Hdm2- and proteasome-dependent turnover limits p21 accumulation during S phase Journal Article
| Authors: | Ciznadija, D.; Zhu, X. H.; Koff, A. |
| Article Title: | Hdm2- and proteasome-dependent turnover limits p21 accumulation during S phase |
| Abstract: | Double-strand DNA breaks detected in different phases of the cell cycle induce molecularly distinct checkpoints downstream of the ATM kinase. p53 is known to induce arrest of cells in G1, and occasionally G2 phase but not S phase following ionizing radiation, a time at which the MRN complex and cdc25-dependent mechanisms induce arrest. Our understanding of how cell cycle phase modulates pathway choice and the reasons certain pathways might be favored at different times is limited. In this report, we examined how cell cycle phase affects the activation of the p53 checkpoint and its ability to induce accumulation of the cdk2 inhibitor p21. Using flow cytometric tools and centrifugal elutriation we find that the p53 response to ionizing radiation is largely intact in all phases of the cell cycle; however, the accumulation of p21 protein is limited to the G1 and G2 phase of the cell cycle because of the activity of a proteasome-dependent p21 turnover pathway in S-phase cells. We found that the turnover of p21 was independent of the SCFskp2 E3 ligase, but could be inhibited, at least in part, by reducing hdm2, although this depended on the cell type studied. Our results suggest that there are several redundant pathways active in S-phase cells that can prevent the accumulation of p21. © 2011 Landes Bioscience. |
| Keywords: | human cell; flow cytometry; protein function; cell cycle s phase; proteasome; proteasome endopeptidase complex; rna, small interfering; rna interference; protein p53; cell type; ionizing radiation; cell line, transformed; dna breaks, double-stranded; radiation, ionizing; tumor suppressor protein p53; cell cycle g2 phase; cyclin-dependent kinase inhibitor p21; centrifugation; cell cycle g1 phase; s phase; p21 activated kinase; s-phase kinase-associated proteins; p21; protein mdm2; proto-oncogene proteins c-mdm2; ligase; skp2; cyclin dependent kinase 2 inhibitor; cell cycle phase dependent; hdm2; protein turnover; cell cycle checkpoints |
| Journal Title: | Cell Cycle |
| Volume: | 10 |
| Issue: | 16 |
| ISSN: | 1538-4101 |
| Publisher: | Taylor & Francis Inc. |
| Date Published: | 2011-08-15 |
| Start Page: | 2714 |
| End Page: | 2723 |
| Language: | English |
| DOI: | 10.4161/cc.10.16.16725 |
| PROVIDER: | scopus |
| PUBMED: | 21768776 |
| PMCID: | PMC3219540 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 3 October 2011" - "Source: Scopus" |
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