Phospholipase D2 downregulation induces cellular senescence through a reactive oxygen species-p53-p21Cip1/WAF1 pathway

FEBS Lett. 2014 Aug 25;588(17):3251-8. doi: 10.1016/j.febslet.2014.07.009. Epub 2014 Jul 23.

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.

Keywords: Phospholipase D2; Protein kinase CK2; Reactive oxygen species; Senescence; p21(Cip1/WAF1); p53.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Casein Kinase II / antagonists & inhibitors
  • Casein Kinase II / metabolism
  • Cellular Senescence* / drug effects
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
  • Down-Regulation* / drug effects
  • HCT116 Cells
  • Humans
  • Intracellular Space / drug effects
  • Intracellular Space / metabolism
  • NADPH Oxidases / metabolism
  • Phospholipase D / genetics*
  • Protein Kinase Inhibitors / pharmacology
  • Reactive Oxygen Species / metabolism*
  • Signal Transduction* / drug effects
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Cyclin-Dependent Kinase Inhibitor p21
  • Protein Kinase Inhibitors
  • Reactive Oxygen Species
  • Tumor Suppressor Protein p53
  • NADPH Oxidases
  • Casein Kinase II
  • phospholipase D2
  • Phospholipase D
  • phospholipase D1