cAMP-mediated inhibition of DNA replication and S phase progression: involvement of Rb, p21Cip1, and PCNA
| Autor: | Soheil Naderi, Tung-Ti Chen, Jean Y. J. Wang, Kristine B. Gutzkow, Heidi Kiil Blomhoff |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
Cyclin-Dependent Kinase Inhibitor p21
DNA Replication Time Factors Immunoblotting Apoptosis Cell Cycle Proteins Models Biological Retinoblastoma Protein S Phase Mice Proliferating Cell Nuclear Antigen Cyclic AMP Animals Humans Lymphocytes Kinase activity Cloning Molecular Phosphorylation Molecular Biology Cell Proliferation Cell Nucleus biology DNA synthesis Dose-Response Relationship Drug Cell growth Cell Cycle Colforsin DNA replication Retinoblastoma protein G1 Phase Cell Biology DNA Articles Cell cycle Blotting Northern Flow Cytometry Molecular biology Chromatin Proliferating cell nuclear antigen Cell biology Microscopy Fluorescence biology.protein NIH 3T3 Cells Signal Transduction Subcellular Fractions |
| Zdroj: | Molecular biology of the cell. 16(3) |
| ISSN: | 1059-1524 |
| Popis: | cAMP exerts an antiproliferative effect on a number of cell types including lymphocytes. This effect of cAMP is proposed to be mediated by its ability to inhibit G1/S transition. In this report, we provide evidence for a new mechanism whereby cAMP might inhibit cellular proliferation. We show that elevation of intracellular levels of cAMP inhibits DNA replication and arrests the cells in S phase. The cAMP-induced inhibition of DNA synthesis was associated with the increased binding of p21Cip1to Cdk2-cyclin complexes, inhibition of Cdk2 kinase activity, dephosphorylation of Rb, and dissociation of PCNA from chromatin in S phase cells. The ability of cAMP to inhibit DNA replication and trigger release of PCNA from chromatin required Rb and p21Cip1proteins, since both processes were only marginally affected by increased levels of cAMP in Rb-/-and p21Cip1-/-3T3 fibroblasts. Importantly, the implications of cAMP-induced inhibition of DNA synthesis in cancer treatment was demonstrated by the ability of cAMP to reduce apoptosis induced by S phase–specific cytotoxic drugs. Taken together, these results demonstrate a novel role for cAMP in regulation of DNA synthesis and support a model in which activation of cAMP-dependent signaling protects cells from the effect of S phase–specific antitumor agents. |
| Databáze: | OpenAIRE |
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