitin-independent manner. In summary, MDM2 degrades the E2F repressor pRB while stabilizing E2F1 levels and ensuring specif
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