Decreased p21 Levels Are Required for Efficient Restart of DNA Synthesis after S Phase Block
| Autor: | Carol Prives, Kristine McKinney, Masha V. Poyurovsky, Vanesa Gottifredi |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
Cyclin-Dependent Kinase Inhibitor p21
G2 Phase Proteasome Endopeptidase Complex Time Factors Transcription Genetic DNA damage Down-Regulation Cyclin A Biology Models Biological Biochemistry S Phase Multienzyme Complexes Cell Line Tumor Cyclins Proliferating Cell Nuclear Antigen Humans Hydroxyurea Molecular Biology S phase Cyclin Cell Nucleus DNA synthesis Kinase G1 Phase DNA Cell Biology Cell cycle Blotting Northern Molecular biology Recombinant Proteins Protein Structure Tertiary Cell biology Proliferating cell nuclear antigen Cysteine Endopeptidases Cell culture biology.protein Tumor Suppressor Protein p53 |
| Zdroj: | Journal of Biological Chemistry. 279:5802-5810 |
| ISSN: | 0021-9258 |
| Popis: | The cyclin-dependent kinase inhibitor p21, a major transcriptional target of the tumor suppressor p53, plays a critical role in cell cycle arrest in G1 and G2 after DNA damage. It was previously shown that in some human cell lines when S phase is arrested, p53 is transcriptionally impaired such that some p53 targets including p21 are only weakly induced. We show here that during S phase arrest proteasome-mediated turnover of p21 is significantly increased in a manner that is independent of p53. It is well established that p21 can interact both with cyclin-dependent kinase complexes and with proliferating cell nuclear antigen (PCNA). Interestingly, the scant amount of p21 detected during S phase block cannot fully saturate cyclin A-cyclin-dependent kinase 2 complexes and does not interact detectably with PCNA. Importantly, DNA elongation assays in isolated nuclei show that the C terminus of p21 containing the PCNA-binding domain effectively blocks this process. This implies that p21 down-regulation could be an essential requirement for efficient restart of DNA synthesis. In line with this, only cells expressing low levels of p21 immediately progress through the cell cycle upon release from S phase arrest, whereas the remaining few high p21 producing cells move much more slowly through S. Thus, p21 down-regulation is multiply determined and is required for the reversibility of the arrest in S phase. |
| Databáze: | OpenAIRE |
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