p53-dependent but ATM-independent inhibition of DNA synthesis and G2 arrest in cadmium-treated human fibroblasts
| Autor: | William K. Kaufmann, Marila Cordeiro-Stone, Taiyi Jin, Yingchun Zhou, Jayne C. Boyer, Bo Chen, Feng Cao, Tong Zhou, Dennis A. Simpson |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
Cyclin-Dependent Kinase Inhibitor p21
DNA Replication G2 Phase inorganic chemicals Cell cycle checkpoint DNA damage Blotting Western chemistry.chemical_element Cell Cycle Proteins Ataxia Telangiectasia Mutated Proteins Protein Serine-Threonine Kinases Biology Cadmium chloride Toxicology Article Cell Line Colony-Forming Units Assay Ataxia Telangiectasia chemistry.chemical_compound Humans RNA Small Interfering Cells Cultured Pharmacology Cadmium DNA synthesis Tumor Suppressor Proteins G1 Phase DNA replication DNA Fibroblasts Cell cycle Molecular biology DNA-Binding Proteins Comet assay chemistry Comet Assay Tumor Suppressor Protein p53 DNA Damage Plasmids |
| Zdroj: | Toxicology and Applied Pharmacology. 218:174-185 |
| ISSN: | 0041-008X |
| Popis: | This study focused on the activation of cell cycle checkpoint responses in diploid human fibroblasts that were treated with cadmium chloride and the potential roles of ATM and p53 signaling pathways in cadmium-induced responses. The alkaline comet assay indicated that cadmium caused a dose-dependent increase in DNA damage. Cells that were rendered p53-defective by expression of a dominant-negative p53 allele or knockdown of p53 mRNA were more resistant to cadmium-induced inactivation of colony formation than normal and ataxia telangiectasia (AT) cells. Synchronized fibroblasts in S were more sensitive to cadmium toxicity than cells in G1, suggesting that cadmium may target some element of DNA replication. Cadmium produced a dose- and time-dependent inhibition of DNA synthesis. An immediate inhibition was associated with severe delay in progression through S phase and a delayed inhibition seen 24 h after treatment was associated with accumulation of cells in G2. AT and normal cells displayed similar patterns of inhibition of DNA synthesis and G2 delay after treatment with cadmium, while p53-defective cells displayed significantly less of the delayed inhibition of DNA synthesis and accumulation in G2 post-treatment. Total p53 protein and ser15-phosphorylated p53 were induced by cadmium in normal and AT cells. The p53 transactivationmore » target Gadd45{alpha} was induced in both p53-effective and p53-defective cells after 4 h cadmium treatment, and this was associated with an acute inhibition of mitosis. Cadmium produced a very unusual pattern of toxicity in human fibroblasts, inhibiting DNA replication and inducing p53-dependent growth arrest but without induction of p21{sup Cip1/Waf1} or activation of Chk1.« less |
| Databáze: | OpenAIRE |
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