title: Long-term arsenite exposure induces premature senescence in B cell lymphoma A20 cells.
abstract: Chronic arsenite exposure induces immunosuppression, but the precise mechanisms remain elusive. Our previous studies demonstrated that arsenite exposure for 24 h induces G0/G1 arrest in mouse B lymphoma A20 cells and the arrest is caused through induction of cyclin-dependent kinase inhibitor p16(INK4a) followed by accumulation of an Rb family protein, p130. In this study, we further investigated the consequences of long-term arsenite exposure of A20 cells. The results demonstrated that exposure to 10 μM sodium arsenite up to 14 days induces a great increase in G0/G1 arrest, irreversible cell growth suppression, cellular morphological changes and positive staining for senescence-associated β-galactosidase. The long-term arsenite exposure also induced up-regulation of p16(INK4a) followed by robust accumulation of p130 and activation of the p53 pathway. Knockdown experiments with siRNA showed that p130 accumulation is essential for cell cycle arrest by long-term arsenite exposure. Since p16(INK4a) and the p53 pathway are known to be activated by DNA damage, we investigated the involvement of DNA damage formation by long-term arsenite exposure. We found that a variety of DNA repair-related genes were significantly down-regulated from 24 h of arsenite exposure and activation-induced cytidine deaminase was greatly up-regulated after long-term arsenite exposure. Consistent with these findings, long-term arsenite exposure increased a DNA double-strand break marker, γ-H2AX and increased mutation frequency in a Bcl6 gene region. These results revealed that long-term arsenite exposure induces premature senescence through DNA damage increase and p130 accumulation in lymphoid cells.
authors: Center for Environmental Health Sciences, National Institute for Environmental Studies, Tsukuba, 305-8506, Japan.
authors: Kazuyuki
authors: K
authors: Okamura
authors: Center for Environmental Health Sciences, National Institute for Environmental Studies, Tsukuba, 305-8506, Japan. keikon@nies.go.jp.
authors: Keiko
authors: K
authors: Nohara
mesh_terms: D000818:Animals; D018053:Arsenites / Q000633:toxicity*; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D005786:Gene Expression Regulation; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D009154:Mutation; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000235:genetics; D050717:Retinoblastoma-Like Protein p130 / Q000235:genetics / Q000378:metabolism; D017670:Sodium Compounds / Q000633:toxicity; D036401:Toxicity Tests, Chronic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D018053:Arsenites; C490010:Bcl6 protein, mouse; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D051560:Proto-Oncogene Proteins c-bcl-6; C493838:Rbl2 protein, mouse; D050717:Retinoblastoma-Like Protein p130; D017670:Sodium Compounds; D016159:Tumor Suppressor Protein p53; C017947:sodium arsenite; C015001:arsenite
keywords: Activation-induced cytidine deaminase (Aid); Arsenite; DNA repair; Senescence; p130