PloS one, 2013-11, Vol.8 (11), p.e80111-e80111
2013
Details
- Autor(en) / Beteiligte
- Titel
- Coordination between p21 and DDB2 in the cellular response to UV radiation
- Ist Teil von
- PloS one, 2013-11, Vol.8 (11), p.e80111-e80111
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2013
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- The tumor suppressor p53 guides the cellular response to DNA damage mainly by regulating expression of target genes. The cyclin-dependent kinase inhibitor p21, which is induced by p53, can both arrest the cell cycle and inhibit apoptosis. Interestingly, p53-inducible DDB2 (damaged-DNA binding protein 2) promotes apoptosis by mediating p21 degradation after ultraviolet (UV)-induced DNA damage. Here, we developed an integrated model of the p53 network to explore how the UV-irradiated cell makes a decision between survival and death and how the activities of p21 and DDB2 are modulated. By numerical simulations, we found that p53 is activated progressively and the promoter selectivity of p53 depends on its concentration. For minor DNA damage, p53 settles at an intermediate level. p21 is induced by p53 to arrest the cell cycle via inhibiting E2F1 activity, allowing for DNA repair. The proapoptotic genes are expressed at low levels. For severe DNA damage, p53 undergoes a two-phase behavior and accumulates to high levels in the second phase. Consequently, those proapoptotic proteins accumulate remarkably. Bax activates the release of cytochrome c, while DDB2 promotes the degradation of p21, which leads to activation of E2F1 and induction of Apaf-1. Finally, the caspase cascade is activated to trigger apoptosis. We revealed that the downregulation of p21 is necessary for apoptosis induction and PTEN promotes apoptosis by amplifying p53 activation. This work demonstrates that how the dynamics of the p53 network can be finely regulated through feed-forward and feedback loops within the network and emphasizes the importance of p21 regulation in the DNA damage response.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0080111Titel-ID: cdi_plos_journals_1459403985
- Format
- –
- Schlagworte
- Activation, Apaf-1 protein, Apoptosis, Apoptosis - genetics, Apoptotic Protease-Activating Factor 1 - genetics, Apoptotic Protease-Activating Factor 1 - metabolism, Bax protein, bcl-2-Associated X Protein - genetics, bcl-2-Associated X Protein - metabolism, Cancer, Caspase, Caspases - genetics, Caspases - metabolism, Cell cycle, Cell Cycle - genetics, Cell survival, Computer simulation, Cyclin-dependent kinase, Cyclin-dependent kinase inhibitor p21, Cyclin-Dependent Kinase Inhibitor p21 - genetics, Cyclin-Dependent Kinase Inhibitor p21 - metabolism, Cytochrome, Cytochrome c, Cytochromes c - genetics, Cytochromes c - metabolism, Damage accumulation, Degradation, Deoxyribonucleic acid, DNA, DNA damage, DNA Damage - genetics, DNA repair, DNA Repair - genetics, DNA-Binding Proteins - genetics, DNA-Binding Proteins - metabolism, E2F1 Transcription Factor - genetics, E2F1 Transcription Factor - metabolism, Enzyme inhibitors, Feedback loops, Gene expression, Genes, Genomes, GTP-binding protein, Kinases, Laboratories, Mathematical models, Mutation, Numerical analysis, Numerical simulations, Ordinary differential equations, p53 Protein, Physics, Protein binding, Proteins, PTEN protein, Radiation, Radiation (Physics), Radiation damage, Selectivity, Transcription factors, Tumor proteins, Tumor suppressor genes, Tumor Suppressor Protein p53 - genetics, Tumor Suppressor Protein p53 - metabolism, U.V. radiation, Ultraviolet radiation, Ultraviolet Rays