title: Phospholipase D2 downregulation induces cellular senescence through a reactive oxygen species-p53-p21Cip1/WAF1 pathway.
abstract: The expression of phospholipase D1 (PLD1) and PLD2 were found to decrease at the transcription level during both replicative and premature senescence in human lung fibroblast IMR-90 cells. Knockdown of PLD2 dramatically induced senescent phenotype in proliferating IMR-90 cells and wild-type HCT116 colon cancer cells, whereas this response was nearly abolished in p53- or p21(Cip1/WAF1)-null HCT116 cells. PLD2 knockdown increased the intracellular reactive oxygen species (ROS). Antioxidant N-acetyl-L-cysteine, NADPH oxidase inhibitor apocynin, and p22(phox) small interfering RNA (siRNA) reduced ROS generation and thus suppressed the appearance of senescence markers. Elevated CK2 α subunit (CK2α) expression repressed PLD2 downregulation-mediated senescence. PLD2 overexpression increased protein kinase CK2 (also known as casein kinase 2) (CK2) activity. Taken together, these results show that PLD2 downregulation causes senescence through the p53-p21(Cip1/WAF1) pathway by stimulating ROS production, which is induced by CK2 inhibition.
authors: School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu 702-701, Republic of Korea.
authors: Young-Hoon
authors: YH
authors: Lee
authors: School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu 702-701, Republic of Korea. Electronic address: ysbae@knu.ac.kr.
authors: Young-Seuk
authors: YS
authors: Bae
mesh_terms: D001483:Base Sequence; D047390:Casein Kinase II / Q000037:antagonists & inhibitors / Q000378:metabolism; D016922:Cellular Senescence / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D010739:Phospholipase D / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D019255:NADPH Oxidases; D047390:Casein Kinase II; C105606:phospholipase D2; D010739:Phospholipase D; C106801:phospholipase D1
keywords: Phospholipase D2; Protein kinase CK2; Reactive oxygen species; Senescence; p21(Cip1/WAF1); p53