p53 and p73: seeing double?
- Biology, MedicineNature Genetics
It is established that p73 is a transcriptional target of E2F1 and its ability to induce apoptosis in TP53−/− cells indicates a tumour-control mechanism that runs parallel to but independent of that mediated by p53.
DNA-PK, ATM and ATR as sensors of DNA damage: variations on a theme?
- BiologyCurrent opinion in cell biology
Characterization of the E3 Ubiquitin Ligase Pirh2
This study is able to address the question of functional redundancy by indicating that Pirh2 can target serine 15 phosphorylated p53 which is reported to not be regulated by Mdm2.
Collaboration of Brca1 and Chk2 in tumorigenesis.
- BiologyGenes & development
A critical role is identified for Chk2 as a component of the DNA damage-signaling pathway activated in response to Brca1 deficiency, which facilitates the development, survival, and proliferation of Brca 1-deficient T cells at the expense of genomic integrity.
Inhibition of p63 Transcriptional Activity by p14ARF: Functional and Physical Link between Human ARF Tumor Suppressor and a Member of the p53 Family
- BiologyMolecular and Cellular Biology
It is suggested that stimuli inducing p14ARF expression can, at the same time, activate p53 and impair p63 transcriptional activity, altering the pattern of p53 target gene expression.
Functional impact of concomitant versus alternative defects in the Chk2-p53 tumour suppressor pathway
In human cells, Chk2 and p53 form protein–protein complexes whose abundance increased upon DNA damage, and whose formation was abrogated through cancer associated mutations in the FHA domain of Chk1, or mutations inThe tetramerization domain of p53.
Studies of ATM Kinase Activity Using Engineered ATM Sensitive to ATP Analogues (ATM-AS).
- BiologyMethods in molecular biology
It is shown that not only ATM preferentially phosphorylates S/T-Q sequences, but also Ser46, which is a noncanonical site with an S-P sequence for ATM, which was previously shown to be a target for ATM.
Ataxia Telangiectasia-mutated Protein Can Regulate p53 and Neuronal Death Independent of Chk2 in Response to DNA Damage*
- BiologyJournal of Biological Chemistry
This work shows that p53 phosphorylation, stability, as well as neuronal death is regulated, in part, by the ataxia telangiectasia-mutated (ATM) protein, which functions separately from Chk2 to regulate p53 stability and neuronal death.
Linkage of ATM to cell cycle regulation by the Chk2 protein kinase.
Chk2, the mammalian homolog of the Saccharomyces cerevisiae Rad53 and Schizosac charomyces pombe Cds1 protein kinases required for the DNA damage and replication checkpoints, was identified and phosphorylated and activated in response to replication blocks and DNA damage.
DNA damage-induced activation of p53 by the checkpoint kinase Chk2.
Chk2 directly phosphorylated p53 on serine 20, which is known to interfere with Mdm2 binding, and provides a mechanism for increased stability of p53 by prevention of ubiquitination in response to DNA damage.
Rapid ATM-dependent phosphorylation of MDM2 precedes p53 accumulation in response to DNA damage.
- BiologyProceedings of the National Academy of Sciences of the United States of America
It is shown that after treatment of cells with ionizing radiation or a radiomimetic chemical, but not UV radiation, MDM2 is phosphorylated rapidly in an ATM-dependent manner, independent of p53 and the DNA-dependent protein kinase.
ATM-dependent activation of p53 involves dephosphorylation and association with 14-3-3 proteins
- Biology, ChemistryNature Genetics
This data indicates that the p53 tumour-suppressor protein is a sequence-specific DNA-binding transcription factor that induces cell cycle arrest or apoptosis in response to genotoxic stress and that this region of p53 is targeted by DNA-damage signalling pathways in vivo.
Serine 15 phosphorylation stimulates p53 transactivation but does not directly influence interaction with HDM2
- BiologyThe EMBO journal
Biochemical data indicate that the mechanism by which phosphorylation of Ser15 stimulates p53‐dependent transactivation occurs through increased binding to the p300 coactivator protein, and indicate that Ser15‐dependent regulation of transactivation is independent of any involvement in modulating MDM2 binding.
Evidence that the ATM-Rad3-related protein ATR regulates phosphorylation of Ser-15 in DNA-damaged cells is provided and it is suggested that p53 is a target for phosphorylated by ATR by blocking UV-induced Ser- 15 phosphorylations in a time-independent manner.
- BiologyThe EMBO journal
In response to environmental stress, the p53 phosphoprotein is stabilized and activated to inhibit cell growth. p53 stability and activity are negatively regulated by the murine double minute (Mdm2)…
Phosphorylation of Ser-20 mediates stabilization of human p53 in response to DNA damage.
- Biology, ChemistryProceedings of the National Academy of Sciences of the United States of America
It is proposed that ATM and ATR activate an, as yet unidentified, kinase that stabilizes p53 by phosphorylating it on Ser-20, which involved the majority of nuclear p53 protein and weakened the interaction of p53 with Mdm2 in vitro.
Regulation of p53 in response to DNA damage
The nature of p53 modifications, the enzymes that bring them about, and how changes in p53 modification lead to p53 activation are discussed are discussed.
- Biology, ChemistryMolecular and Cellular Biology
Examining the activity of p53 proteins with combined mutations at all of the reported N-terminal phosphorylation sites showed that all of these mutant proteins retained the ability to be stabilized following DNA damage, indicating that phosphorylated is not essential for DNA damage-induced stabilization of p 53, although phosphorus could clearly contribute to p53 stabilization under some conditions.