Chk2 kinase is required for methylglyoxal-induced G2/M cell-cycle checkpoint arrest: implication of cell-cycle checkpoint regulation in diabetic oxidative stress signaling
| Autor: | Nobuyuki Onishi, Shuichi Kani, Yasuhiro Hamada, Tsuyoshi Umeda, Kohsuke Takeda, Yuki Hazaka, Yasuhiro Minami, Emiko Nakayama, Hidenori Ichijo, Akinori Yoda, Nagako Sougawa |
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| Rok vydání: | 2007 |
| Předmět: |
G2 Phase
animal structures Cell cycle checkpoint p38 mitogen-activated protein kinases Mitosis Protein Serine-Threonine Kinases Biology MAP Kinase Kinase Kinase 5 medicine.disease_cause Guanidines p38 Mitogen-Activated Protein Kinases environment and public health Cell Line chemistry.chemical_compound Diabetes Mellitus Genetics medicine Humans CHEK1 Phosphorylation RNA Small Interfering Checkpoint Kinase 2 Kinase Methylglyoxal JNK Mitogen-Activated Protein Kinases Deoxyguanosine Cell Biology Pyruvaldehyde Acetylcysteine Cell biology Enzyme Activation Kinetics Oxidative Stress enzymes and coenzymes (carbohydrates) chemistry 8-Hydroxy-2'-Deoxyguanosine Checkpoint Kinase 1 Mesangial Cells biological phenomena cell phenomena and immunity Protein Kinases Oxidative stress Signal Transduction |
| Zdroj: | Genes to Cells. 12:919-928 |
| ISSN: | 1365-2443 1356-9597 |
| DOI: | 10.1111/j.1365-2443.2007.01100.x |
| Popis: | Methylglyoxal (MG) is a reactive endogenous metabolite that is produced from the process of degradation of triose-phosphates. Under hyperglycemic conditions the rate of MG formation increases as a result of elevated concentrations of precursors. It has been established that MG elicits oxidative stress signaling, leading to the activation of MAP kinases, p38 MAPK and JNK, yet it remains largely unknown about a role of cell-cycle checkpoint regulation in MG-induced signaling. Here, we show that checkpoint kinases, Chk1 and Chk2, as well as their upstream ATM kinase are phosphorylated and activated following MG treatment of cultured cells. This MG-induced activation of Chk1 and Chk2 were inhibited by either aminoguanidine (AG), an inhibitor of production of advanced glycation end products (AGEs) or N-acetyl-l-cysteine (NAC), an anti-oxidant in dose dependent manners, indicating that oxidative stress via AGEs is involved critically in the activation of Chk1 and Chk2 by MG. Furthermore, it was found that cell-cycle synchronized cells exhibited G(2)/M checkpoint arrest following MG treatment, and that siRNA-mediated knock-down of Chk2, but not Chk1, results in a failure of MG-induced G(2)/M arrest. Thus, the results indicate a critical role for Chk2 in MG-induced G(2)/M cell-cycle checkpoint arrest. |
| Databáze: | OpenAIRE |
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